Next Article in Journal
Noble 3,4-Seco-triterpenoid Glycosides from the Fruits of Acanthopanax sessiliflorus and Their Anti-Neuroinflammatory Effects
Next Article in Special Issue
Alveolar Nitric Oxide as a Biomarker of COVID-19 Lung Sequelae: A Pivotal Study
Previous Article in Journal
Discovery of Novel Pterostilbene Derivatives That Might Treat Sepsis by Attenuating Oxidative Stress and Inflammation through Modulation of MAPKs/NF-κB Signaling Pathways
Previous Article in Special Issue
Neonatal Extracellular Superoxide Dismutase Knockout Mice Increase Total Superoxide Dismutase Activity and VEGF Expression after Chronic Hyperoxia
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Oxidative Stress Promotes Corticosteroid Insensitivity in Asthma and COPD

Center for Perinatal Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
Department of Pediatrics, The Ohio State University, Columbus, OH 43210, USA
Author to whom correspondence should be addressed.
Antioxidants 2021, 10(9), 1335;
Received: 30 July 2021 / Revised: 18 August 2021 / Accepted: 23 August 2021 / Published: 24 August 2021
(This article belongs to the Special Issue Antioxidants and Lung Diseases)


Corticosteroid insensitivity is a key characteristic of patients with severe asthma and COPD. These individuals experience greater pulmonary oxidative stress and inflammation, which contribute to diminished lung function and frequent exacerbations despite the often and prolonged use of systemic, high dose corticosteroids. Reactive oxygen and nitrogen species (RONS) promote corticosteroid insensitivity by disrupting glucocorticoid receptor (GR) signaling, leading to the sustained activation of pro-inflammatory pathways in immune and airway structural cells. Studies in asthma and COPD models suggest that corticosteroids need a balanced redox environment to be effective and to reduce airway inflammation. In this review, we discuss how oxidative stress contributes to corticosteroid insensitivity and the importance of optimizing endogenous antioxidant responses to enhance corticosteroid sensitivity. Future studies should aim to identify how antioxidant-based therapies can complement corticosteroids to reduce the need for prolonged high dose regimens in patients with severe asthma and COPD.

1. Introduction

Increased oxidative stress is commonly linked with the pathogenesis and severity of inflammatory lung diseases [1,2,3,4,5]. Oxidative stress develops due to the accumulation of reactive oxygen or nitrogen species (RONS) and/or the loss of antioxidant capacity. RONS contribute to the development of airway inflammation, mucus hypersecretion, airway hyperresponsiveness, and thickening or remodeling, which are hallmark pathological features of asthma and chronic obstructive pulmonary disease (COPD) [6,7,8,9]. Asthma and COPD are associated with several factors that contribute to pathophysiology, including environmental exposures, which induce oxidative stress by damaging the airway epithelium and instigate immune cell infiltration [10,11,12,13]. Functional changes involving airway thickening and stiffening contribute to airflow obstruction and acute exacerbation. These structural and functional alterations are worsened in asthma and COPD patients with corticosteroid insensitivity [14,15,16].
Asthma and COPD adversely affect millions worldwide and remain significant health burdens [17,18]. Asthma is among the leading causes of hospitalization among children who experience respiratory symptoms, including wheezing, coughing, and difficulty breathing [17]. COPD is among the leading causes of death in adults worldwide and is characterized by emphysema, bronchitis, and small airway disease [18,19]. In addition to respiratory symptoms, patients with asthma or COPD are at risk of acute exacerbations, which can be life-threatening events that increase lung morbidity and are potentially fatal [20,21].
Corticosteroids are key anti-inflammatory drugs used to manage symptoms, and corticosteroid sensitivity is commonly used to characterize disease severity and phenotype [19,22,23,24,25,26]. Patients with mild-moderate asthma or COPD have relatively high corticosteroid sensitivity, as inhaled corticosteroids at low doses improve lung function and acute exacerbation frequency [26]. In contrast, patients with severe asthma or moderate-severe COPD require the administration of inhaled or systemic corticosteroids at greater doses with decreased effectiveness, resulting in persistent airway inflammation, airflow obstruction, and more frequent exacerbations [22,27]. The healthcare burden and costs associated with corticosteroid insensitivity are substantial, and patients with moderate-severe asthma or COPD contribute to over 50% of the asthma- and COPD-related healthcare costs [28,29,30]. The prolonged use of systemic, high dose corticosteroids leads to adverse side effects [31], and its cumulative burden complicates disease management [32,33,34,35].
Oxidative stress has been shown to decrease responsiveness to corticosteroids through altering the glucocorticoid receptor (GR) expression and signaling, which is likely one mechanism for corticosteroid insensitivity [36,37]. Several studies show a correlation between oxidative stress and airway disease severity, implicating oxidative stress in corticosteroid insensitivity [38,39,40]. In the present review, we discuss oxidative stress as a key driver of pro-inflammatory responses that promote airway inflammation in the presence of corticosteroids. The importance of this mechanism is highlighted by accumulating evidence that oxidative stress can disrupt glucocorticoid receptor (GR) activity. We also discuss the potential for strategies that stimulate endogenous antioxidant responses in the airway to enhance corticosteroid sensitivity.

2. Corticosteroid Insensitivity in Asthma and COPD Pathophysiology

Chronic airway inflammation is key for the development of structural and functional changes to the airway that restrict airflow and contribute to exacerbations in asthma and COPD [41]. The inflammatory milieu in the airway is complex, heterogenous, and possibly dynamic. This complexity and the broad anti-inflammatory properties of corticosteroids make their use appealing to manage symptoms and disease progression. Studies in asthma or COPD patient cohorts have identified different physiological and immunological responses that are thought to influence disease severity and corticosteroid sensitivity [42,43].

2.1. Airway Inflammation

T helper 2 (Th2) Inflammation. The adaptive Th2 immune response is the predominant immune phenotype in allergic asthma and is observed in the majority of pediatric and adult patients with mild-moderate asthma [44]. These patients exhibit increases in Th2 effector cytokine levels (IL-4, IL-5, IL-13) that are produced by the CD4+ Th2 cells and group 2 innate lymphoid cells (ILC2). While IL-5 is the main driver of eosinophil recruitment, IL-4 and IL-13 promote mucous cell metaplasia, airway hyperresponsiveness, and remodeling [45]. Corticosteroid sensitivity in patients with Th2 inflammation is variable, with some having high sensitivity while others with more severe disease have moderate to low sensitivity.
Th1 and Th17 Inflammation. For COPD, Th1 and/or Th17 inflammation is the predominant adaptive immune response. However, the same responses are also present in patients with severe asthma [46,47,48]. The presence of Th1 and Th17 inflammation is associated with more severe disease and reduced corticosteroid sensitivity [23,27,46,49]. Th1 and Th17 adaptive immune responses are characterized by the infiltration of Th cells producing IFNγ and IL-17A, respectively. These adaptive immune phenotypes are often associated with responses to lung injury or infection. Increases in Th1 and Th17 inflammation are accompanied by neutrophil infiltration, which correlates with corticosteroid insensitivity [50,51]. IFNγ and IL-17A induce pro-inflammatory responses in other immune cells, airway epithelium, and smooth muscle to promote neutrophil airway infiltration, airway hyperresponsiveness, and remodeling [49,52,53].

2.2. Airway Structure and Function

Airway epithelium. The airway epithelium is a layer of cells that lines the airway lumen and is responsible for maintaining an innate barrier to airborne debris and pathogens [54]. The airway epithelium is composed of ciliated cells that are responsible for removing airborne pathogens and mucus away from lower airways and goblet cells that secrete mucus. In asthma and COPD, the airway epithelial barrier integrity is compromised with increased mucus production and accumulation, resulting in structural changes and airflow obstruction [55,56]. In addition to airway structure, the airway epithelium also contributes airway inflammation releasing pro-inflammatory cytokines such as TNFα and IL-33, which contribute to Th1 and Th2 inflammation, respectively [57,58]. Corticosteroids inhibit pro-inflammatory responses in the airway epithelium and preserve epithelial integrity upon injury by infection or environmental insult [59,60,61]. Airway mucus production and epithelial integrity remain unaffected by corticosteroid treatment in severe asthma and COPD [59,62].
Airway Smooth Muscle (ASM) and Fibroblasts. Persistent airway thickening and remodeling, which are hallmark pathological features in asthma and COPD, contribute to airflow obstruction and impaired lung function [14,63,64,65]. Increases in ASM and airway fibroblasts in the sub-epithelial layer can be attributed to increases in proliferation, extracellular matrix deposition, and hypertrophy [66,67,68,69,70]. Airway hyperresponsiveness is a functional characteristic that affects airway tone, acute exacerbations, and contributes to airway narrowing in response to bronchoconstrictors such as histamine [68]. Airway inflammation augments ASM Ca2+ responses and hypercontractility that lead to airway hyperresponsiveness, contributing to poor lung function and exacerbations [71]. Studies show these structural and function characteristics in airway disease are largely unresponsive to corticosteroids, worsening airway structure overtime [72,73,74].

3. Factors Contributing to Oxidative Stress

Reactive oxygen and nitrogen species (RONS) are critical for the homeostatic cellular and physiological functions in the lung. Within a pro-oxidant and pro-inflammatory environment, RONS accumulation has numerous detrimental consequences on cellular metabolism, tissue damage, and, ultimately, cell death [75]. Macromolecules such as proteins and lipids are highly susceptible to oxidative reactions that modify molecular structure and function. In asthma and COPD, RONS (e.g., superoxide, hydrogen peroxide, hydroxyl radicals, and nitrogen dioxide) levels are found to be increased in the plasma, sputum, and bronchoalveolar lavage tissue. This is illustrated by the substantial increases in the levels of oxidative stress biomarkers, including malondialdehyde (MDA), thiol oxidation, protein carbonyls, oxidized fatty acids, and exhaled nitric oxide (FeNO) [76,77].
Patients with severe asthma and COPD often exhibit greater levels of oxidative stress biomarkers, with increased levels correlating with worsened symptoms, decreased lung function, and corticosteroid insensitivity [37,75,78,79,80,81,82,83]. This oxidative burden is achieved by exposure to environmental and cellular sources of RONS. Both immune and airway structural cells respond and contribute to increased oxidative stress in the lung. Innate immune cells, e.g., macrophages, neutrophils, and eosinophils, produce RONS as a consequence of activation during pro-inflammatory responses (Figure 1) [75,84]. In airway structural cells, mitochondria generate RONS to enhance oxidative stress and contribute to airway inflammation [85,86,87].

3.1. Environmental Sources

Allergens. Indoor and outdoor allergens are sources of proteases that damage the airway epithelium and induce robust innate and adaptive immune responses [88,89]. Allergens such as house dust mite (HDM), dander, pollen, and fungal allergens contribute heavily to the pathogenesis of asthma in both children and adults [90,91]. Allergens, such as HDM, can induce Th2-mediated inflammatory responses, resulting in cellular injury and destruction and ultimately the disruption of the airway epithelial barrier [88]. In asthma, oxidative stress and DNA damage are generated following the sensitization and challenge to HDM [92]. Allergen sensitization is increasingly recognized as a factor that can affect asthma severity and corticosteroid sensitivity, particularly in individuals sensitized to fungal allergens [90,91].
Smoking. Exposure to cigarette smoke is a leading factor in the development of COPD with increases in lung inflammation. Smoking can also induce acute exacerbations that are associated with a decreased sensitivity to corticosteroids [78,93,94,95,96]. With its toxic chemicals, chronic exposure to cigarette smoke damages lung epithelial barriers and initiates pro-inflammatory responses with increased immune cell infiltration and cytokine release [97,98]. Components of cigarette smoke readily increase RONS production in mitochondria, resulting in increased oxidative stress with the significant oxidation of proteins and lipids [99,100]. Smoking-mediated damage to the airway and alveolar compartments is largely unaffected by treatment with corticosteroids [101], making cigarette smoke an important factor in corticosteroid insensitivity.
Air pollution. Air quality is an important factor that is affected by ozone and particulate matter concentrations. Increases in pollutant levels contribute to disease pathogenesis and exacerbations in asthma and COPD [80,81,102]. Ozone is an oxidant that induces Th17-mediated neutrophilic airway inflammation and is associated with decreased corticosteroid sensitivity [79,103,104]. Exposure to other environmental pollutants, such as diesel exhaust and <2.5 µm particulate matter (PM2.5), also induces high levels of oxidative stress in the lung [82,83,105]. Similar to ozone, diesel exhaust induces Th17 inflammation with increases in IL-17A levels and neutrophil infiltration [106,107]. Airway inflammation and hyperresponsiveness remain increased in diesel exhaust-exposed mice treated with corticosteroids [108]. Although PM2.5 is known to increase airway inflammation and augment allergic responses [109,110], its impact on corticosteroid sensitivity remains poorly understood.

3.2. Cellular Sources of Oxidative Stress

Macrophages. Lung macrophages play a pivotal role in asthma and COPD [111,112]. Macrophages are abundant in the lung and generate RONS to kill invading pathogens [113,114,115]. In respiratory burst, increased inducible nitric oxide synthase (iNOS) and NAPDH oxidase activity in macrophages results in increased hydrogen peroxide, nitric oxide, superoxide, and peroxynitrite production [116,117]. Increased RONS levels in lung macrophages lead to greater pro-inflammatory cytokine release [11]. RONS also affect lung macrophage function, reducing their ability to phagocytize pathogens and apoptotic cells, which is an important process [118]. Persistent oxidative stress in lung macrophages may contribute to reduced corticosteroid sensitivity in severe asthma and COPD [119,120].
Eosinophils. Following lung infiltration and activation during allergic responses, eosinophils release eosinophilic extracellular traps (EETs) that contain eosinophilic peroxidase (EPO), releasing hydrogen peroxide [121,122]. Pharmacological studies suggest that EET formation and EPO activity are dependent upon the generation of RONS and oxidative stress [123]. Conversely, recent studies show that hydrogen peroxide can also contribute to eosinophil apoptosis, an important mechanism in the resolution of allergic responses in the lung [124]. Corticosteroids are largely effective at reducing airway eosinophilia, but in severe asthma, greater doses are required to reduce their levels in circulation and the lung [125,126].
Neutrophils. Neutrophil lung infiltration and the expression levels of chemoattractants, CXCL1 and CXCL8, are increased in patients unresponsive to corticosteroids, implicating neutrophils in corticosteroid insensitivity in asthma and COPD [127,128,129,130,131]. Increased neutrophils in the lung can be attributed to their enhanced survival [132], which contributes to increased oxidative stress from myeloperoxidase (MPO)-mediated oxidative burst [84]. MPO produces hydrogen peroxide and is part of neutrophil extracellular traps (NETs), which are composed of antimicrobial proteins and enzymes. While NETs are needed for the neutrophil clearance of pathogens, they can also contribute to oxidative stress and persistent lung inflammation [133,134,135]. Neutrophils isolated from patients with severe asthma produced higher NET levels, suggesting that NETs may contribute to corticosteroid insensitivity [132,136,137]. Pham et al. concluded that the release of NETs induced the cell death of human airway epithelial cells, while treatment with NET and MPO antibodies increased epithelial cell survival [136]. In summary, these data highlight the role of neutrophils in airway inflammation and the severity of airway disease.
Airway epithelium. Airway injury results in the loss of epithelial barrier integrity. As a result, airway epithelial cells generate a substantial amount of RONS, including nitric oxide (NO) and chemoattractants that recruit immune cells to the airway [138]. Mitochondria are an important source of energy through ATP production. In the context of cell injury and mitochondrial dysfunction, ATP can be released into extracellular spaces and function as a damage associated molecular pattern molecule (DAMP). ATP can induce pro-inflammatory responses in the surrounding tissue through P2X/2Y receptor-mediated responses [85,139]. In asthma and COPD, ATP levels are increased in bronchoalveolar lavage fluid and correlated with disease severity, implying that ATP may be an important epithelial-derived DAMP that contributes to inflammatory responses in airway disease [140,141,142,143].
Intracellular RONS contribute to increased IL-33 release, which is a key mechanism for initiating Th2-mediated inflammation in asthma [10]. IL-33 was also found to be increased in mice exposed to cigarette smoke, implicating a role in COPD [144]. IL-13, another key cytokine in Th2 inflammation and asthma, induces airway epithelial cell superoxide production through the NADPH oxidase, DUOX1, during allergen challenges [145]. Overall, the airway epithelium is an important source of RONS and secretes pro-inflammatory mediators that are regulated by oxidative stress.
Airway Smooth Muscle (ASM). Upon pro-inflammatory cytokine stimulation, intracellular RONS contribute to increased ASM contractility, proliferation, and pro-inflammatory cytokine/chemokine release [146,147,148]. Intracellular Ca2+ ([Ca2+]i) regulation is central to how ASM responds to pro-inflammatory cytokines, and its regulation by mitochondria is emerging as an important mechanism [68,85]. Recent studies show that ozone exposure decreases mitochondrial membrane potential and RONS generation to contribute to airway hyperresponsiveness and increased ASM mass [4]. Mitochondria can contribute to [Ca2+]i through membrane-bound Ca2+ channels, which, during exposure to TNFα, leads to Ca2+ efflux from the mitochondria to the cytosol [149]. Increases in oxidative stress and [Ca2+]i also enhance ASM proliferation, which contributes to increased ASM mass and airway thickening [150]. Targeting antioxidants to the mitochondria reduces ASM proliferation and CXCL8 release [4], highlighting the importance of mitochondria in ASM dysfunction during airway inflammation. Although RONS are known to affect ASM responses to airway inflammation, little is known about the release of RONS by ASM and the effects on the surrounding cells. Furthermore, impact of mitochondrial dysfunction during oxidative stress conditions on corticosteroid sensitivity in ASM remains largely unexplored.

4. Oxidative Stress Promotes Corticosteroid Insensitivity

Corticosteroids reduce inflammation by binding to the glucocorticoid receptor (GR) in the cytosol and stimulating GR to translocate to the nucleus, where it regulates gene expression [36]. Within the context of airway disease, GR affects several genes and pathways associated with inflammation and metabolic processes [151]. The current model by which GR is thought to suppress inflammation involves modulating chromatin structure, suppressing promoter activity at pro-inflammatory genes, and enhancing the expression of anti-inflammatory mediators [152,153]. The wide-ranging anti-inflammatory effects of corticosteroids are centered on their ability to modulate gene expression in multiple cell types, including immune cells, epithelium, smooth muscle, and fibroblasts. However, recent studies show that the effects of GR are cell-type dependent [154,155], which is an important factor that may influence corticosteroid sensitivity in asthma and COPD.

4.1. Disruption of Glucocorticoid Receptor (GR) Signaling

GR Expression. Oxidative stress has been implicated in contributing to corticosteroid insensitivity by affecting GR signaling and activity [59]. The expression of the active isoform that mediates corticosteroid anti-inflammatory effects, GRα, is reduced in the lungs of patients with severe asthma and COPD [156]. Immune and airway epithelial cells isolated from patients with corticosteroid insensitivity show an increased expression of GRβ, a dominant negative isoform that is unable to induce anti-inflammatory responses [157,158]. Similarly, impaired GR nuclear translocation has been observed in both immune and airway structural cells from patients with asthma and COPD [159,160,161]. Oxidative stress reduces GRα expression and impairs GR DNA binding activity in airway epithelial and smooth muscle cells, in vitro [162,163,164]. These studies highlight the negative impact of oxidative stress on GR signaling through a reduction in GRα expression.
GR Phosphorylation. Post-translational modifications on GR, notably phosphorylation, are important for GR activity. GR phosphorylation regulates nuclear translocation and DNA binding activity, influencing corticosteroid sensitivity [165,166,167]. On human GR, Ser211 phosphorylation is important for DNA binding activity, while Ser226 phosphorylation impairs GR nuclear translocation [168,169]. These residues are among multiple phosphorylation sites within GR that are targeted by several kinases and phosphatases, affecting GR activation and its regulation of gene expression [170,171]. Oxidant sensitive mitogen activated protein kinase (MAPK) pathways, p38 and JNK, target and phosphorylate Ser226, leading to reduced GR nuclear translocation and GR activity [172,173,174,175]. The inhibition of p38 improves corticosteroid sensitivity in immune and structural epithelial cells isolated from severe asthmatics and allergen challenged mice with severe allergic airway inflammation [173,176,177,178]. In ASM, exposure to pro-inflammatory cytokines increases protein phosphatase 5 expression, which reduces Ser211 phosphorylation and GR activity [167,179]. These studies highlight the impact of oxidative stress on GR phosphorylation and activity through its modulation of MAP kinases.
GR and HDAC2. In severe asthma and COPD, histone deacetylase 2 (HDAC2) expression and activity are reduced, resulting in the deacetylation of GR (Lys494 and Lys495) and reduced HDAC2 activity at histones associated with pro-inflammatory genes [180,181,182,183]. HDAC2 is recognized as an important factor for the anti-inflammatory effects of corticosteroids. Oxidative stress generated by cigarette smoke leads to PI3Kδ activation, which phosphorylates HDAC2, reducing its activity and corticosteroid sensitivity [184]. The role for PI3K is further highlighted in allergen-challenged mice, where miR-21 antagonizes PTEN, a negative regulator of PI3K, to reduce HDAC2 activation. Mice treated with miR-21 antagomir or PI3K pharmacological inhibition demonstrated increased HDAC2 expression and improved corticosteroid insensitivity [185].
Several strategies have been identified to restore HDAC2 activity and corticosteroid sensitivity in asthma and COPD [37]. Theophylline, a nonspecific phosphodiesterase (PDE) inhibitor and bronchodilator, was identified to improve HDAC2 expression in COPD, which led to examining its potential to improve corticosteroid sensitivity in patients with COPD. While early studies showed increased HDAC activity and reduced inflammation in COPD patients treated with corticosteroids and low-dose theophylline [186,187,188], larger clinical studies showed no improvement in lung function or exacerbation frequency [189].

4.2. Oxidative Stress and Pro-Inflammatory Signaling

MAP Kinase and NFκB pathways. Oxidative stress augments pro-inflammatory signaling that contributes to poorly controlled inflammation and corticosteroid insensitivity [190]. Increases in RONS within the lung are associated with increased pro-inflammatory cytokine expression [191]. Hydrogen peroxide increases CXCL8 secretion, which is insensitive to the corticosteroid, budesonide [59]. Under oxidative stress and cellular injury, RONS can directly activate p38 and JNK, which subsequently leads to the activation of key pro-inflammatory transcription factors, namely, nuclear factor κB (NFκB) and activator protein-1 (AP-1) [192,193,194]. NFκB activation by oxidants enhances inflammatory cytokine expression and oxidative stress in asthma [195]. AP-1 is a heterodimer that is essential for the transcription of many immune, inflammatory, and antioxidant genes such as γ-glutamine-cysteine ligase (γ-GLCL) but can also contribute to the activation of second messengers to further propagate inflammation [193,196]. Despite being important targets of corticosteroids and GR signaling, NFκB and AP-1 activation are found to be higher in patients with asthma and COPD [197,198,199]. In poorly controlled asthma, NFκB activation remains elevated, suggesting that its activation may be insensitive to corticosteroids in individuals with more severe airway disease [200].
JAK/Stat pathways. The binding of specific cytokines and interferons to their receptors leads to the transphosphorylation of tyrosine residues on Janus Kinases (JAK) [201]. The activation of JAK in turn recruits and phosphorylates the tyrosine residues of signal transducers and the activators of the transcription (STAT) family of signaling molecules. JAK/STAT activation is enhanced in response to elevated levels of H2O2 or GSH depletion and inhibited by antioxidant treatment [202]. Moreover, activated STAT1 is found at high levels in the airway epithelium of asthmatics, with increased IL-4 and IFNγ expression as contributors to STAT1 activation [203]. We recently observed corticosteroid insensitivity in human airway smooth muscle cells treated with both TNFα and IFNγ, while GR expression, phosphorylation, and activity was maintained [204]. This was found to involve augmented NFκB and JAK/Stat1 signaling pathways that were potentially unresponsive to negative regulatory mechanisms induced by corticosteroids [205]. These findings support the theory that pro-inflammatory signaling pathways can interact to override negative regulatory signals induced by corticosteroids (Figure 2) [204]. The positive feedback loop between ROS production, oxidative stress, and persistent inflammation may offer a novel therapeutic target for the control of severe asthma and COPD.
Alarmins. Damaged or dying cells release alarmins and damage associated molecular patterns (DAMPs) as distress signals for innate immune responses to initiate repair mechanisms [206,207]. Compromised by oxidative stress, airway epithelial cells are injured and lose their integrity, becoming a primary source of alarmins and DAMP in asthma and COPD [207]. Thymic stromal lymphopoietin (TSLP), a key alarmin in asthma pathogenesis, initiates Th2 responses that promote allergic airway inflammation [191,208] and are implicated in contributing to corticosteroid insensitivity in asthma [209,210,211]. Additionally, airway epithelial cells from COPD donors produce greater TSLP levels upon inflammatory stimulation, which was found to be insensitive to dexamethasone [212]. In ASM, cigarette smoke exposure increased TSLPR expression and augmented the pro-inflammatory effects of TSLP on ASM [213]. TSLP has recently emerged following phase 3 clinical trials as a promising therapeutic target for severe asthma [214]. However, its potential for COPD remains unclear.
NLR family pyrin domain containing 3, (NLRP3). Inflammasomes are multiprotein complexes that play an essential role in innate immunity by sensing pathogens and injury and directing the maturation of inflammatory cytokines [215]. The best studied inflammasome, NLRP3, consists of the NLRP3 receptor, an adapter protein, ASC, and caspase-1. Upon stimulation, procaspase-1 is recruited, cleaved, and bound to the receptor via ASC [216]. The assembly of NLRP3 can be dependent on ROS, ion flux, DAMPs, cytokines, or ATP. Once active, NLRP3 can further influence oxidative stress by enhancing the production of proinflammatory mediators and ROS. A primary function of the NLRP3 is the cleavage of the precursors of IL-1β and IL-18 to their active forms and their subsequent release into the extracellular space, where they promote inflammation [216,217,218]. IL-1β levels are higher in the serum and induced sputum of symptomatic asthmatics than in asymptomatic patients [219], while in rodent models of asthma, IL-1β is increased and contributes to airway inflammation [220,221]. Recent studies demonstrated an important role NLRP3 and IL-1β play in mediating neutrophil infiltration and corticosteroid insensitivity in a mouse model of severe allergic airway inflammation [222]. Overall, these data highlight the redox-sensitive NLRP3 inflammasome as a key mechanism that contributes to corticosteroid insensitivity.

5. Targeting Oxidative Stress to Improve Corticosteroid Sensitivity

The cell protects itself from injury caused by oxidative stress through an extensive network of enzymatic and non-enzymatic molecules, collectively called antioxidants. Antioxidants function by maintaining a physiological balance between the generation of RONS and their removal [75,223]. Imbalances in oxidant/antioxidant status are causally linked to asthma and COPD pathophysiology such as airflow obstruction, airway hyperreactivity, and remodeling [75,112]. Moreover, the severity of airway disease is directly correlated with the amount of RONS generated [224,225,226]. In addition to greater quantities of RONS produced in the lungs of asthmatic patients, the levels of antioxidants such as superoxide dismutase (SOD) and catalase are lower than those found in healthy lungs [227], and diminished antioxidant capacities likely contribute to corticosteroid insensitivity [37,228].

5.1. Key Antioxidant Systems

Glutathione (GSH). GSH is a major non-enzymatic antioxidant in the lung and is synthesized intracellularly from the amino acids cysteine, glycine, and glutamate by the activity of γ-glutamyl ligase (rate limiting) and glutathione synthetase [229]. Approximately 90% of all lung GSH is maintained in the reduced form, and epithelial lining fluid contains roughly 50 times more reduced GSH than plasma (300 µM) [230]. Mechanistically, glutathione peroxidases (GPXs) use the reducing equivalents of GSH to reduce cellularly generated hydrogen peroxide to H2O, changing GSH to its oxidized form glutathione disulfide (GSSG). GSSG is then reduced back to GSH by the activity of glutathione reductase and by reducing equivalents from NADPH [231]. In addition to the endogenous production of GSH and the reduction of GSSG, the rapid import of GSH into the cell and the export of GSSG from the cell facilitates overcoming oxidant stress and the accumulation of GSSG [232,233]. Thus, a pool of reduced GSH is essential for maintaining the cell in a principally reduced state and the cellular components, such as proteins and enzymes, in a functional configuration [231].
Overall, GSH levels are lower in the serum and lung cells of children and adults diagnosed with asthma [29,234]. GSH levels are also lower in the exhaled breath condensates of children with severe asthma than in healthy children. However, the levels are higher in lung lining fluids [234]. More significantly, in children with asthma and adults with COPD, glutathione levels in exhaled breath were lower than control, and these levels increased with oral steroid treatment [235,236]. In mice, GSH depletion augments allergic airway inflammation through increased p38 activation and iNOS activity [237]. These studies highlight the importance of glutathione in maintaining redox balance in the airway.
Superoxide Dismutases (SODs). SODs are responsible for catalyzing the reaction of superoxide to hydrogen peroxide [238]. There are three isoforms of SOD in mammals, copper-zinc (CuZn)SOD, manganese (Mn)SOD, and extra-cellular (EC)-SOD [2]. CuZnSOD accounts for about 80–90% of the intracellular SOD activity and is located primarily in the cytosol [239]. MnSOD makes up approximately 10% of the intracellular SOD activity and while it is initially expressed in the cytosol, it is imported into the mitochondria and is located primarily in the mitochondrial matrix [2,239]. EC-SOD is the secretory and extracellular form. It is found in the interstitial space of the lungs, primarily surrounding blood vessels and airways [238,240].
SODs are present in every mammalian cell, but lower expression levels and activity are observed in the lung lining fluids and airway epithelial cells of individuals with asthma and COPD compared to healthy controls [241,242]. A loss of activity can occur within minutes of an acute response and is related to modifications of the SOD protein that impairs enzymatic function [243]. Specifically, CuZnSOD is inactivated by the oxidation of critical histidine residues, while MnSOD and ECSOD are inactivated through the chlorination and nitration of tyrosine residues, respectively [75,244,245]. These modifications are a contributing factor to the increase in RONS, increased oxidant stress, and ultimately increased airway hyperreactivity and remodeling during asthma exacerbation [225,241,246,247].
Catalase. Catalase is an oxidoreductase that works in concert with GPX to neutralize hydrogen peroxide. While catalase is effective on small molecules and at high concentrations, prolonged oxidant stress causes catalase activity to decrease [248]. This reduction is due to modifications to the tyrosine residues found in the lungs of asthmatics, similar to that of SOD [249,250]. Although catalase is considered a first line of defense against hydrogen peroxide, its effectiveness in chronic oxidant stress is limited. Inactivation of this important antioxidant mechanism likely contributes to persistent airway inflammation and corticosteroid insensitivity.
Thioredoxin (TRX). TRX is an oxidoreductase that contains a dithiol-disulfide active site [75,251]. Much like glutathione, TRX is maintained in the reduced state by the activity of thioredoxin reductase and the reducing equivalents of NADPH. There are two isoforms of TRX: TRX1, located primarily in the cytosol, and TRX2, located primarily in the mitochondria [252]. In the context of asthma and COPD, TRX has been shown to have a protective role [253]. Allergen-challenged mice treated to enhance TRX1 expression levels exhibited reduced eosinophil lung recruitment, mucous cell metaplasia, and airway remodeling [254,255,256]. Similarly, enhanced TRX1 expression protects mice from cigarette smoke-induced lung inflammation and emphysema [257,258,259]. Less is known about TRX expression and activity in patients with asthma and COPD. Levels of serum TRX1 were found to be increased during an asthma exacerbation and inversely correlated with lung function [260]. Conversely in COPD acute exacerbation, TRX1 and TRXR1 expression is reduced in serum samples with increased levels of 4-hydroxy-2-nonenal (4HNE)-protein adducts. The role of the TRX system in asthma and COPD is not clear, particularly in the context of more severe phenotypes and corticosteroid sensitivity.
Nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 is a transcription factor that regulates the expression of genes associated with protecting the cells from oxidant stress and damage [261,262]. Nrf2 is tethered in the cytosol by its interaction with Keap1 but is released by the presence of oxidative stress to translocate to the nucleus, bind to the antioxidant response elements, and activate the expression of genes involved in endogenous antioxidant responses [38]. Nrf2 directly regulates more than 500 genes, including those part of the GSH and TRX systems [261,262]. The antioxidant program regulated by Nrf2 is critical to maintaining lung homeostasis, tolerating oxidant-induced lung injury, and is important for limiting pro-inflammatory responses [261]. Nrf2 knockout mice challenged with allergens and cigarette smoke develop greater airway inflammation that includes increases in leukocyte infiltration and cytokine levels [263,264,265,266]. Further, the genetic deletion of Keap1 protects mice from oxidative stress and inflammation during exposure to acute cigarette smoke [267].
In severe asthma and COPD, Nrf2 expression and activity are substantially reduced, contributing to pronounced oxidative stress and inflammation [268,269,270]. Altered Nrf2 expression and post-translational modifications are implicated in its reduced activity in children with severe asthma [38]. Nrf2 protein levels and Nrf2-mediated antioxidant responses are reduced in asthmatic airway smooth muscle cells compared to non-asthmatics, suggesting that Nrf2 mechanisms are also important for airway hyperresponsiveness and remodeling [271]. The critical roles it plays in lung inflammation and the regulation of endogenous antioxidant responses make Nrf2 an appealing target for therapies in asthma and COPD.

5.2. Endogenous Antioxidant Response and Corticosteroid Sensitivity

Targeting oxidative stress and improving redox balance in the airway could improve corticosteroid sensitivity. Advancements in understanding antioxidant mechanisms and their pharmacological targeting may provide an opportunity to improve corticosteroid sensitivity, reducing the burden of high dose corticosteroid while retaining the broad anti-inflammatory effects. In preclinical animal models of asthma and COPD, the administration of antioxidants or the stimulation of endogenous antioxidant responses both reduce airway inflammation and improve lung function. Recent studies also suggest that improving the redox balance in the lung can improve corticosteroid sensitivity [37]. In recent years, several candidate antioxidant strategies have been identified, and some have been tested in combination with corticosteroids (Table A1).
Vitamins C and E. Fruits and vegetables are rich in vitamins and other molecules that serve as antioxidants or important cofactors for antioxidant enzyme reactions. Vitamins C and E scavenge and eliminate oxidation by RONS, particularly membrane lipids [272]. Vitamin C has been shown to reduce airway inflammation, remodeling, and oxidative stress in a model of allergic airway inflammation [273,274]. Similarly, the vitamin E isoform, γ-tocotrienol, was shown to reduce house dust mite-induced allergic airway inflammation through the inhibition of NFκB and increased Nrf2 activation [275]. In humans, γ-tocopherol supplementation was recently shown to reduce eosinophil and neutrophil infiltration in patients with asthma [276]. In mice exposed to cigarette smoke, γ-tocotrienol reduced lung inflammation and enhanced endogenous antioxidant responses. The effects of γ-tocotrienol on inflammation were comparable to treatment with corticosteroids. However, γ-tocotrienol also reduces levels of oxidative stress markers [277].
Polyphenols. Polyphenols and flavonoids are also found in various fruits and vegetables and demonstrate antioxidant activity. Compounds, such as resveratrol and quercetin, have been shown to reduce lung inflammation and oxidative stress while increasing endogenous Nrf2 activation [278,279,280,281,282]. In primary human airway epithelial cells, curcumin was shown to increase HDAC2 expression and improve corticosteroid sensitivity in cells exposed to cigarette smoke extract [283]. Enhanced corticosteroid sensitivity was also observed in ovalbumin challenged mice treated with tetrahyrdocurcumin, suggesting that polyphenols have the potential to improve the corticosteroid efficacy. Despite these observations, the impact of dietary antioxidants on corticosteroid sensitivity needs further exploration to be considered as steroid-sparing treatments in asthma and COPD.
Thiol Supplementation. The administration of thiols to alleviate oxidative stress in chronic lung diseases has been extensively explored. Their ability to scavenge RONS and enhance GSH levels helps protect cells and maintain a healthy redox balance. In a mouse model of corticosteroid resistant asthma, treatment with N-acetylcysteine (NAC) reduced airway inflammation to a greater extent than dexamethasone [284]. NAC increases GSH levels, which are correlated with improved lung function in COPD patients [285,286]. Carbocysteine, a mucolytic agent with antioxidant and anti-inflammatory effects, has been shown to improve corticosteroid sensitivity by increasing HDAC2 expression and GSH levels [287,288]. Although these approaches have been evaluated in clinical studies, their viability as a therapeutic strategy remains limited.
Nrf2 Agonists. Given its broad effects on antioxidant responses, targeting Nrf2 directly is an appealing strategy to suppress oxidative stress and improve corticosteroid sensitivity in severe asthma and COPD. Natural Nrf2 agonists such as sulforaphane have demonstrated efficacy in experimental models of asthma by enhancing antioxidant responses and protecting epithelial tight junction proteins [266]. In COPD models, sulforaphane promotes a robust antioxidant response, inhibits lung inflammation, and protects from cellular damage [289,290,291]. Treatment with sulforaphane improves corticosteroid sensitivity in mice challenged with cockroach allergen extract or exposed to cigarette smoke [292,293]. These effects were absent in Nrf2 knockout mice, suggesting that sulforaphane requires Nrf2 to enhance corticosteroid sensitivity [293]. Further, recently developed Nrf2-enhancing drugs such as RTA-408 have reduced airway hyperresponsiveness, oxidant stress, and inflammatory responses in mouse models of asthma [294]. Although targeting Nrf2 with specific agonists has potential in pre-clinical models, these agonists have yet to demonstrate significant efficacy in patients with asthma or COPD [295,296,297].
H2S. Hydrogen sulfide (H2S) is a gasotransmitter endogenously generated within cells and has been shown to have several physiological effects [298,299]. H2S enhances antioxidant responses by acting as a RONS scavenger and increasing GSH levels in the mitochondria [300,301,302]. Studies show that H2S donors can inhibit lung inflammation and increase antioxidant responses [303]. However, its effects in asthma and COPD models remain poorly understood. In alveolar macrophages isolated from patients with COPD, a H2S donor was shown to enhance the efficacy of dexamethasone to inhibit IL-8 and TNFα production [304]. Although roles for H2S in airway disease are emerging, its ability to enhance endogenous antioxidant responses in the lung provides an additional target to improve corticosteroid sensitivity in asthma and COPD.

6. Conclusions

Corticosteroids will likely remain the standard of care, as their unique ability to effectively reduce inflammation in immune cells and airway structural cells make them suitable for managing asthma and COPD. As we have discussed, oxidative stress is a significant contributor to airway inflammation and promotes corticosteroid insensitivity by disrupting GR signaling and augmenting pro-inflammatory responses. Optimal corticosteroid efficacy may be dependent upon maintaining low levels of oxidative stress [226], highlighting the need to develop strategies that can preserve homeostatic redox balance in patients receiving corticosteroids.
Pre-clinical asthma and COPD models clearly demonstrate that enhancing endogenous antioxidant responses, particularly those mediated by Nrf2, can further enhance corticosteroid sensitivity. However, these findings have yet to be translated into effective therapeutics that improve symptoms and reduce exacerbations in airway disease. This discrepancy can be attributed to several factors, including the lack of optimization in dosing, timing, and route administration. Additionally, antioxidant strategies have not been carefully developed nor optimized to work in combination with corticosteroids. While reducing the oxidative burden may have therapeutic promise, additional investigations are needed to understand the mechanisms related to oxidative stress in the airway and how enhanced antioxidant responses can be leveraged to improve corticosteroid efficacy. We propose that targeting antioxidant responses in the lung remains an appealing strategy to augment corticosteroid sensitivity in airway disease.

Author Contributions

B.W.L. and R.D.B.J. conceptualized the content. B.W.L., M.L.F., L.K.R., and R.D.B.J. wrote, edited, and approved the manuscript. The figures and table were prepared by B.W.L., M.L.F., L.K.R., and R.D.B.J. All authors have read and agreed to the published version of the manuscript.


This research was funded by the National Institutes of Health to R.D.B.J. (R00 HL131682, R01 HL155095) and L.K.R. (R01 HD088033).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Appendix A

Table A1. Candidate Compounds to Improve Corticosteroid Sensitivity.
Table A1. Candidate Compounds to Improve Corticosteroid Sensitivity.
CompoundDisease ModelExperimental Model Primary Endpoint (s) Dose Reference
Antagomir-21 and LY294002AsthmaMouse
  • ↑ HDAC2 expression
  • ↓ AHR
  • 2 mg/kg LY294002
  • 50 ug Ant-21
  • 2 mg/kg Dexamethasone
(NLRP3 Inhibitor)
  • ↓ Neutrophils
  • ↓ AHR
  • ↓ IL-1β levels
  • 10 mg/kg MCC950
  • 2 mg/kg Dexamethasone
  • ↑ Nrf2 expression
  • ↓ AHR
  • ↓ IgE
  • 250 mg/kg γ-tocotrienol
  • 10 mg/kg Prednisolone
  • ↓ TNFα levels
  • ↓ Mast cell degranulation
  • 50 mg/kg Resveratrol
  • 1 mg/kg Dexamethasone
CurcuminCOPDHuman monocytes (U937)
  • ↑ HDAC2 expression
  • 1 μM Curcumin
  • 100 nM Dexamethasone or 1 nM budesonide
N-acetylcysteine (NAC)AsthmaMouse
  • ↓ Eosinophils and neutrophils
  • ↓ IL-5 and IL-13 levels
  • 320 mg/kg NAC
  • 1 mg/kg dexamethasone
CarbocysteineCOPDAlveolar epithelial cells
  • ↑ HDAC2 expression and activity
  • ↑ Glutathione levels
  • 300 mg/kg Carbocysteine
  • 5 mg/kg Dexamethasone
(Nrf2 Agonist)
  • ↑ Nrf2 activity
  • ↓ Neutrophils
  • ↓ IL-17A and IL-23
  • 25 mg/kg Sulforaphane
  • 1 mg/kg Dexamethasone
  • ↑HDAC2 activity
  • 12.5 mg/kg Sulforaphane
  • 2.5 mg/kg Dexamethasone
(H2S donor)
COPDHuman monocytes (U937)
  • ↓ TNFα and IL-8 secretion
  • 100–500 μM of GYY4137
  • 10 nM dexamethasone
AndrographolideCOPDHuman PBMCs and monocytes (U937)
  • ↑ Nrf2 and HDAC2 expression
  • ↓ CXCL8 secretion
  • 1–30 μM Andrographolide
  • 0.1 nM–10 µM Dexamethasone
Antagomir-9AsthmaMouse pulmonary macrophages and human sputum cells
  • ↓ PP2A activity
  • ↓ AHR
  • ↑ GR nuclear translocation
  • 50 mg Antagomir-9
  • 1 mg/kg Dexamethasone
(p38 inhibitor)
  • ↓ CXCL8 and IL-6 secretion
  • ↓ p38 MAPK activity
  • 1 nM GW856553
  • 1 µM dexamethasone


  1. Jesenak, M.; Zelieskova, M.; Babusikova, E. Oxidative Stress and Bronchial Asthma in Children-Causes or Consequences? Front. Pediatr. 2017, 5, 162. [Google Scholar] [CrossRef]
  2. Kinnula, V.L.; Crapo, J.D. Superoxide dismutases in the lung and human lung diseases. Am. J. Respir. Crit. Care Med. 2003, 167, 1600–1619. [Google Scholar] [CrossRef] [PubMed]
  3. Zuo, L.; He, F.; Sergakis, G.G.; Koozehchian, M.S.; Stimpfl, J.N.; Rong, Y.; Diaz, P.T.; Best, T.M. Interrelated role of cigarette smoking, oxidative stress, and immune response in COPD and corresponding treatments. Am. J. Physiol. Lung Cell Mol. Physiol. 2014, 307, L205–L218. [Google Scholar] [CrossRef] [PubMed][Green Version]
  4. Wiegman, C.H.; Michaeloudes, C.; Haji, G.; Narang, P.; Clarke, C.J.; Russell, K.E.; Bao, W.; Pavlidis, S.; Barnes, P.J.; Kanerva, J.; et al. Oxidative stress-induced mitochondrial dysfunction drives inflammation and airway smooth muscle remodeling in patients with chronic obstructive pulmonary disease. J. Allergy Clin. Immunol. 2015, 136, 769–780. [Google Scholar] [CrossRef] [PubMed][Green Version]
  5. Mates, J.M.; Segura, J.A.; Alonso, F.J.; Marquez, J. Intracellular redox status and oxidative stress: Implications for cell proliferation, apoptosis, and carcinogenesis. Arch. Toxicol. 2008, 82, 273–299. [Google Scholar] [CrossRef] [PubMed]
  6. Martin, J.G.; Campbell, H.R.; Iijima, H.; Gautrin, D.; Malo, J.L.; Eidelman, D.H.; Hamid, Q.; Maghni, K. Chlorine-induced injury to the airways in mice. Am. J. Respir. Crit. Care Med. 2003, 168, 568–574. [Google Scholar] [CrossRef] [PubMed][Green Version]
  7. Song, W.; Wei, S.; Liu, G.; Yu, Z.; Estell, K.; Yadav, A.K.; Schwiebert, L.M.; Matalon, S. Postexposure administration of a {beta}2-agonist decreases chlorine-induced airway hyperreactivity in mice. Am. J. Respir. Cell Mol. Biol. 2011, 45, 88–94. [Google Scholar] [CrossRef] [PubMed][Green Version]
  8. Balakrishna, S.; Song, W.; Achanta, S.; Doran, S.F.; Liu, B.; Kaelberer, M.M.; Yu, Z.; Sui, A.; Cheung, M.; Leishman, E.; et al. TRPV4 inhibition counteracts edema and inflammation and improves pulmonary function and oxygen saturation in chemically induced acute lung injury. Am. J. Physiol. Lung Cell Mol. Physiol. 2014, 307, L158–L172. [Google Scholar] [CrossRef] [PubMed][Green Version]
  9. Jang, M.K.; Kim, S.H.; Lee, K.Y.; Kim, T.B.; Moon, K.A.; Park, C.S.; Bae, Y.J.; Zhu, Z.; Moon, H.B.; Cho, Y.S. The tyrosine phosphatase, SHP-1, is involved in bronchial mucin production during oxidative stress. Biochem. Biophys. Res. Commun. 2010, 393, 137–143. [Google Scholar] [CrossRef]
  10. Uchida, M.; Anderson, E.L.; Squillace, D.L.; Patil, N.; Maniak, P.J.; Iijima, K.; Kita, H.; O’Grady, S.M. Oxidative stress serves as a key checkpoint for IL-33 release by airway epithelium. Allergy 2017, 72, 1521–1531. [Google Scholar] [CrossRef]
  11. Brown, D.M.; Hutchison, L.; Donaldson, K.; MacKenzie, S.J.; Dick, C.A.; Stone, V. The effect of oxidative stress on macrophages and lung epithelial cells: The role of phosphodiesterases 1 and 4. Toxicol. Lett. 2007, 168, 1–6. [Google Scholar] [CrossRef]
  12. Choo-Wing, R.; Syed, M.A.; Harijith, A.; Bowen, B.; Pryhuber, G.; Janer, C.; Andersson, S.; Homer, R.J.; Bhandari, V. Hyperoxia and interferon-gamma-induced injury in developing lungs occur via cyclooxygenase-2 and the endoplasmic reticulum stress-dependent pathway. Am. J. Respir. Cell Mol. Biol. 2013, 48, 749–757. [Google Scholar] [CrossRef][Green Version]
  13. Deng, X.; Zhang, F.; Rui, W.; Long, F.; Wang, L.; Feng, Z.; Chen, D.; Ding, W. PM2.5-induced oxidative stress triggers autophagy in human lung epithelial A549 cells. Toxicol. Vitr. 2013, 27, 1762–1770. [Google Scholar] [CrossRef] [PubMed]
  14. Eapen, M.S.; Lu, W.; Hackett, T.L.; Singhera, G.K.; Mahmood, M.Q.; Hardikar, A.; Ward, C.; Walters, E.H.; Sohal, S.S. Increased myofibroblasts in the small airways, and relationship to remodelling and functional changes in smokers and COPD patients: Potential role of epithelial-mesenchymal transition. ERJ Open Res. 2021, 7, 00876–2020. [Google Scholar] [CrossRef] [PubMed]
  15. Higham, A.; Quinn, A.M.; Cancado, J.E.D.; Singh, D. The pathology of small airways disease in COPD: Historical aspects and future directions. Respir. Res. 2019, 20, 49. [Google Scholar] [CrossRef] [PubMed][Green Version]
  16. Bourdin, A.; Neveu, D.; Vachier, I.; Paganin, F.; Godard, P.; Chanez, P. Specificity of basement membrane thickening in severe asthma. J. Allergy Clin. Immunol. 2007, 119, 1367–1374. [Google Scholar] [CrossRef]
  17. Yaghoubi, M.; Adibi, A.; Safari, A.; FitzGerald, J.M.; Sadatsafavi, M. The Projected Economic and Health Burden of Uncontrolled Asthma in the United States. Am. J. Respir. Crit. Care Med. 2019, 200, 1102–1112. [Google Scholar] [CrossRef]
  18. Adeloye, D.; Chua, S.; Lee, C.; Basquill, C.; Papana, A.; Theodoratou, E.; Nair, H.; Gasevic, D.; Sridhar, D.; Campbell, H.; et al. Global and regional estimates of COPD prevalence: Systematic review and meta-analysis. J. Glob. Health 2015, 5, 020415. [Google Scholar] [CrossRef]
  19. Vogelmeier, C.F.; Criner, G.J.; Martinez, F.J.; Anzueto, A.; Barnes, P.J.; Bourbeau, J.; Celli, B.R.; Chen, R.; Decramer, M.; Fabbri, L.M.; et al. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report. GOLD Executive Summary. Am. J. Respir. Crit. Care Med. 2017, 195, 557–582. [Google Scholar] [CrossRef]
  20. Papadopoulos, N.G.; Christodoulou, I.; Rohde, G.; Agache, I.; Almqvist, C.; Bruno, A.; Bonini, S.; Bont, L.; Bossios, A.; Bousquet, J.; et al. Viruses and bacteria in acute asthma exacerbations—A GA(2) LEN-DARE systematic review. Allergy 2011, 66, 458–468. [Google Scholar] [CrossRef]
  21. Rehman, A.U.; Shah, S.; Abbas, G.; Harun, S.N.; Shakeel, S.; Hussain, R.; Hassali, M.A.A.; Rasool, M.F. Assessment of risk factors responsible for rapid deterioration of lung function over a period of one year in patients with chronic obstructive pulmonary disease. Sci. Rep. 2021, 11, 13578. [Google Scholar] [CrossRef] [PubMed]
  22. Chung, K.F.; Wenzel, S.E.; Brozek, J.L.; Bush, A.; Castro, M.; Sterk, P.J.; Adcock, I.M.; Bateman, E.D.; Bel, E.H.; Bleecker, E.R.; et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur. Respir. J. 2014, 43, 343–373. [Google Scholar] [CrossRef] [PubMed][Green Version]
  23. Jarjour, N.N.; Erzurum, S.C.; Bleecker, E.R.; Calhoun, W.J.; Castro, M.; Comhair, S.A.; Chung, K.F.; Curran-Everett, D.; Dweik, R.A.; Fain, S.B.; et al. Severe asthma: Lessons learned from the National Heart, Lung, and Blood Institute Severe Asthma Research Program. Am. J. Respir. Crit. Care Med. 2012, 185, 356–362. [Google Scholar] [CrossRef] [PubMed][Green Version]
  24. Ramadan, A.A.; Gaffin, J.M.; Israel, E.; Phipatanakul, W. Asthma and Corticosteroid Responses in Childhood and Adult Asthma. Clin. Chest Med. 2019, 40, 163–177. [Google Scholar] [CrossRef]
  25. Holgate, S.T. Pathophysiology of asthma: What has our current understanding taught us about new therapeutic approaches? J. Allergy Clin. Immunol. 2011, 128, 495–505. [Google Scholar] [CrossRef]
  26. Raissy, H.H.; Kelly, H.W.; Harkins, M.; Szefler, S.J. Inhaled corticosteroids in lung diseases. Am. J. Respir. Crit. Care Med. 2013, 187, 798–803. [Google Scholar] [CrossRef][Green Version]
  27. Wenzel, S.E. Asthma phenotypes: The evolution from clinical to molecular approaches. Nat. Med. 2012, 18, 716–725. [Google Scholar] [CrossRef]
  28. Sullivan, S.D.; Rasouliyan, L.; Russo, P.A.; Kamath, T.; Chipps, B.E.; Group, T.S. Extent, patterns, and burden of uncontrolled disease in severe or difficult-to-treat asthma. Allergy 2007, 62, 126–133. [Google Scholar] [CrossRef] [PubMed]
  29. Fitzpatrick, A.M.; Baena-Cagnani, C.E.; Bacharier, L.B. Severe asthma in childhood: Recent advances in phenotyping and pathogenesis. Curr. Opin. Allergy Clin. Immunol. 2012, 12, 193–201. [Google Scholar] [CrossRef][Green Version]
  30. Patel, J.G.; Nagar, S.P.; Dalal, A.A. Indirect costs in chronic obstructive pulmonary disease: A review of the economic burden on employers and individuals in the United States. Int. J. Chronic Obstr. Pulm. Dis. 2014, 9, 289–300. [Google Scholar] [CrossRef] [PubMed][Green Version]
  31. Hanania, N.A.; Chapman, K.R.; Kesten, S. Adverse effects of inhaled corticosteroids. Am. J. Med. 1995, 98, 196–208. [Google Scholar] [CrossRef]
  32. Loke, Y.K.; Gilbert, D.; Thavarajah, M.; Blanco, P.; Wilson, A.M. Bone mineral density and fracture risk with long-term use of inhaled corticosteroids in patients with asthma: Systematic review and meta-analysis. BMJ Open 2015, 5, e008554. [Google Scholar] [CrossRef][Green Version]
  33. Sullivan, P.W.; Ghushchyan, V.H.; Globe, G.; Schatz, M. Oral corticosteroid exposure and adverse effects in asthmatic patients. J. Allergy Clin. Immunol. 2018, 141, 110–116. [Google Scholar] [CrossRef] [PubMed][Green Version]
  34. Singanayagam, A.; Johnston, S.L. Long-term impact of inhaled corticosteroid use in asthma and chronic obstructive pulmonary disease (COPD): Review of mechanisms that underlie risks. J. Allergy Clin. Immunol. 2020, 146, 1292–1294. [Google Scholar] [CrossRef] [PubMed][Green Version]
  35. Fahy, J.V. Type 2 inflammation in asthma--present in most, absent in many. Nat. Rev. Immunol. 2015, 15, 57–65. [Google Scholar] [CrossRef] [PubMed]
  36. Barnes, P.J. Glucocorticosteroids: Current and future directions. Br. J. Pharmacol. 2011, 163, 29–43. [Google Scholar] [CrossRef][Green Version]
  37. Mei, D.; Tan, W.S.D.; Wong, W.S.F. Pharmacological strategies to regain steroid sensitivity in severe asthma and COPD. Curr. Opin. Pharmacol. 2019, 46, 73–81. [Google Scholar] [CrossRef] [PubMed]
  38. Fitzpatrick, A.M.; Stephenson, S.T.; Hadley, G.R.; Burwell, L.; Penugonda, M.; Simon, D.M.; Hansen, J.; Jones, D.P.; Brown, L.A. Thiol redox disturbances in children with severe asthma are associated with posttranslational modification of the transcription factor nuclear factor (erythroid-derived 2)-like 2. J. Allergy Clin. Immunol. 2011, 127, 1604–1611. [Google Scholar] [CrossRef] [PubMed][Green Version]
  39. Fitzpatrick, A.M.; Teague, W.G.; Burwell, L.; Brown, M.S.; Brown, L.A.; Program, N.N.S.A.R. Glutathione oxidation is associated with airway macrophage functional impairment in children with severe asthma. Pediatr. Res. 2011, 69, 154–159. [Google Scholar] [CrossRef][Green Version]
  40. Zhu, T.; Li, S.; Wang, J.; Liu, C.; Gao, L.; Zeng, Y.; Mao, R.; Cui, B.; Ji, H.; Chen, Z. Induced sputum metabolomic profiles and oxidative stress are associated with chronic obstructive pulmonary disease (COPD) severity: Potential use for predictive, preventive, and personalized medicine. EPMA J. 2020, 11, 645–659. [Google Scholar] [CrossRef]
  41. Vestbo, J.; Hansen, E.F. Airway hyperresponsiveness and COPD mortality. Thorax 2001, 56 (Suppl. 2), ii11–ii14. [Google Scholar]
  42. Ray, A.; Camiolo, M.; Fitzpatrick, A.; Gauthier, M.; Wenzel, S.E. Are We Meeting the Promise of Endotypes and Precision Medicine in Asthma? Physiol. Rev. 2020, 100, 983–1017. [Google Scholar] [CrossRef]
  43. Phipatanakul, W.; Mauger, D.T.; Sorkness, R.L.; Gaffin, J.M.; Holguin, F.; Woodruff, P.G.; Ly, N.P.; Bacharier, L.B.; Bhakta, N.R.; Moore, W.C.; et al. Effects of Age and Disease Severity on Systemic Corticosteroid Responses in Asthma. Am. J. Respir. Crit. Care Med. 2017, 195, 1439–1448. [Google Scholar] [CrossRef]
  44. Woodruff, P.G.; Modrek, B.; Choy, D.F.; Jia, G.; Abbas, A.R.; Ellwanger, A.; Koth, L.L.; Arron, J.R.; Fahy, J.V. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am. J. Respir. Crit. Care Med. 2009, 180, 388–395. [Google Scholar] [CrossRef] [PubMed]
  45. Kubo, M. Innate and adaptive type 2 immunity in lung allergic inflammation. Immunol. Rev. 2017, 278, 162–172. [Google Scholar] [CrossRef]
  46. Wisniewski, J.A.; Muehling, L.M.; Eccles, J.D.; Capaldo, B.J.; Agrawal, R.; Shirley, D.A.; Patrie, J.T.; Workman, L.J.; Schuyler, A.J.; Lawrence, M.G.; et al. TH1 signatures are present in the lower airways of children with severe asthma, regardless of allergic status. J. Allergy Clin. Immunol. 2018, 141, 2048–2060.e2013. [Google Scholar] [CrossRef][Green Version]
  47. Zhang, J.; Zhu, Z.; Zuo, X.; Pan, H.; Gu, Y.; Yuan, Y.; Wang, G.; Wang, S.; Zheng, R.; Liu, Z.; et al. The role of NTHi colonization and infection in the pathogenesis of neutrophilic asthma. Respir. Res. 2020, 21, 170. [Google Scholar] [CrossRef] [PubMed]
  48. Xu, W.; Li, R.; Sun, Y. Increased IFN-gamma-producing Th17/Th1 cells and their association with lung function and current smoking status in patients with chronic obstructive pulmonary disease. BMC Pulm. Med. 2019, 19, 137. [Google Scholar] [CrossRef] [PubMed][Green Version]
  49. Raundhal, M.; Morse, C.; Khare, A.; Oriss, T.B.; Milosevic, J.; Trudeau, J.; Huff, R.; Pilewski, J.; Holguin, F.; Kolls, J.; et al. High IFN-gamma and low SLPI mark severe asthma in mice and humans. J. Clin. Investig. 2015, 125, 3037–3050. [Google Scholar] [CrossRef] [PubMed][Green Version]
  50. Moore, W.C.; Hastie, A.T.; Li, X.; Li, H.; Busse, W.W.; Jarjour, N.N.; Wenzel, S.E.; Peters, S.P.; Meyers, D.A.; Bleecker, E.R.; et al. Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis. J. Allergy Clin. Immunol. 2014, 133, 1557–1563.e1555. [Google Scholar] [CrossRef] [PubMed][Green Version]
  51. Christenson, S.A.; van den Berge, M.; Faiz, A.; Inkamp, K.; Bhakta, N.; Bonser, L.R.; Zlock, L.T.; Barjaktarevic, I.Z.; Barr, R.G.; Bleecker, E.R.; et al. An airway epithelial IL-17A response signature identifies a steroid-unresponsive COPD patient subgroup. J. Clin. Investig. 2019, 129, 169–181. [Google Scholar] [CrossRef]
  52. Yanagisawa, H.; Hashimoto, M.; Minagawa, S.; Takasaka, N.; Ma, R.; Moermans, C.; Ito, S.; Araya, J.; Budelsky, A.; Goodsell, A.; et al. Role of IL-17A in murine models of COPD airway disease. Am. J. Physiol. Lung Cell Mol. Physiol. 2017, 312, L122–L130. [Google Scholar] [CrossRef]
  53. Ouyang, S.; Liu, C.; Xiao, J.; Chen, X.; Lui, A.C.; Li, X. Targeting IL-17A/glucocorticoid synergy to CSF3 expression in neutrophilic airway diseases. JCI Insight 2020, 5, e132836. [Google Scholar] [CrossRef]
  54. Holgate, S.T. The sentinel role of the airway epithelium in asthma pathogenesis. Immunol. Rev. 2011, 242, 205–219. [Google Scholar] [CrossRef] [PubMed]
  55. Curran, D.R.; Cohn, L. Advances in mucous cell metaplasia: A plug for mucus as a therapeutic focus in chronic airway disease. Am. J. Respir. Cell Mol. Biol. 2010, 42, 268–275. [Google Scholar] [CrossRef] [PubMed][Green Version]
  56. Carlier, F.M.; de Fays, C.; Pilette, C. Epithelial Barrier Dysfunction in Chronic Respiratory Diseases. Front. Physiol. 2021, 12, 691227. [Google Scholar] [CrossRef]
  57. Drake, L.Y.; Kita, H. IL-33: Biological properties, functions, and roles in airway disease. Immunol. Rev. 2017, 278, 173–184. [Google Scholar] [CrossRef] [PubMed]
  58. Rada, B.; Gardina, P.; Myers, T.G.; Leto, T.L. Reactive oxygen species mediate inflammatory cytokine release and EGFR-dependent mucin secretion in airway epithelial cells exposed to Pseudomonas pyocyanin. Mucosal Immunol. 2011, 4, 158–171. [Google Scholar] [CrossRef] [PubMed]
  59. Heijink, I.; van Oosterhout, A.; Kliphuis, N.; Jonker, M.; Hoffmann, R.; Telenga, E.; Klooster, K.; Slebos, D.J.; ten Hacken, N.; Postma, D.; et al. Oxidant-induced corticosteroid unresponsiveness in human bronchial epithelial cells. Thorax 2014, 69, 5–13. [Google Scholar] [CrossRef][Green Version]
  60. Klassen, C.; Karabinskaya, A.; Dejager, L.; Vettorazzi, S.; Van Moorleghem, J.; Luhder, F.; Meijsing, S.H.; Tuckermann, J.P.; Bohnenberger, H.; Libert, C.; et al. Airway Epithelial Cells Are Crucial Targets of Glucocorticoids in a Mouse Model of Allergic Asthma. J. Immunol. 2017, 199, 48–61. [Google Scholar] [CrossRef][Green Version]
  61. Sekiyama, A.; Gon, Y.; Terakado, M.; Takeshita, I.; Kozu, Y.; Maruoka, S.; Matsumoto, K.; Hashimoto, S. Glucocorticoids enhance airway epithelial barrier integrity. Int. Immunopharmacol. 2012, 12, 350–357. [Google Scholar] [CrossRef] [PubMed]
  62. Milara, J.; Morell, A.; de Diego, A.; Artigues, E.; Morcillo, E.; Cortijo, J. Mucin 1 deficiency mediates corticosteroid insensitivity in asthma. Allergy 2019, 74, 111–121. [Google Scholar] [CrossRef] [PubMed]
  63. Pepe, C.; Foley, S.; Shannon, J.; Lemiere, C.; Olivenstein, R.; Ernst, P.; Ludwig, M.S.; Martin, J.G.; Hamid, Q. Differences in airway remodeling between subjects with severe and moderate asthma. J. Allergy Clin. Immunol. 2005, 116, 544–549. [Google Scholar] [CrossRef]
  64. Smith, B.M.; Zhao, N.; Olivenstein, R.; Lemiere, C.; Hamid, Q.; Martin, J.G. Asthma and fixed airflow obstruction: Long-term trajectories suggest distinct endotypes. Clin. Exp. Allergy 2021, 51, 39–48. [Google Scholar] [CrossRef]
  65. Hogg, J.C.; Chu, F.; Utokaparch, S.; Woods, R.; Elliott, W.M.; Buzatu, L.; Cherniack, R.M.; Rogers, R.M.; Sciurba, F.C.; Coxson, H.O.; et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N. Engl. J. Med. 2004, 350, 2645–2653. [Google Scholar] [CrossRef] [PubMed]
  66. Bento, A.M.; Hershenson, M.B. Airway remodeling: Potential contributions of subepithelial fibrosis and airway smooth muscle hypertrophy/hyperplasia to airway narrowing in asthma. Allergy Asthma Proc. 1998, 19, 353–358. [Google Scholar] [CrossRef] [PubMed]
  67. Jeffery, P.K. Remodeling in asthma and chronic obstructive lung disease. Am. J. Respir. Crit. Care Med. 2001, 164, S28–S38. [Google Scholar] [CrossRef]
  68. Prakash, Y.S. Emerging concepts in smooth muscle contributions to airway structure and function: Implications for health and disease. Am. J. Physiol. Lung Cell Mol. Physiol. 2016, 311, L1113–L1140. [Google Scholar] [CrossRef]
  69. James, A.L.; Bai, T.R.; Mauad, T.; Abramson, M.J.; Dolhnikoff, M.; McKay, K.O.; Maxwell, P.S.; Elliot, J.G.; Green, F.H. Airway smooth muscle thickness in asthma is related to severity but not duration of asthma. Eur. Respir. J. 2009, 34, 1040–1045. [Google Scholar] [CrossRef] [PubMed]
  70. Munakata, M. Airway remodeling and airway smooth muscle in asthma. Allergol. Int. 2006, 55, 235–243. [Google Scholar] [CrossRef] [PubMed][Green Version]
  71. Camoretti-Mercado, B.; Lockey, R.F. Airway smooth muscle pathophysiology in asthma. J. Allergy Clin. Immunol. 2021, 147, 1983–1995. [Google Scholar] [CrossRef] [PubMed]
  72. Berry, M.; Morgan, A.; Shaw, D.E.; Parker, D.; Green, R.; Brightling, C.; Bradding, P.; Wardlaw, A.J.; Pavord, I.D. Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma. Thorax 2007, 62, 1043–1049. [Google Scholar] [CrossRef] [PubMed][Green Version]
  73. Lo, C.Y.; Michaeloudes, C.; Bhavsar, P.K.; Huang, C.D.; Wang, C.H.; Kuo, H.P.; Chung, K.F. Increased phenotypic differentiation and reduced corticosteroid sensitivity of fibrocytes in severe asthma. J. Allergy Clin. Immunol. 2015, 135, 1186–1195.e6. [Google Scholar] [CrossRef] [PubMed]
  74. Bossley, C.J.; Saglani, S.; Kavanagh, C.; Payne, D.N.; Wilson, N.; Tsartsali, L.; Rosenthal, M.; Balfour-Lynn, I.M.; Nicholson, A.G.; Bush, A. Corticosteroid responsiveness and clinical characteristics in childhood difficult asthma. Eur. Respir. J. 2009, 34, 1052–1059. [Google Scholar] [CrossRef]
  75. Comhair, S.A.; Erzurum, S.C. Redox control of asthma: Molecular mechanisms and therapeutic opportunities. Antioxid. Redox Signal. 2010, 12, 93–124. [Google Scholar] [CrossRef] [PubMed][Green Version]
  76. Zinellu, E.; Zinellu, A.; Fois, A.G.; Pau, M.C.; Scano, V.; Piras, B.; Carru, C.; Pirina, P. Oxidative Stress Biomarkers in Chronic Obstructive Pulmonary Disease Exacerbations: A Systematic Review. Antioxidants 2021, 10, 710. [Google Scholar] [CrossRef]
  77. Couillard, S.; Shrimanker, R.; Chaudhuri, R.; Mansur, A.H.; McGarvey, L.P.; Heaney, L.G.; Fowler, S.J.; Bradding, P.; Pavord, I.D.; Hinks, T.S.C.; et al. FeNO Non-Suppression Identifies Corticosteroid-Resistant Type-2 Signaling in Severe Asthma. Am. J. Respir. Crit. Care Med. 2021. Published electronically. [Google Scholar] [CrossRef]
  78. Schwartz, J.; Timonen, K.L.; Pekkanen, J. Respiratory effects of environmental tobacco smoke in a panel study of asthmatic and symptomatic children. Am. J. Respir. Crit. Care Med. 2000, 161, 802–806. [Google Scholar] [CrossRef][Green Version]
  79. Flayer, C.H.; Ge, M.Q.; Hwang, J.W.; Kokalari, B.; Redai, I.G.; Jiang, Z.; Haczku, A. Ozone Inhalation Attenuated the Effects of Budesonide on Aspergillus fumigatus-Induced Airway Inflammation and Hyperreactivity in Mice. Front. Immunol. 2019, 10, 2173. [Google Scholar] [CrossRef] [PubMed][Green Version]
  80. Zmirou, D.; Gauvin, S.; Pin, I.; Momas, I.; Sahraoui, F.; Just, J.; Le Moullec, Y.; Bremont, F.; Cassadou, S.; Reungoat, P.; et al. Traffic related air pollution and incidence of childhood asthma: Results of the Vesta case-control study. J. Epidemiol. Community Health 2004, 58, 18–23. [Google Scholar] [CrossRef] [PubMed][Green Version]
  81. Wilhelm, M.; Meng, Y.Y.; Rull, R.P.; English, P.; Balmes, J.; Ritz, B. Environmental public health tracking of childhood asthma using California health interview survey, traffic, and outdoor air pollution data. Environ. Health Perspect. 2008, 116, 1254–1260. [Google Scholar] [CrossRef][Green Version]
  82. De Homdedeu, M.; Cruz, M.; Sanchez-Diez, S.; Ojanguren, I.; Romero-Mesones, C.; Vanoirbeek, J.; Velde, G.V.; Muñoz, X. The immunomodulatory effects of diesel exhaust particles in asthma. Environ. Pollut. 2020, 263, 114600. [Google Scholar] [CrossRef]
  83. He, X.; Zhang, L.; Xiong, A.; Ran, Q.; Wang, J.; Wu, D.; Niu, B.; Liu, S.; Li, G. PM2.5 aggravates NQO1-induced mucus hyper-secretion through release of neutrophil extracellular traps in an asthma model. Ecotoxicol. Environ. Saf. 2021, 218, 112272. [Google Scholar] [CrossRef] [PubMed]
  84. McGovern, T.K.; Chen, M.; Allard, B.; Larsson, K.; Martin, J.G.; Adner, M. Neutrophilic oxidative stress mediates organic dust-induced pulmonary inflammation and airway hyperresponsiveness. Am. J. Physiol. Lung Cell Mol. Physiol. 2016, 310, L155–L165. [Google Scholar] [CrossRef] [PubMed][Green Version]
  85. Prakash, Y.S.; Pabelick, C.M.; Sieck, G.C. Mitochondrial Dysfunction in Airway Disease. Chest 2017, 152, 618–626. [Google Scholar] [CrossRef] [PubMed]
  86. Schumacker, P.T.; Gillespie, M.N.; Nakahira, K.; Choi, A.M.; Crouser, E.D.; Piantadosi, C.A.; Bhattacharya, J. Mitochondria in lung biology and pathology: More than just a powerhouse. Am. J. Physiol. Lung Cell Mol. Physiol. 2014, 306, L962–L974. [Google Scholar] [CrossRef][Green Version]
  87. Thannickal, V.J.; Fanburg, B.L. Reactive oxygen species in cell signaling. Am. J. Physiol. Lung Cell Mol. Physiol. 2000, 279, L1005–L1028. [Google Scholar] [CrossRef][Green Version]
  88. Wang, J.Y. The innate immune response in house dust mite-induced allergic inflammation. Allergy Asthma Immunol. Res. 2013, 5, 68–74. [Google Scholar] [CrossRef][Green Version]
  89. Tham, R.; Vicendese, D.; Dharmage, S.C.; Hyndman, R.J.; Newbigin, E.; Lewis, E.; O’Sullivan, M.; Lowe, A.J.; Taylor, P.; Bardin, P.; et al. Associations between outdoor fungal spores and childhood and adolescent asthma hospitalizations. J. Allergy Clin. Immunol. 2017, 139, 1140–1147.e1144. [Google Scholar] [CrossRef][Green Version]
  90. Roberts, G.; Fontanella, S.; Selby, A.; Howard, R.; Filippi, S.; Hedlin, G.; Nordlund, B.; Howarth, P.; Hashimoto, S.; Brinkman, P.; et al. Connectivity patterns between multiple allergen specific IgE antibodies and their association with severe asthma. J. Allergy Clin. Immunol. 2020, 146, 821–830. [Google Scholar] [CrossRef]
  91. Fraczek, M.G.; Chishimba, L.; Niven, R.M.; Bromley, M.; Simpson, A.; Smyth, L.; Denning, D.W.; Bowyer, P. Corticosteroid treatment is associated with increased filamentous fungal burden in allergic fungal disease. J. Allergy Clin. Immunol. 2018, 142, 407–414. [Google Scholar] [CrossRef] [PubMed][Green Version]
  92. Chan, T.K.; Loh, X.Y.; Peh, H.Y.; Tan, W.N.F.; Tan, W.S.D.; Li, N.; Tay, I.J.J.; Wong, W.S.F.; Engelward, B.P. House dust mite-induced asthma causes oxidative damage and DNA double-strand breaks in the lungs. J. Allergy Clin. Immunol. 2016, 138, 84–96.e81. [Google Scholar] [CrossRef] [PubMed][Green Version]
  93. Mannino, D.M.; Homa, D.M.; Redd, S.C. Involuntary smoking and asthma severity in children: Data from the Third National Health and Nutrition Examination Survey. Chest 2002, 122, 409–415. [Google Scholar] [CrossRef] [PubMed][Green Version]
  94. Chalmers, G.W.; Macleod, K.J.; Little, S.A.; Thomson, L.J.; McSharry, C.P.; Thomson, N.C. Influence of cigarette smoking on inhaled corticosteroid treatment in mild asthma. Thorax 2002, 57, 226–230. [Google Scholar] [CrossRef] [PubMed][Green Version]
  95. Lazarus, S.C.; Chinchilli, V.M.; Rollings, N.J.; Boushey, H.A.; Cherniack, R.; Craig, T.J.; Deykin, A.; DiMango, E.; Fish, J.E.; Ford, J.G.; et al. Smoking affects response to inhaled corticosteroids or leukotriene receptor antagonists in asthma. Am. J. Respir. Crit. Care Med. 2007, 175, 783–790. [Google Scholar] [CrossRef]
  96. Winickoff, J.P.; Friebely, J.; Tanski, S.E.; Sherrod, C.; Matt, G.E.; Hovell, M.F.; McMillen, R.C. Beliefs about the health effects of "thirdhand" smoke and home smoking bans. Pediatrics 2009, 123, e74–e79. [Google Scholar] [CrossRef][Green Version]
  97. Heijink, I.H.; Brandenburg, S.M.; Postma, D.S.; van Oosterhout, A.J. Cigarette smoke impairs airway epithelial barrier function and cell-cell contact recovery. Eur. Respir. J. 2012, 39, 419–428. [Google Scholar] [CrossRef][Green Version]
  98. Hackett, T.L.; Singhera, G.K.; Shaheen, F.; Hayden, P.; Jackson, G.R.; Hegele, R.G.; Van Eeden, S.; Bai, T.R.; Dorscheid, D.R.; Knight, D.A. Intrinsic phenotypic differences of asthmatic epithelium and its inflammatory responses to respiratory syncytial virus and air pollution. Am. J. Respir. Cell Mol. Biol. 2011, 45, 1090–1100. [Google Scholar] [CrossRef]
  99. Valavanidis, A.; Vlachogianni, T.; Fiotakis, K. Tobacco smoke: Involvement of reactive oxygen species and stable free radicals in mechanisms of oxidative damage, carcinogenesis and synergistic effects with other respirable particles. Int. J. Environ. Res. Public Health 2009, 6, 445–462. [Google Scholar] [CrossRef]
  100. van der Toorn, M.; Rezayat, D.; Kauffman, H.F.; Bakker, S.J.; Gans, R.O.; Koeter, G.H.; Choi, A.M.; van Oosterhout, A.J.; Slebos, D.J. Lipid-soluble components in cigarette smoke induce mitochondrial production of reactive oxygen species in lung epithelial cells. Am. J. Physiol. Lung Cell Mol. Physiol. 2009, 297, L109–L114. [Google Scholar] [CrossRef][Green Version]
  101. Jiang, Z.; Zhu, L. Update on molecular mechanisms of corticosteroid resistance in chronic obstructive pulmonary disease. Pulm. Pharmacol. Ther. 2016, 37, 1–8. [Google Scholar] [CrossRef]
  102. Brandt, E.B.; Myers, J.M.; Ryan, P.H.; Hershey, G.K. Air pollution and allergic diseases. Curr. Opin. Pediatr. 2015, 27, 724–735. [Google Scholar] [CrossRef] [PubMed][Green Version]
  103. Che, L.; Jin, Y.; Zhang, C.; Lai, T.; Zhou, H.; Xia, L.; Tian, B.; Zhao, Y.; Liu, J.; Wu, Y.; et al. Ozone-induced IL-17A and neutrophilic airway inflammation is orchestrated by the caspase-1-IL-1 cascade. Sci. Rep. 2016, 6, 18680. [Google Scholar] [CrossRef] [PubMed][Green Version]
  104. Mathews, J.A.; Krishnamoorthy, N.; Kasahara, D.I.; Hutchinson, J.; Cho, Y.; Brand, J.D.; Williams, A.S.; Wurmbrand, A.P.; Ribeiro, L.; Cuttitta, F.; et al. Augmented Responses to Ozone in Obese Mice Require IL-17A and Gastrin-Releasing Peptide. Am. J. Respir. Cell Mol. Biol. 2018, 58, 341–351. [Google Scholar] [CrossRef] [PubMed]
  105. Lee, G.B.; Brandt, E.B.; Xiao, C.; Gibson, A.M.; Le Cras, T.D.; Brown, L.A.; Fitzpatrick, A.M.; Khurana Hershey, G.K. Diesel exhaust particles induce cysteine oxidation and s-glutathionylation in house dust mite induced murine asthma. PLoS ONE 2013, 8, e60632. [Google Scholar] [CrossRef][Green Version]
  106. Brandt, E.B.; Kovacic, M.B.; Lee, G.B.; Gibson, A.M.; Acciani, T.H.; Le Cras, T.D.; Ryan, P.H.; Budelsky, A.L.; Khurana Hershey, G.K. Diesel exhaust particle induction of IL-17A contributes to severe asthma. J. Allergy Clin. Immunol. 2013, 132, 1194–1204.e1192. [Google Scholar] [CrossRef][Green Version]
  107. Acciani, T.H.; Brandt, E.B.; Khurana Hershey, G.K.; Le Cras, T.D. Diesel exhaust particle exposure increases severity of allergic asthma in young mice. Clin. Exp. Allergy 2013, 43, 1406–1418. [Google Scholar] [CrossRef]
  108. Brandt, E.B.; Khurana Hershey, G.K. A combination of dexamethasone and anti-IL-17A treatment can alleviate diesel exhaust particle-induced steroid insensitive asthma. J. Allergy Clin. Immunol. 2016, 138, 924–928.e922. [Google Scholar] [CrossRef][Green Version]
  109. Liu, M.; Shi, Z.; Yin, Y.; Wang, Y.; Mu, N.; Li, C.; Ma, H.; Wang, Q. Particulate matter 2.5 triggers airway inflammation and bronchial hyperresponsiveness in mice by activating the SIRT2-p65 pathway. Front. Med. 2021. Published electronically. [Google Scholar] [CrossRef]
  110. Castaneda, A.R.; Vogel, C.F.A.; Bein, K.J.; Hughes, H.K.; Smiley-Jewell, S.; Pinkerton, K.E. Ambient particulate matter enhances the pulmonary allergic immune response to house dust mite in a BALB/c mouse model by augmenting Th2- and Th17-immune responses. Physiol. Rep. 2018, 6, e13827. [Google Scholar] [CrossRef]
  111. Tiotiu, A.; Kermani, N.Z.; Badi, Y.; Pavlidis, S.; Hansbro, P.M.; Guo, Y.K.; Chung, K.F.; Adcock, I.M.; U-BIOPRED Consortium Project Team. Sputum macrophage diversity and activation in asthma: Role of severity and inflammatory phenotype. Allergy 2021, 76, 775–788. [Google Scholar] [CrossRef] [PubMed]
  112. De Groot, L.E.S.; van der Veen, T.A.; Martinez, F.O.; Hamann, J.; Lutter, R.; Melgert, B.N. Oxidative stress and macrophages: Driving forces behind exacerbations of asthma and chronic obstructive pulmonary disease? Am. J. Physiol. Lung Cell Mol. Physiol. 2019, 316, L369–L384. [Google Scholar] [CrossRef] [PubMed][Green Version]
  113. Slauch, J.M. How does the oxidative burst of macrophages kill bacteria? Still an open question. Mol. Microbiol. 2011, 80, 580–583. [Google Scholar] [CrossRef] [PubMed][Green Version]
  114. Balhara, J.; Gounni, A.S. The alveolar macrophages in asthma: A double-edged sword. Mucosal Immunol. 2012, 5, 605–609. [Google Scholar] [CrossRef]
  115. Miki, H.; Pei, H.; Gracias, D.T.; Linden, J.; Croft, M. Clearance of apoptotic cells by lung alveolar macrophages prevents development of house dust mite-induced asthmatic lung inflammation. J. Allergy Clin. Immunol. 2021, 147, 1087–1092. [Google Scholar] [CrossRef] [PubMed]
  116. Iles, K.E.; Forman, H.J. Macrophage signaling and respiratory burst. Immunol. Res. 2002, 26, 95–105. [Google Scholar] [CrossRef]
  117. Brune, B.; Dehne, N.; Grossmann, N.; Jung, M.; Namgaladze, D.; Schmid, T.; von Knethen, A.; Weigert, A. Redox control of inflammation in macrophages. Antioxid. Redox Signal. 2013, 19, 595–637. [Google Scholar] [CrossRef][Green Version]
  118. Belchamber, K.B.R.; Singh, R.; Batista, C.M.; Whyte, M.K.; Dockrell, D.H.; Kilty, I.; Robinson, M.J.; Wedzicha, J.A.; Barnes, P.J.; Donnelly, L.E.; et al. Defective bacterial phagocytosis is associated with dysfunctional mitochondria in COPD macrophages. Eur. Respir. J. 2019, 54, 1802244. [Google Scholar] [CrossRef]
  119. Higham, A.; Booth, G.; Lea, S.; Southworth, T.; Plumb, J.; Singh, D. The effects of corticosteroids on COPD lung macrophages: A pooled analysis. Respir. Res. 2015, 16, 98. [Google Scholar] [CrossRef][Green Version]
  120. Staples, K.J.; Hinks, T.S.; Ward, J.A.; Gunn, V.; Smith, C.; Djukanovic, R. Phenotypic characterization of lung macrophages in asthmatic patients: Overexpression of CCL17. J. Allergy Clin. Immunol. 2012, 130, 1404–1412.e1407. [Google Scholar] [CrossRef][Green Version]
  121. Morshed, M.; Yousefi, S.; Stockle, C.; Simon, H.U.; Simon, D. Thymic stromal lymphopoietin stimulates the formation of eosinophil extracellular traps. Allergy 2012, 67, 1127–1137. [Google Scholar] [CrossRef]
  122. Aldridge, R.E.; Chan, T.; van Dalen, C.J.; Senthilmohan, R.; Winn, M.; Venge, P.; Town, G.I.; Kettle, A.J. Eosinophil peroxidase produces hypobromous acid in the airways of stable asthmatics. Free Radic. Biol. Med. 2002, 33, 847–856. [Google Scholar] [CrossRef]
  123. Silveira, J.S.; Antunes, G.L.; Kaiber, D.B.; da Costa, M.S.; Marques, E.P.; Ferreira, F.S.; Gassen, R.B.; Breda, R.V.; Wyse, A.T.S.; Pitrez, P.; et al. Reactive oxygen species are involved in eosinophil extracellular traps release and in airway inflammation in asthma. J. Cell. Physiol. 2019, 234, 23633–23646. [Google Scholar] [CrossRef] [PubMed]
  124. Reis, A.C.; Alessandri, A.L.; Athayde, R.M.; Perez, D.A.; Vago, J.P.; Avila, T.V.; Ferreira, T.P.; de Arantes, A.C.; Coutinho Dde, S.; Rachid, M.A.; et al. Induction of eosinophil apoptosis by hydrogen peroxide promotes the resolution of allergic inflammation. Cell Death Dis. 2015, 6, e1632. [Google Scholar] [CrossRef] [PubMed]
  125. Sousa, A.R.; Marshall, R.P.; Warnock, L.C.; Bolton, S.; Hastie, A.; Symon, F.; Hargadon, B.; Marshall, H.; Richardson, M.; Brightling, C.E.; et al. Responsiveness to oral prednisolone in severe asthma is related to the degree of eosinophilic airway inflammation. Clin. Exp. Allergy 2017, 47, 890–899. [Google Scholar] [CrossRef][Green Version]
  126. Demarche, S.F.; Schleich, F.N.; Henket, M.A.; Paulus, V.A.; van Hees, T.J.; Louis, R.E. Effectiveness of inhaled corticosteroids in real life on clinical outcomes, sputum cells and systemic inflammation in asthmatics: A retrospective cohort study in a secondary care centre. BMJ Open 2017, 7, e018186. [Google Scholar] [CrossRef]
  127. Nabe, T. Steroid-Resistant Asthma and Neutrophils. Biol. Pharm. Bull. 2020, 43, 31–35. [Google Scholar] [CrossRef][Green Version]
  128. Cox, G. Glucocorticoid treatment inhibits apoptosis in human neutrophils. Separation of survival and activation outcomes. J. Immunol. 1995, 154, 4719–4725. [Google Scholar]
  129. Fahy, J.V. Eosinophilic and neutrophilic inflammation in asthma: Insights from clinical studies. Proc. Am. Thorac Soc. 2009, 6, 256–259. [Google Scholar] [CrossRef]
  130. Bruijnzeel, P.L.; Uddin, M.; Koenderman, L. Targeting neutrophilic inflammation in severe neutrophilic asthma: Can we target the disease-relevant neutrophil phenotype? J. Leukoc. Biol. 2015, 98, 549–556. [Google Scholar] [CrossRef]
  131. Mann, B.S.; Chung, K.F. Blood neutrophil activation markers in severe asthma: Lack of inhibition by prednisolone therapy. Respir. Res. 2006, 7, 59. [Google Scholar] [CrossRef][Green Version]
  132. Grunwell, J.R.; Stephenson, S.T.; Tirouvanziam, R.; Brown, L.A.S.; Brown, M.R.; Fitzpatrick, A.M. Children with Neutrophil-Predominant Severe Asthma Have Proinflammatory Neutrophils With Enhanced Survival and Impaired Clearance. J. Allergy Clin. Immunol. Pract 2019, 7, 516–525.e516. [Google Scholar] [CrossRef]
  133. Wang, Y.; Wang, W.; Wang, N.; Tall, A.R.; Tabas, I. Mitochondrial Oxidative Stress Promotes Atherosclerosis and Neutrophil Extracellular Traps in Aged Mice. Arter. Thromb. Vasc. Biol. 2017, 37, e99–e107. [Google Scholar] [CrossRef][Green Version]
  134. Brinkmann, V.; Reichard, U.; Goosmann, C.; Fauler, B.; Uhlemann, Y.; Weiss, D.S.; Weinrauch, Y.; Zychlinsky, A. Neutrophil extracellular traps kill bacteria. Science 2004, 303, 1532–1535. [Google Scholar] [CrossRef]
  135. Grabcanovic-Musija, F.; Obermayer, A.; Stoiber, W.; Krautgartner, W.D.; Steinbacher, P.; Winterberg, N.; Bathke, A.C.; Klappacher, M.; Studnicka, M. Neutrophil extracellular trap (NET) formation characterises stable and exacerbated COPD and correlates with airflow limitation. Respir. Res. 2015, 16, 59. [Google Scholar] [CrossRef][Green Version]
  136. Pham, D.L.; Ban, G.Y.; Kim, S.H.; Shin, Y.S.; Ye, Y.M.; Chwae, Y.J.; Park, H.S. Neutrophil autophagy and extracellular DNA traps contribute to airway inflammation in severe asthma. Clin. Exp. Allergy 2017, 47, 57–70. [Google Scholar] [CrossRef]
  137. Gal, Z.; Gezsi, A.; Pallinger, E.; Visnovitz, T.; Nagy, A.; Kiss, A.; Sultesz, M.; Csoma, Z.; Tamasi, L.; Galffy, G.; et al. Plasma neutrophil extracellular trap level is modified by disease severity and inhaled corticosteroids in chronic inflammatory lung diseases. Sci. Rep. 2020, 10, 4320. [Google Scholar] [CrossRef][Green Version]
  138. Saito, T.; Ichikawa, T.; Numakura, T.; Yamada, M.; Koarai, A.; Fujino, N.; Murakami, K.; Yamanaka, S.; Sasaki, Y.; Kyogoku, Y.; et al. PGC-1alpha regulates airway epithelial barrier dysfunction induced by house dust mite. Respir. Res. 2021, 22, 63. [Google Scholar] [CrossRef] [PubMed]
  139. Huang, X.; Tan, X.; Liang, Y.; Hou, C.; Qu, D.; Li, M.; Huang, Q. Differential DAMP release was observed in the sputum of COPD, asthma and asthma-COPD overlap (ACO) patients. Sci. Rep. 2019, 9, 19241. [Google Scholar] [CrossRef][Green Version]
  140. Srisomboon, Y.; Squillace, D.L.; Maniak, P.J.; Kita, H.; O’Grady, S.M. Fungal allergen-induced IL-33 secretion involves cholesterol-dependent, VDAC-1-mediated ATP release from the airway epithelium. J. Physiol. 2020, 598, 1829–1845. [Google Scholar] [CrossRef][Green Version]
  141. Arzola Martinez, L.; Benavente, R.; Vega, G.; Rios, M.; Fonseca, W.; Rasky, A.J.; Morris, S.; Lukacs, N.W.; Villalon, M.J. Blocking ATP releasing channels prevents high extracellular ATP levels and airway hyperreactivity in an asthmatic mouse model. Am. J. Physiol. Lung Cell Mol. Physiol. 2021, 321, L466–L476. [Google Scholar] [CrossRef] [PubMed]
  142. Idzko, M.; Hammad, H.; van Nimwegen, M.; Kool, M.; Willart, M.A.; Muskens, F.; Hoogsteden, H.C.; Luttmann, W.; Ferrari, D.; di Virgilio, F.; et al. Extracellular ATP triggers and maintains asthmatic airway inflammation by activating dendritic cells. Nat. Med. 2007, 13, 913–919. [Google Scholar] [CrossRef]
  143. Pouwels, S.D.; Zijlstra, G.J.; van der Toorn, M.; Hesse, L.; Gras, R.; Ten Hacken, N.H.; Krysko, D.V.; Vandenabeele, P.; de Vries, M.; van Oosterhout, A.J.; et al. Cigarette smoke-induced necroptosis and DAMP release trigger neutrophilic airway inflammation in mice. Am. J. Physiol. Lung Cell Mol. Physiol. 2016, 310, L377–L386. [Google Scholar] [CrossRef][Green Version]
  144. Zou, S.C.; Jiang, J.; Song, J. IL-33 induced inflammation exacerbated the development of chronic obstructive pulmonary disease through oxidative stress. Eur. Rev. Med. Pharmacol. Sci. 2018, 22, 1758–1764. [Google Scholar] [CrossRef]
  145. Dickinson, J.D.; Sweeter, J.M.; Warren, K.J.; Ahmad, I.M.; De Deken, X.; Zimmerman, M.C.; Brody, S.L. Autophagy regulates DUOX1 localization and superoxide production in airway epithelial cells during chronic IL-13 stimulation. Redox Biol. 2018, 14, 272–284. [Google Scholar] [CrossRef]
  146. Ravasi, S.; Citro, S.; Viviani, B.; Capra, V.; Rovati, G.E. CysLT1 receptor-induced human airway smooth muscle cells proliferation requires ROS generation, EGF receptor transactivation and ERK1/2 phosphorylation. Respir. Res. 2006, 7, 42. [Google Scholar] [CrossRef][Green Version]
  147. Chen, G.; Khalil, N. TGF-beta1 increases proliferation of airway smooth muscle cells by phosphorylation of map kinases. Respir. Res. 2006, 7, 2. [Google Scholar] [CrossRef] [PubMed][Green Version]
  148. Yin, L.M.; Han, X.J.; Duan, T.T.; Xu, Y.D.; Wang, Y.; Ulloa, L.; Yang, Y.Q. Decreased S100A9 Expression Promoted Rat Airway Smooth Muscle Cell Proliferation by Stimulating ROS Generation and Inhibiting p38 MAPK. Can. Respir. J. 2016, 2016, 1462563. [Google Scholar] [CrossRef]
  149. Delmotte, P.; Yang, B.; Thompson, M.A.; Pabelick, C.M.; Prakash, Y.S.; Sieck, G.C. Inflammation alters regional mitochondrial Ca(2)+ in human airway smooth muscle cells. Am. J. Physiol. Cell Physiol. 2012, 303, C244–C256. [Google Scholar] [CrossRef][Green Version]
  150. Hartman, W.R.; Smelter, D.F.; Sathish, V.; Karass, M.; Kim, S.; Aravamudan, B.; Thompson, M.A.; Amrani, Y.; Pandya, H.C.; Martin, R.J.; et al. Oxygen dose responsiveness of human fetal airway smooth muscle cells. Am. J. Physiol. Lung Cell Mol. Physiol. 2012, 303, L711–L719. [Google Scholar] [CrossRef][Green Version]
  151. Vandevyver, S.; Dejager, L.; Tuckermann, J.; Libert, C. New insights into the anti-inflammatory mechanisms of glucocorticoids: An emerging role for glucocorticoid-receptor-mediated transactivation. Endocrinology 2013, 154, 993–1007. [Google Scholar] [CrossRef] [PubMed][Green Version]
  152. Gerber, A.N.; Newton, R.; Sasse, S.K. Repression of transcription by the glucocorticoid receptor: A parsimonious model for the genomics era. J. Biol. Chem. 2021, 296, 100687. [Google Scholar] [CrossRef] [PubMed]
  153. Syed, A.P.; Greulich, F.; Ansari, S.A.; Uhlenhaut, N.H. Anti-inflammatory glucocorticoid action: Genomic insights and emerging concepts. Curr. Opin. Pharmacol. 2020, 53, 35–44. [Google Scholar] [CrossRef]
  154. Franco, L.M.; Gadkari, M.; Howe, K.N.; Sun, J.; Kardava, L.; Kumar, P.; Kumari, S.; Hu, Z.; Fraser, I.D.C.; Moir, S.; et al. Immune regulation by glucocorticoids can be linked to cell type-dependent transcriptional responses. J. Exp. Med. 2019, 216, 384–406. [Google Scholar] [CrossRef][Green Version]
  155. Kan, M.; Koziol-White, C.; Shumyatcher, M.; Johnson, M.; Jester, W.; Panettieri, R.A., Jr.; Himes, B.E. Airway Smooth Muscle-Specific Transcriptomic Signatures of Glucocorticoid Exposure. Am. J. Respir. Cell Mol. Biol. 2019, 61, 110–120. [Google Scholar] [CrossRef]
  156. Reddy, A.T.; Lakshmi, S.P.; Banno, A.; Reddy, R.C. Glucocorticoid Receptor alpha Mediates Roflumilast’s Ability to Restore Dexamethasone Sensitivity in COPD. Int. J. Chronic Obstr. Pulm. Dis. 2020, 15, 125–134. [Google Scholar] [CrossRef][Green Version]
  157. Goleva, E.; Li, L.B.; Eves, P.T.; Strand, M.J.; Martin, R.J.; Leung, D.Y. Increased glucocorticoid receptor beta alters steroid response in glucocorticoid-insensitive asthma. Am. J. Respir. Crit. Care Med. 2006, 173, 607–616. [Google Scholar] [CrossRef][Green Version]
  158. Leung, D.Y.; Hamid, Q.; Vottero, A.; Szefler, S.J.; Surs, W.; Minshall, E.; Chrousos, G.P.; Klemm, D.J. Association of glucocorticoid insensitivity with increased expression of glucocorticoid receptor beta. J. Exp. Med. 1997, 186, 1567–1574. [Google Scholar] [CrossRef] [PubMed]
  159. Hodge, G.; Roscioli, E.; Jersmann, H.; Tran, H.B.; Holmes, M.; Reynolds, P.N.; Hodge, S. Steroid resistance in COPD is associated with impaired molecular chaperone Hsp90 expression by pro-inflammatory lymphocytes. Respir. Res. 2016, 17, 135. [Google Scholar] [CrossRef] [PubMed][Green Version]
  160. Chang, P.J.; Michaeloudes, C.; Zhu, J.; Shaikh, N.; Baker, J.; Chung, K.F.; Bhavsar, P.K. Impaired nuclear translocation of the glucocorticoid receptor in corticosteroid-insensitive airway smooth muscle in severe asthma. Am. J. Respir. Crit. Care Med. 2015, 191, 54–62. [Google Scholar] [CrossRef]
  161. Matthews, J.G.; Ito, K.; Barnes, P.J.; Adcock, I.M. Defective glucocorticoid receptor nuclear translocation and altered histone acetylation patterns in glucocorticoid-resistant patients. J. Allergy Clin. Immunol. 2004, 113, 1100–1108. [Google Scholar] [CrossRef]
  162. Sun, X.J.; Li, Z.H.; Zhang, Y.; Zhou, G.; Zhang, J.Q.; Deng, J.M.; Bai, J.; Liu, G.N.; Li, M.H.; MacNee, W.; et al. Combination of erythromycin and dexamethasone improves corticosteroid sensitivity induced by CSE through inhibiting PI3K-delta/Akt pathway and increasing GR expression. Am. J. Physiol. Lung Cell Mol. Physiol. 2015, 309, L139–L146. [Google Scholar] [CrossRef]
  163. Randall, M.J.; Haenen, G.R.; Bouwman, F.G.; van der Vliet, A.; Bast, A. The tobacco smoke component acrolein induces glucocorticoid resistant gene expression via inhibition of histone deacetylase. Toxicol. Lett. 2016, 240, 43–49. [Google Scholar] [CrossRef][Green Version]
  164. Ferraro, M.; Gjomarkaj, M.; Siena, L.; Di Vincenzo, S.; Pace, E. Formoterol and fluticasone propionate combination improves histone deacetylation and anti-inflammatory activities in bronchial epithelial cells exposed to cigarette smoke. Biochim. Biophys. Acta Mol. Basis Dis. 2017, 1863, 1718–1727. [Google Scholar] [CrossRef]
  165. Galliher-Beckley, A.J.; Cidlowski, J.A. Emerging roles of glucocorticoid receptor phosphorylation in modulating glucocorticoid hormone action in health and disease. IUBMB Life 2009, 61, 979–986. [Google Scholar] [CrossRef]
  166. Kobayashi, Y.; Mercado, N.; Barnes, P.J.; Ito, K. Defects of protein phosphatase 2A causes corticosteroid insensitivity in severe asthma. PLoS ONE 2011, 6, e27627. [Google Scholar] [CrossRef] [PubMed]
  167. Bouazza, B.; Krytska, K.; Debba-Pavard, M.; Amrani, Y.; Honkanen, R.E.; Tran, J.; Tliba, O. Cytokines alter glucocorticoid receptor phosphorylation in airway cells: Role of phosphatases. Am. J. Respir. Cell Mol. Biol. 2012, 47, 464–473. [Google Scholar] [CrossRef] [PubMed][Green Version]
  168. Chen, W.; Dang, T.; Blind, R.D.; Wang, Z.; Cavasotto, C.N.; Hittelman, A.B.; Rogatsky, I.; Logan, S.K.; Garabedian, M.J. Glucocorticoid receptor phosphorylation differentially affects target gene expression. Mol. Endocrinol. 2008, 22, 1754–1766. [Google Scholar] [CrossRef] [PubMed][Green Version]
  169. Wang, Z.; Chen, W.; Kono, E.; Dang, T.; Garabedian, M.J. Modulation of glucocorticoid receptor phosphorylation and transcriptional activity by a C-terminal-associated protein phosphatase. Mol. Endocrinol. 2007, 21, 625–634. [Google Scholar] [CrossRef] [PubMed][Green Version]
  170. Wang, Z.; Frederick, J.; Garabedian, M.J. Deciphering the phosphorylation "code" of the glucocorticoid receptor in vivo. J. Biol. Chem. 2002, 277, 26573–26580. [Google Scholar] [CrossRef] [PubMed][Green Version]
  171. Blind, R.D.; Garabedian, M.J. Differential recruitment of glucocorticoid receptor phospho-isoforms to glucocorticoid-induced genes. J. Steroid Biochem. Mol. Biol. 2008, 109, 150–157. [Google Scholar] [CrossRef][Green Version]
  172. Itoh, M.; Adachi, M.; Yasui, H.; Takekawa, M.; Tanaka, H.; Imai, K. Nuclear export of glucocorticoid receptor is enhanced by c-Jun N-terminal kinase-mediated phosphorylation. Mol. Endocrinol. 2002, 16, 2382–2392. [Google Scholar] [CrossRef] [PubMed]
  173. Lea, S.; Li, J.; Plumb, J.; Gaffey, K.; Mason, S.; Gaskell, R.; Harbron, C.; Singh, D. P38 MAPK and glucocorticoid receptor crosstalk in bronchial epithelial cells. J. Mol. Med. 2020, 98, 361–374. [Google Scholar] [CrossRef] [PubMed][Green Version]
  174. Bouazza, B.; Debba-Pavard, M.; Amrani, Y.; Isaacs, L.; O’Connell, D.; Ahamed, S.; Formella, D.; Tliba, O. Basal p38 mitogen-activated protein kinase regulates unliganded glucocorticoid receptor function in airway smooth muscle cells. Am. J. Respir. Cell Mol. Biol. 2014, 50, 301–315. [Google Scholar] [CrossRef] [PubMed]
  175. Kobayashi, Y.; Ito, K.; Kanda, A.; Tomoda, K.; Miller-Larsson, A.; Barnes, P.J.; Mercado, N. Protein tyrosine phosphatase PTP-RR regulates corticosteroid sensitivity. Respir. Res. 2016, 17, 30. [Google Scholar] [CrossRef][Green Version]
  176. Qian, L.; Xu, D.; Xue, F.; Li, M.; Wang, X.; Liu, G. Interleukin-35 sensitizes monocytes from patients with asthma to glucocorticoid therapy by regulating p38 MAPK. Exp. Ther. Med. 2020, 19, 3247–3258. [Google Scholar] [CrossRef] [PubMed]
  177. Zhang, Y.; Leung, D.Y.; Goleva, E. Anti-inflammatory and corticosteroid-enhancing actions of vitamin D in monocytes of patients with steroid-resistant and those with steroid-sensitive asthma. J. Allergy Clin. Immunol. 2014, 133, 1744–1752.e1741. [Google Scholar] [CrossRef] [PubMed][Green Version]
  178. Mercado, N.; Hakim, A.; Kobayashi, Y.; Meah, S.; Usmani, O.S.; Chung, K.F.; Barnes, P.J.; Ito, K. Restoration of corticosteroid sensitivity by p38 mitogen activated protein kinase inhibition in peripheral blood mononuclear cells from severe asthma. PLoS ONE 2012, 7, e41582. [Google Scholar] [CrossRef][Green Version]
  179. Chachi, L.; Abbasian, M.; Gavrila, A.; Alzahrani, A.; Tliba, O.; Bradding, P.; Wardlaw, A.J.; Brightling, C.; Amrani, Y. Protein phosphatase 5 mediates corticosteroid insensitivity in airway smooth muscle in patients with severe asthma. Allergy 2017, 72, 126–136. [Google Scholar] [CrossRef]
  180. Ito, K.; Yamamura, S.; Essilfie-Quaye, S.; Cosio, B.; Ito, M.; Barnes, P.J.; Adcock, I.M. Histone deacetylase 2-mediated deacetylation of the glucocorticoid receptor enables NF-kappaB suppression. J. Exp. Med. 2006, 203, 7–13. [Google Scholar] [CrossRef][Green Version]
  181. Kobayashi, Y.; Bossley, C.; Gupta, A.; Akashi, K.; Tsartsali, L.; Mercado, N.; Barnes, P.J.; Bush, A.; Ito, K. Passive smoking impairs histone deacetylase-2 in children with severe asthma. Chest 2014, 145, 305–312. [Google Scholar] [CrossRef][Green Version]
  182. Hew, M.; Bhavsar, P.; Torrego, A.; Meah, S.; Khorasani, N.; Barnes, P.J.; Adcock, I.; Chung, K.F. Relative corticosteroid insensitivity of peripheral blood mononuclear cells in severe asthma. Am. J. Respir. Crit. Care Med. 2006, 174, 134–141. [Google Scholar] [CrossRef][Green Version]
  183. Ito, K.; Barnes, P.J.; Adcock, I.M. Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits interleukin-1beta-induced histone H4 acetylation on lysines 8 and 12. Mol. Cell Biol. 2000, 20, 6891–6903. [Google Scholar] [CrossRef][Green Version]
  184. Mercado, N.; To, Y.; Ito, K.; Barnes, P.J. Nortriptyline reverses corticosteroid insensitivity by inhibition of phosphoinositide-3-kinase-delta. J. Pharmacol. Exp. Ther. 2011, 337, 465–470. [Google Scholar] [CrossRef][Green Version]
  185. Kim, R.Y.; Horvat, J.C.; Pinkerton, J.W.; Starkey, M.R.; Essilfie, A.T.; Mayall, J.R.; Nair, P.M.; Hansbro, N.G.; Jones, B.; Haw, T.J.; et al. MicroRNA-21 drives severe, steroid-insensitive experimental asthma by amplifying phosphoinositide 3-kinase-mediated suppression of histone deacetylase 2. J. Allergy Clin. Immunol. 2017, 139, 519–532. [Google Scholar] [CrossRef][Green Version]
  186. Spears, M.; Donnelly, I.; Jolly, L.; Brannigan, M.; Ito, K.; McSharry, C.; Lafferty, J.; Chaudhuri, R.; Braganza, G.; Adcock, I.M.; et al. Effect of low-dose theophylline plus beclometasone on lung function in smokers with asthma: A pilot study. Eur. Respir. J. 2009, 33, 1010–1017. [Google Scholar] [CrossRef] [PubMed][Green Version]
  187. Ford, P.A.; Durham, A.L.; Russell, R.E.; Gordon, F.; Adcock, I.M.; Barnes, P.J. Treatment effects of low-dose theophylline combined with an inhaled corticosteroid in COPD. Chest 2010, 137, 1338–1344. [Google Scholar] [CrossRef]
  188. Cosio, B.G.; Iglesias, A.; Rios, A.; Noguera, A.; Sala, E.; Ito, K.; Barnes, P.J.; Agusti, A. Low-dose theophylline enhances the anti-inflammatory effects of steroids during exacerbations of COPD. Thorax 2009, 64, 424–429. [Google Scholar] [CrossRef] [PubMed][Green Version]
  189. Devereux, G.; Cotton, S.; Fielding, S.; McMeekin, N.; Barnes, P.J.; Briggs, A.; Burns, G.; Chaudhuri, R.; Chrystyn, H.; Davies, L.; et al. Effect of Theophylline as Adjunct to Inhaled Corticosteroids on Exacerbations in Patients With COPD: A Randomized Clinical Trial. JAMA 2018, 320, 1548–1559. [Google Scholar] [CrossRef]
  190. Okros, Z.; Endreffy, E.; Novak, Z.; Maroti, Z.; Monostori, P.; Varga, I.S.; Kiraly, A.; Turi, S. Changes in NADPH oxidase mRNA level can be detected in blood at inhaled corticosteroid treated asthmatic children. Life Sci. 2012, 91, 907–911. [Google Scholar] [CrossRef]
  191. Lv, Y.; Li, Y.; Zhang, D.; Zhang, A.; Guo, W.; Zhu, S. HMGB1-induced asthmatic airway inflammation through GRP75-mediated enhancement of ER-mitochondrial Ca(2+) transfer and ROS increased. J. Cell. Biochem. 2018, 119, 4205–4215. [Google Scholar] [CrossRef]
  192. Marks-Konczalik, J.; Chu, S.C.; Moss, J. Cytokine-mediated transcriptional induction of the human inducible nitric oxide synthase gene requires both activator protein 1 and nuclear factor kappaB-binding sites. J. Biol. Chem. 1998, 273, 22201–22208. [Google Scholar] [CrossRef][Green Version]
  193. Sen, C.K.; Packer, L. Antioxidant and redox regulation of gene transcription. FASEB J. 1996, 10, 709–720. [Google Scholar] [CrossRef]
  194. Pourazar, J.; Mudway, I.S.; Samet, J.M.; Helleday, R.; Blomberg, A.; Wilson, S.J.; Frew, A.J.; Kelly, F.J.; Sandstrom, T. Diesel exhaust activates redox-sensitive transcription factors and kinases in human airways. Am. J. Physiol. Lung Cell Mol. Physiol. 2005, 289, L724–L730. [Google Scholar] [CrossRef]
  195. Liu, X.; Lin, R.; Zhao, B.; Guan, R.; Li, T.; Jin, R. Correlation between oxidative stress and the NF-kappaB signaling pathway in the pulmonary tissues of obese asthmatic mice. Mol. Med. Rep. 2016, 13, 1127–1134. [Google Scholar] [CrossRef][Green Version]
  196. Rahman, I.; Smith, C.A.; Lawson, M.F.; Harrison, D.J.; MacNee, W. Induction of gamma-glutamylcysteine synthetase by cigarette smoke is associated with AP-1 in human alveolar epithelial cells. FEBS Lett. 1996, 396, 21–25. [Google Scholar] [CrossRef][Green Version]
  197. Fu, L.; Fei, J.; Tan, Z.X.; Chen, Y.H.; Hu, B.; Xiang, H.X.; Zhao, H.; Xu, D.X. Low Vitamin D Status Is Associated with Inflammation in Patients with Chronic Obstructive Pulmonary Disease. J. Immunol. 2021, 206, 515–523. [Google Scholar] [CrossRef]
  198. Gagliardo, R.; Chanez, P.; Profita, M.; Bonanno, A.; Albano, G.D.; Montalbano, A.M.; Pompeo, F.; Gagliardo, C.; Merendino, A.M.; Gjomarkaj, M. IkappaB kinase-driven nuclear factor-kappaB activation in patients with asthma and chronic obstructive pulmonary disease. J. Allergy Clin. Immunol. 2011, 128, 635–645.e2. [Google Scholar] [CrossRef] [PubMed]
  199. Edwards, M.R.; Bartlett, N.W.; Clarke, D.; Birrell, M.; Belvisi, M.; Johnston, S.L. Targeting the NF-kappaB pathway in asthma and chronic obstructive pulmonary disease. Pharmacol. Ther. 2009, 121, 1–13. [Google Scholar] [CrossRef]
  200. Gagliardo, R.; Chanez, P.; Mathieu, M.; Bruno, A.; Costanzo, G.; Gougat, C.; Vachier, I.; Bousquet, J.; Bonsignore, G.; Vignola, A.M. Persistent activation of nuclear factor-kappaB signaling pathway in severe uncontrolled asthma. Am. J. Respir. Crit. Care Med. 2003, 168, 1190–1198. [Google Scholar] [CrossRef][Green Version]
  201. Villarino, A.V.; Kanno, Y.; O’Shea, J.J. Mechanisms and consequences of Jak-STAT signaling in the immune system. Nat. Immunol. 2017, 18, 374–384. [Google Scholar] [CrossRef]
  202. Simon, A.R.; Rai, U.; Fanburg, B.L.; Cochran, B.H. Activation of the JAK-STAT pathway by reactive oxygen species. Am. J. Physiol. 1998, 275, C1640–C1652. [Google Scholar] [CrossRef]
  203. Guo, F.H.; Uetani, K.; Haque, S.J.; Williams, B.R.; Dweik, R.A.; Thunnissen, F.B.; Calhoun, W.; Erzurum, S.C. Interferon gamma and interleukin 4 stimulate prolonged expression of inducible nitric oxide synthase in human airway epithelium through synthesis of soluble mediators. J. Clin. Investig. 1997, 100, 829–838. [Google Scholar] [CrossRef][Green Version]
  204. Britt, R.D., Jr.; Thompson, M.A.; Sasse, S.; Pabelick, C.M.; Gerber, A.N.; Prakash, Y.S. Th1 cytokines TNF-alpha and IFN-gamma promote corticosteroid resistance in developing human airway smooth muscle. Am. J. Physiol. Lung Cell Mol. Physiol. 2019, 316, L71–L81. [Google Scholar] [CrossRef]
  205. Gauthier, M.; Chakraborty, K.; Oriss, T.B.; Raundhal, M.; Das, S.; Chen, J.; Huff, R.; Sinha, A.; Fajt, M.; Ray, P.; et al. Severe asthma in humans and mouse model suggests a CXCL10 signature underlies corticosteroid-resistant Th1 bias. JCI Insight 2017, 2, e94580. [Google Scholar] [CrossRef]
  206. Patel, S. Danger-Associated Molecular Patterns (DAMPs): The Derivatives and Triggers of Inflammation. Curr. Allergy Asthma Rep. 2018, 18, 63. [Google Scholar] [CrossRef]
  207. Roan, F.; Obata-Ninomiya, K.; Ziegler, S.F. Epithelial cell-derived cytokines: More than just signaling the alarm. J. Clin. Investig. 2019, 129, 1441–1451. [Google Scholar] [CrossRef] [PubMed][Green Version]
  208. Schmitz, J.; Owyang, A.; Oldham, E.; Song, Y.; Murphy, E.; McClanahan, T.K.; Zurawski, G.; Moshrefi, M.; Qin, J.; Li, X.; et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 2005, 23, 479–490. [Google Scholar] [CrossRef][Green Version]
  209. van der Ploeg, E.K.; Golebski, K.; van Nimwegen, M.; Fergusson, J.R.; Heesters, B.A.; Martinez-Gonzalez, I.; Kradolfer, C.M.A.; van Tol, S.; Scicluna, B.P.; de Bruijn, M.J.W.; et al. Steroid-resistant human inflammatory ILC2s are marked by CD45RO and elevated in type 2 respiratory diseases. Sci. Immunol. 2021, 6, eabd3489. [Google Scholar] [CrossRef] [PubMed]
  210. Saglani, S.; Lui, S.; Ullmann, N.; Campbell, G.A.; Sherburn, R.T.; Mathie, S.A.; Denney, L.; Bossley, C.J.; Oates, T.; Walker, S.A.; et al. IL-33 promotes airway remodeling in pediatric patients with severe steroid-resistant asthma. J. Allergy Clin. Immunol. 2013, 132, 676–685.e613. [Google Scholar] [CrossRef][Green Version]
  211. Kabata, H.; Moro, K.; Fukunaga, K.; Suzuki, Y.; Miyata, J.; Masaki, K.; Betsuyaku, T.; Koyasu, S.; Asano, K. Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation. Nat. Commun. 2013, 4, 2675. [Google Scholar] [CrossRef][Green Version]
  212. Brandelius, A.; Mahmutovic Persson, I.; Calven, J.; Bjermer, L.; Persson, C.G.; Andersson, M.; Uller, L. Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors. Br. J. Pharmacol. 2013, 168, 363–374. [Google Scholar] [CrossRef][Green Version]
  213. Smelter, D.F.; Sathish, V.; Thompson, M.A.; Pabelick, C.M.; Vassallo, R.; Prakash, Y.S. Thymic stromal lymphopoietin in cigarette smoke-exposed human airway smooth muscle. J. Immunol. 2010, 185, 3035–3040. [Google Scholar] [CrossRef]
  214. Menzies-Gow, A.; Wechsler, M.E.; Brightling, C.E. Unmet need in severe, uncontrolled asthma: Can anti-TSLP therapy with tezepelumab provide a valuable new treatment option? Respir. Res. 2020, 21, 268. [Google Scholar] [CrossRef]
  215. Martinon, F. Signaling by ROS drives inflammasome activation. Eur. J. Immunol. 2010, 40, 616–619. [Google Scholar] [CrossRef] [PubMed]
  216. Birrell, M.A.; Eltom, S. The role of the NLRP3 inflammasome in the pathogenesis of airway disease. Pharmacol. Ther. 2011, 130, 364–370. [Google Scholar] [CrossRef] [PubMed]
  217. dos Santos, G.; Kutuzov, M.A.; Ridge, K.M. The inflammasome in lung diseases. Am. J. Physiol. Lung Cell Mol. Physiol. 2012, 303, L627–L633. [Google Scholar] [CrossRef] [PubMed][Green Version]
  218. Xu, F.; Wen, Z.; Shi, X.; Fan, J. Inflammasome in the Pathogenesis of Pulmonary Diseases. Exp. Suppl. 2018, 108, 111–151. [Google Scholar] [CrossRef] [PubMed]
  219. Thomas, S.S.; Chhabra, S.K. A study on the serum levels of interleukin-1beta in bronchial asthma. J. Indian Med. Assoc. 2003, 101, 282–284. [Google Scholar]
  220. Wang, C.C.; Fu, C.L.; Yang, Y.H.; Lo, Y.C.; Wang, L.C.; Chuang, Y.H.; Chang, D.M.; Chiang, B.L. Adenovirus expressing interleukin-1 receptor antagonist alleviates allergic airway inflammation in a murine model of asthma. Gene Ther. 2006, 13, 1414–1421. [Google Scholar] [CrossRef] [PubMed]
  221. Konno, S.; Gonokami, Y.; Kurokawa, M.; Kawazu, K.; Asano, K.; Okamoto, K.; Adachi, M. Cytokine concentrations in sputum of asthmatic patients. Int. Arch. Allergy Immunol. 1996, 109, 73–78. [Google Scholar] [CrossRef] [PubMed]
  222. Kim, R.Y.; Pinkerton, J.W.; Essilfie, A.T.; Robertson, A.A.B.; Baines, K.J.; Brown, A.C.; Mayall, J.R.; Ali, M.K.; Starkey, M.R.; Hansbro, N.G.; et al. Role for NLRP3 Inflammasome-mediated, IL-1beta-Dependent Responses in Severe, Steroid-Resistant Asthma. Am. J. Respir. Crit. Care Med. 2017, 196, 283–297. [Google Scholar] [CrossRef] [PubMed]
  223. Holguin, F. Oxidative stress in airway diseases. Ann. Am. Thorac Soc. 2013, 10, S150–S157. [Google Scholar] [CrossRef]
  224. Jarjour, N.N.; Calhoun, W.J. Enhanced production of oxygen radicals in asthma. J. Lab. Clin. Med. 1994, 123, 131–136. [Google Scholar] [CrossRef] [PubMed]
  225. Calhoun, W.J.; Reed, H.E.; Moest, D.R.; Stevens, C.A. Enhanced superoxide production by alveolar macrophages and air-space cells, airway inflammation, and alveolar macrophage density changes after segmental antigen bronchoprovocation in allergic subjects. Am. Rev. Respir. Dis. 1992, 145, 317–325. [Google Scholar] [CrossRef]
  226. Zeng, M.; Li, Y.; Jiang, Y.; Lu, G.; Huang, X.; Guan, K. Local and systemic oxidative stress status in chronic obstructive pulmonary disease patients. Can. Respir. J. 2013, 20, 35–41. [Google Scholar] [CrossRef]
  227. Erzurum, S.C. New Insights in Oxidant Biology in Asthma. Ann. Am. Thorac Soc. 2016, 13 (Suppl. 1), S35–S39. [Google Scholar] [CrossRef]
  228. Stephenson, S.T.; Brown, L.A.; Helms, M.N.; Qu, H.; Brown, S.D.; Brown, M.R.; Fitzpatrick, A.M. Cysteine oxidation impairs systemic glucocorticoid responsiveness in children with difficult-to-treat asthma. J. Allergy Clin. Immunol. 2015, 136, 454–461.e459. [Google Scholar] [CrossRef][Green Version]
  229. Reynaert, N.L. Glutathione biochemistry in asthma. Biochim. Biophys. Acta 2011, 1810, 1045–1051. [Google Scholar] [CrossRef]
  230. Roum, J.H.; Buhl, R.; McElvaney, N.G.; Borok, Z.; Crystal, R.G. Systemic deficiency of glutathione in cystic fibrosis. J. Appl Physiol. 1993, 75, 2419–2424. [Google Scholar] [CrossRef]
  231. Pizzorno, J. Glutathione! Integr. Med. (Encinitas) 2014, 13, 8–12. [Google Scholar]
  232. Deneke, S.M.; Fanburg, B.L. Regulation of cellular glutathione. Am. J. Physiol. 1989, 257, L163–L173. [Google Scholar] [CrossRef]
  233. Meister, A.; Anderson, M.E. Glutathione. Annu. Rev. Biochem. 1983, 52, 711–760. [Google Scholar] [CrossRef]
  234. Fitzpatrick, A.M.; Teague, W.G.; Holguin, F.; Yeh, M.; Brown, L.A.; Severe Asthma Research, P. Airway glutathione homeostasis is altered in children with severe asthma: Evidence for oxidant stress. J. Allergy Clin. Immunol. 2009, 123, 146–152.e148. [Google Scholar] [CrossRef][Green Version]
  235. Corradi, M.; Folesani, G.; Andreoli, R.; Manini, P.; Bodini, A.; Piacentini, G.; Carraro, S.; Zanconato, S.; Baraldi, E. Aldehydes and glutathione in exhaled breath condensate of children with asthma exacerbation. Am. J. Respir. Crit. Care Med. 2003, 167, 395–399. [Google Scholar] [CrossRef]
  236. Corradi, M.; Rubinstein, I.; Andreoli, R.; Manini, P.; Caglieri, A.; Poli, D.; Alinovi, R.; Mutti, A. Aldehydes in exhaled breath condensate of patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2003, 167, 1380–1386. [Google Scholar] [CrossRef]
  237. Nadeem, A.; Siddiqui, N.; Alharbi, N.O.; Alharbi, M.M.; Imam, F. Acute glutathione depletion leads to enhancement of airway reactivity and inflammation via p38MAPK-iNOS pathway in allergic mice. Int. Immunopharmacol. 2014, 22, 222–229. [Google Scholar] [CrossRef]
  238. Bowler, R.P.; Crapo, J.D. Oxidative stress in airways: Is there a role for extracellular superoxide dismutase? Am. J. Respir. Crit. Care Med. 2002, 166, S38–S43. [Google Scholar] [CrossRef] [PubMed]
  239. Crapo, J.D.; Oury, T.; Rabouille, C.; Slot, J.W.; Chang, L.Y. Copper, Zinc superoxide dismutase is primarily a cytosolic protein in human cells. Proc. Natl. Acad. Sci. USA 1992, 89, 10405–10409. [Google Scholar] [CrossRef] [PubMed][Green Version]
  240. Gao, F.; Koenitzer, J.R.; Tobolewski, J.M.; Jiang, D.; Liang, J.; Noble, P.W.; Oury, T.D. Extracellular superoxide dismutase inhibits inflammation by preventing oxidative fragmentation of hyaluronan. J. Biol. Chem. 2008, 283, 6058–6066. [Google Scholar] [CrossRef] [PubMed][Green Version]
  241. Comhair, S.A.; Xu, W.; Ghosh, S.; Thunnissen, F.B.; Almasan, A.; Calhoun, W.J.; Janocha, A.J.; Zheng, L.; Hazen, S.L.; Erzurum, S.C. Superoxide dismutase inactivation in pathophysiology of asthmatic airway remodeling and reactivity. Am. J. Pathol. 2005, 166, 663–674. [Google Scholar] [CrossRef][Green Version]
  242. De Raeve, H.R.; Thunnissen, F.B.; Kaneko, F.T.; Guo, F.H.; Lewis, M.; Kavuru, M.S.; Secic, M.; Thomassen, M.J.; Erzurum, S.C. Decreased Cu, Zn-SOD activity in asthmatic airway epithelium: Correction by inhaled corticosteroid in vivo. Am. J. Physiol. 1997, 272, L148–L154. [Google Scholar] [CrossRef]
  243. Comhair, S.A.; Bhathena, P.R.; Dweik, R.A.; Kavuru, M.; Erzurum, S.C. Rapid loss of superoxide dismutase activity during antigen-induced asthmatic response. Lancet 2000, 355, 624. [Google Scholar] [CrossRef]
  244. Alvarez, B.; Demicheli, V.; Duran, R.; Trujillo, M.; Cervenansky, C.; Freeman, B.A.; Radi, R. Inactivation of human Cu, Zn superoxide dismutase by peroxynitrite and formation of histidinyl radical. Free Radic. Biol. Med. 2004, 37, 813–822. [Google Scholar] [CrossRef]
  245. MacMillan-Crow, L.A.; Crow, J.P.; Thompson, J.A. Peroxynitrite-mediated inactivation of manganese superoxide dismutase involves nitration and oxidation of critical tyrosine residues. Biochemistry 1998, 37, 1613–1622. [Google Scholar] [CrossRef]
  246. MacPherson, J.C.; Comhair, S.A.; Erzurum, S.C.; Klein, D.F.; Lipscomb, M.F.; Kavuru, M.S.; Samoszuk, M.K.; Hazen, S.L. Eosinophils are a major source of nitric oxide-derived oxidants in severe asthma: Characterization of pathways available to eosinophils for generating reactive nitrogen species. J. Immunol. 2001, 166, 5763–5772. [Google Scholar] [CrossRef] [PubMed][Green Version]
  247. Wu, W.; Samoszuk, M.K.; Comhair, S.A.; Thomassen, M.J.; Farver, C.F.; Dweik, R.A.; Kavuru, M.S.; Erzurum, S.C.; Hazen, S.L. Eosinophils generate brominating oxidants in allergen-induced asthma. J. Clin. Investig. 2000, 105, 1455–1463. [Google Scholar] [CrossRef] [PubMed][Green Version]
  248. Cantin, A.; Crystal, R.G. Oxidants, antioxidants and the pathogenesis of emphysema. Eur. J. Respir. Dis. Suppl. 1985, 139, 7–17. [Google Scholar] [PubMed]
  249. Kirkman, H.N.; Rolfo, M.; Ferraris, A.M.; Gaetani, G.F. Mechanisms of protection of catalase by NADPH. Kinetics and stoichiometry. J. Biol. Chem. 1999, 274, 13908–13914. [Google Scholar] [CrossRef] [PubMed][Green Version]
  250. Ghosh, S.; Janocha, A.J.; Aronica, M.A.; Swaidani, S.; Comhair, S.A.; Xu, W.; Zheng, L.; Kaveti, S.; Kinter, M.; Hazen, S.L.; et al. Nitrotyrosine proteome survey in asthma identifies oxidative mechanism of catalase inactivation. J. Immunol. 2006, 176, 5587–5597. [Google Scholar] [CrossRef][Green Version]
  251. Hoshino, T.; Okamoto, M.; Takei, S.; Sakazaki, Y.; Iwanaga, T.; Aizawa, H. Redox-regulated mechanisms in asthma. Antioxid. Redox Signal. 2008, 10, 769–783. [Google Scholar] [CrossRef]
  252. Xu, J.; Li, T.; Wu, H.; Xu, T. Role of thioredoxin in lung disease. Pulm. Pharmacol. Ther. 2012, 25, 154–162. [Google Scholar] [CrossRef] [PubMed]
  253. Zhou, J.; Wang, C.; Wu, J.; Fukunaga, A.; Cheng, Z.; Wang, J.; Yamauchi, A.; Yodoi, J.; Tian, H. Anti-Allergic and Anti-Inflammatory Effects and Molecular Mechanisms of Thioredoxin on Respiratory System Diseases. Antioxid. Redox Signal. 2020, 32, 785–801. [Google Scholar] [CrossRef]
  254. Imaoka, H.; Hoshino, T.; Okamoto, M.; Sakazaki, Y.; Sawada, M.; Takei, S.; Kinoshita, T.; Kawayama, T.; Kato, S.; Aizawa, H. Endogenous and exogenous thioredoxin 1 prevents goblet cell hyperplasia in a chronic antigen exposure asthma model. Allergol. Int. 2009, 58, 403–410. [Google Scholar] [CrossRef][Green Version]
  255. Torii, M.; Wang, L.; Ma, N.; Saito, K.; Hori, T.; Sato-Ueshima, M.; Koyama, Y.; Nishikawa, H.; Katayama, N.; Mizoguchi, A.; et al. Thioredoxin suppresses airway inflammation independently of systemic Th1/Th2 immune modulation. Eur. J. Immunol. 2010, 40, 787–796. [Google Scholar] [CrossRef]
  256. Imaoka, H.; Hoshino, T.; Takei, S.; Sakazaki, Y.; Kinoshita, T.; Okamoto, M.; Kawayama, T.; Yodoi, J.; Kato, S.; Iwanaga, T.; et al. Effects of thioredoxin on established airway remodeling in a chronic antigen exposure asthma model. Biochem. Biophys. Res. Commun. 2007, 360, 525–530. [Google Scholar] [CrossRef] [PubMed]
  257. Tanabe, N.; Hoshino, Y.; Marumo, S.; Kiyokawa, H.; Sato, S.; Kinose, D.; Uno, K.; Muro, S.; Hirai, T.; Yodoi, J.; et al. Thioredoxin-1 protects against neutrophilic inflammation and emphysema progression in a mouse model of chronic obstructive pulmonary disease exacerbation. PLoS ONE 2013, 8, e79016. [Google Scholar] [CrossRef][Green Version]
  258. Sato, A.; Hoshino, Y.; Hara, T.; Muro, S.; Nakamura, H.; Mishima, M.; Yodoi, J. Thioredoxin-1 ameliorates cigarette smoke-induced lung inflammation and emphysema in mice. J. Pharmacol. Exp. Ther. 2008, 325, 380–388. [Google Scholar] [CrossRef] [PubMed]
  259. Kinoshita, T.; Hoshino, T.; Imaoka, H.; Ichiki, H.; Okamoto, M.; Kawayama, T.; Yodoi, J.; Kato, S.; Aizawa, H. Thioredoxin prevents the development and progression of elastase-induced emphysema. Biochem. Biophys. Res. Commun. 2007, 354, 712–719. [Google Scholar] [CrossRef]
  260. Yamada, Y.; Nakamura, H.; Adachi, T.; Sannohe, S.; Oyamada, H.; Kayaba, H.; Yodoi, J.; Chihara, J. Elevated serum levels of thioredoxin in patients with acute exacerbation of asthma. Immunol. Lett. 2003, 86, 199–205. [Google Scholar] [CrossRef]
  261. Liu, Q.; Gao, Y.; Ci, X. Role of Nrf2 and Its Activators in Respiratory Diseases. Oxid. Med. Cell Longev. 2019, 2019, 7090534. [Google Scholar] [CrossRef][Green Version]
  262. Mizumura, K.; Maruoka, S.; Shimizu, T.; Gon, Y. Role of Nrf2 in the pathogenesis of respiratory diseases. Respir. Investig. 2020, 58, 28–35. [Google Scholar] [CrossRef]
  263. Iizuka, T.; Ishii, Y.; Itoh, K.; Kiwamoto, T.; Kimura, T.; Matsuno, Y.; Morishima, Y.; Hegab, A.E.; Homma, S.; Nomura, A.; et al. Nrf2-deficient mice are highly susceptible to cigarette smoke-induced emphysema. Genes Cells 2005, 10, 1113–1125. [Google Scholar] [CrossRef] [PubMed]
  264. Ishii, Y.; Itoh, K.; Morishima, Y.; Kimura, T.; Kiwamoto, T.; Iizuka, T.; Hegab, A.E.; Hosoya, T.; Nomura, A.; Sakamoto, T.; et al. Transcription factor Nrf2 plays a pivotal role in protection against elastase-induced pulmonary inflammation and emphysema. J. Immunol. 2005, 175, 6968–6975. [Google Scholar] [CrossRef]
  265. Rangasamy, T.; Guo, J.; Mitzner, W.A.; Roman, J.; Singh, A.; Fryer, A.D.; Yamamoto, M.; Kensler, T.W.; Tuder, R.M.; Georas, S.N.; et al. Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice. J. Exp. Med. 2005, 202, 47–59. [Google Scholar] [CrossRef]
  266. Sussan, T.E.; Gajghate, S.; Chatterjee, S.; Mandke, P.; McCormick, S.; Sudini, K.; Kumar, S.; Breysse, P.N.; Diette, G.B.; Sidhaye, V.K.; et al. Nrf2 reduces allergic asthma in mice through enhanced airway epithelial cytoprotective function. Am. J. Physiol. Lung Cell Mol. Physiol. 2015, 309, L27–L36. [Google Scholar] [CrossRef][Green Version]
  267. Blake, D.J.; Singh, A.; Kombairaju, P.; Malhotra, D.; Mariani, T.J.; Tuder, R.M.; Gabrielson, E.; Biswal, S. Deletion of Keap1 in the lung attenuates acute cigarette smoke-induced oxidative stress and inflammation. Am. J. Respir. Cell Mol. Biol. 2010, 42, 524–536. [Google Scholar] [CrossRef][Green Version]
  268. Li, D.; Sun, D.; Zhu, Y. Expression of nuclear factor erythroid-2-related factor 2, broad complex-tramtrack-bric a brac and Cap‘n’collar homology 1 and gamma-glutamic acid cysteine synthase in peripheral blood of patients with chronic obstructive pulmonary disease and its clinical significance. Exp. Ther. Med. 2021, 21, 516. [Google Scholar] [CrossRef] [PubMed]
  269. Fratta Pasini, A.M.; Stranieri, C.; Ferrari, M.; Garbin, U.; Cazzoletti, L.; Mozzini, C.; Spelta, F.; Peserico, D.; Cominacini, L. Oxidative stress and Nrf2 expression in peripheral blood mononuclear cells derived from COPD patients: An observational longitudinal study. Respir. Res. 2020, 21, 37. [Google Scholar] [CrossRef] [PubMed][Green Version]
  270. Suzuki, M.; Betsuyaku, T.; Ito, Y.; Nagai, K.; Nasuhara, Y.; Kaga, K.; Kondo, S.; Nishimura, M. Down-regulated NF-E2-related factor 2 in pulmonary macrophages of aged smokers and patients with chronic obstructive pulmonary disease. Am. J. Respir. Cell Mol. Biol. 2008, 39, 673–682. [Google Scholar] [CrossRef][Green Version]
  271. Michaeloudes, C.; Chang, P.J.; Petrou, M.; Chung, K.F. Transforming growth factor-beta and nuclear factor E2-related factor 2 regulate antioxidant responses in airway smooth muscle cells: Role in asthma. Am. J. Respir. Crit. Care Med. 2011, 184, 894–903. [Google Scholar] [CrossRef][Green Version]
  272. Janciauskiene, S. The Beneficial Effects of Antioxidants in Health And Diseases. Chronic Obstr. Pulm. Dis. 2020, 7, 182–202. [Google Scholar] [CrossRef]
  273. Kianian, F.; Karimian, S.M.; Kadkhodaee, M.; Takzaree, N.; Seifi, B.; Adeli, S.; Harati, E.; Sadeghipour, H.R. Combination of ascorbic acid and calcitriol attenuates chronic asthma disease by reductions in oxidative stress and inflammation. Respir. Physiol. Neurobiol. 2019, 270, 103265. [Google Scholar] [CrossRef] [PubMed]
  274. Kianian, F.; Karimian, S.M.; Kadkhodaee, M.; Takzaree, N.; Seifi, B.; Sadeghipour, H.R. Protective effects of ascorbic acid and calcitriol combination on airway remodelling in ovalbumin-induced chronic asthma. Pharm. Biol. 2020, 58, 107–115. [Google Scholar] [CrossRef] [PubMed]
  275. Peh, H.Y.; Ho, W.E.; Cheng, C.; Chan, T.K.; Seow, A.C.; Lim, A.Y.; Fong, C.W.; Seng, K.Y.; Ong, C.N.; Wong, W.S. Vitamin E Isoform gamma-Tocotrienol Downregulates House Dust Mite-Induced Asthma. J. Immunol. 2015, 195, 437–444. [Google Scholar] [CrossRef] [PubMed][Green Version]
  276. Burbank, A.J.; Duran, C.G.; Pan, Y.; Burns, P.; Jones, S.; Jiang, Q.; Yang, C.; Jenkins, S.; Wells, H.; Alexis, N.; et al. Gamma tocopherol-enriched supplement reduces sputum eosinophilia and endotoxin-induced sputum neutrophilia in volunteers with asthma. J. Allergy Clin. Immunol. 2018, 141, 1231–1238.e1231. [Google Scholar] [CrossRef][Green Version]
  277. Peh, H.Y.; Tan, W.S.D.; Chan, T.K.; Pow, C.W.; Foster, P.S.; Wong, W.S.F. Vitamin E isoform gamma-tocotrienol protects against emphysema in cigarette smoke-induced COPD. Free Radic. Biol. Med. 2017, 110, 332–344. [Google Scholar] [CrossRef]
  278. Jafarinia, M.; Sadat Hosseini, M.; Kasiri, N.; Fazel, N.; Fathi, F.; Ganjalikhani Hakemi, M.; Eskandari, N. Quercetin with the potential effect on allergic diseases. Allergy Asthma Clin. Immunol. 2020, 16, 36. [Google Scholar] [CrossRef]
  279. Joskova, M.; Sadlonova, V.; Nosalova, G.; Novakova, E.; Franova, S. Polyphenols and their components in experimental allergic asthma. Adv. Exp. Med. Biol. 2013, 756, 91–98. [Google Scholar] [CrossRef]
  280. Chen, J.; Zhou, H.; Wang, J.; Zhang, B.; Liu, F.; Huang, J.; Li, J.; Lin, J.; Bai, J.; Liu, R. Therapeutic effects of resveratrol in a mouse model of HDM-induced allergic asthma. Int. Immunopharmacol. 2015, 25, 43–48. [Google Scholar] [CrossRef]
  281. Park, H.J.; Lee, C.M.; Jung, I.D.; Lee, J.S.; Jeong, Y.I.; Chang, J.H.; Chun, S.H.; Kim, M.J.; Choi, I.W.; Ahn, S.C.; et al. Quercetin regulates Th1/Th2 balance in a murine model of asthma. Int. Immunopharmacol. 2009, 9, 261–267. [Google Scholar] [CrossRef]
  282. Wood, L.G.; Wark, P.A.; Garg, M.L. Antioxidant and anti-inflammatory effects of resveratrol in airway disease. Antioxid. Redox Signal. 2010, 13, 1535–1548. [Google Scholar] [CrossRef]
  283. Meja, K.K.; Rajendrasozhan, S.; Adenuga, D.; Biswas, S.K.; Sundar, I.K.; Spooner, G.; Marwick, J.A.; Chakravarty, P.; Fletcher, D.; Whittaker, P.; et al. Curcumin restores corticosteroid function in monocytes exposed to oxidants by maintaining HDAC2. Am. J. Respir. Cell Mol. Biol. 2008, 39, 312–323. [Google Scholar] [CrossRef] [PubMed][Green Version]
  284. Eftekhari, P.; Hajizadeh, S.; Raoufy, M.R.; Masjedi, M.R.; Yang, M.; Hansbro, N.; Li, J.J.; Foster, P.S. Preventive effect of N-acetylcysteine in a mouse model of steroid resistant acute exacerbation of asthma. EXCLI J. 2013, 12, 184–192. [Google Scholar]
  285. De Backer, J.; Vos, W.; Van Holsbeke, C.; Vinchurkar, S.; Claes, R.; Parizel, P.M.; De Backer, W. Effect of high-dose N-acetylcysteine on airway geometry, inflammation, and oxidative stress in COPD patients. Int. J. Chronic Obstr. Pulm. Dis. 2013, 8, 569–579. [Google Scholar] [CrossRef] [PubMed][Green Version]
  286. van Overveld, F.J.; Demkow, U.; Gorecka, D.; de Backer, W.A.; Zielinski, J. New developments in the treatment of COPD: Comparing the effects of inhaled corticosteroids and N-acetylcysteine. J. Physiol. Pharmacol. 2005, 56 (Suppl. 4), 135–142. [Google Scholar] [PubMed]
  287. Song, Y.; Lu, H.Z.; Xu, J.R.; Wang, X.L.; Zhou, W.; Hou, L.N.; Zhu, L.; Yu, Z.H.; Chen, H.Z.; Cui, Y.Y. Carbocysteine restores steroid sensitivity by targeting histone deacetylase 2 in a thiol/GSH-dependent manner. Pharmacol. Res. 2015, 91, 88–98. [Google Scholar] [CrossRef]
  288. Pace, E.; Ferraro, M.; Di Vincenzo, S.; Cipollina, C.; Gerbino, S.; Cigna, D.; Caputo, V.; Balsamo, R.; Lanata, L.; Gjomarkaj, M. Comparative cytoprotective effects of carbocysteine and fluticasone propionate in cigarette smoke extract-stimulated bronchial epithelial cells. Cell Stress Chaperones 2013, 18, 733–743. [Google Scholar] [CrossRef][Green Version]
  289. Harvey, C.J.; Thimmulappa, R.K.; Sethi, S.; Kong, X.; Yarmus, L.; Brown, R.H.; Feller-Kopman, D.; Wise, R.; Biswal, S. Targeting Nrf2 signaling improves bacterial clearance by alveolar macrophages in patients with COPD and in a mouse model. Sci. Transl. Med. 2011, 3, 78ra32. [Google Scholar] [CrossRef][Green Version]
  290. Starrett, W.; Blake, D.J. Sulforaphane inhibits de novo synthesis of IL-8 and MCP-1 in human epithelial cells generated by cigarette smoke extract. J. Immunotoxicol. 2011, 8, 150–158. [Google Scholar] [CrossRef][Green Version]
  291. Jiao, Z.; Chang, J.; Li, J.; Nie, D.; Cui, H.; Guo, D. Sulforaphane increases Nrf2 expression and protects alveolar epithelial cells against injury caused by cigarette smoke extract. Mol. Med. Rep. 2017, 16, 1241–1247. [Google Scholar] [CrossRef][Green Version]
  292. Al-Harbi, N.O.; Nadeem, A.; Ahmad, S.F.; AlThagfan, S.S.; Alqinyah, M.; Alqahtani, F.; Ibrahim, K.E.; Al-Harbi, M.M. Sulforaphane treatment reverses corticosteroid resistance in a mixed granulocytic mouse model of asthma by upregulation of antioxidants and attenuation of Th17 immune responses in the airways. Eur. J. Pharmacol. 2019, 855, 276–284. [Google Scholar] [CrossRef]
  293. Sakurai, H.; Morishima, Y.; Ishii, Y.; Yoshida, K.; Nakajima, M.; Tsunoda, Y.; Hayashi, S.Y.; Kiwamoto, T.; Matsuno, Y.; Kawaguchi, M.; et al. Sulforaphane ameliorates steroid insensitivity through an Nrf2-dependent pathway in cigarette smoke-exposed asthmatic mice. Free Radic. Biol. Med. 2018, 129, 473–485. [Google Scholar] [CrossRef]
  294. Zhang, J.H.; Yang, X.; Chen, Y.P.; Zhang, J.F.; Li, C.Q. Nrf2 Activator RTA-408 Protects Against Ozone-Induced Acute Asthma Exacerbation by Suppressing ROS and gammadeltaT17 Cells. Inflammation 2019, 42, 1843–1856. [Google Scholar] [CrossRef]
  295. Wise, R.A.; Holbrook, J.T.; Criner, G.; Sethi, S.; Rayapudi, S.; Sudini, K.R.; Sugar, E.A.; Burke, A.; Thimmulappa, R.; Singh, A.; et al. Lack of Effect of Oral Sulforaphane Administration on Nrf2 Expression in COPD: A Randomized, Double-Blind, Placebo Controlled Trial. PLoS ONE 2016, 11, e0163716. [Google Scholar] [CrossRef][Green Version]
  296. Duran, C.G.; Burbank, A.J.; Mills, K.H.; Duckworth, H.R.; Aleman, M.M.; Kesic, M.J.; Peden, D.B.; Pan, Y.; Zhou, H.; Hernandez, M.L. A proof-of-concept clinical study examining the NRF2 activator sulforaphane against neutrophilic airway inflammation. Respir. Res. 2016, 17, 89. [Google Scholar] [CrossRef][Green Version]
  297. Sudini, K.; Diette, G.B.; Breysse, P.N.; McCormack, M.C.; Bull, D.; Biswal, S.; Zhai, S.; Brereton, N.; Peng, R.D.; Matsui, E.C. A Randomized Controlled Trial of the Effect of Broccoli Sprouts on Antioxidant Gene Expression and Airway Inflammation in Asthmatics. J. Allergy Clin. Immunol. Pract. 2016, 4, 932–940. [Google Scholar] [CrossRef][Green Version]
  298. Khattak, S.; Zhang, Q.Q.; Sarfraz, M.; Muhammad, P.; Ngowi, E.E.; Khan, N.H.; Rauf, S.; Wang, Y.Z.; Qi, H.W.; Wang, D.; et al. The Role of Hydrogen Sulfide in Respiratory Diseases. Biomolecules 2021, 11, 682. [Google Scholar] [CrossRef]
  299. Schiliro, M.; Bartman, C.M.; Pabelick, C. Understanding hydrogen sulfide signaling in neonatal airway disease. Expert Rev. Respir. Med. 2021, 15, 351–372. [Google Scholar] [CrossRef]
  300. Kimura, Y.; Goto, Y.; Kimura, H. Hydrogen sulfide increases glutathione production and suppresses oxidative stress in mitochondria. Antioxid. Redox Signal. 2010, 12, 1–13. [Google Scholar] [CrossRef]
  301. Jia, G.; Yu, S.; Sun, W.; Yang, J.; Wang, Y.; Qi, Y.; Chen, Y. Hydrogen Sulfide Attenuates Particulate Matter-Induced Emphysema and Airway Inflammation Through Nrf2-Dependent Manner. Front. Pharmacol. 2020, 11, 29. [Google Scholar] [CrossRef]
  302. Guan, R.; Wang, J.; Cai, Z.; Li, Z.; Wang, L.; Li, Y.; Xu, J.; Li, D.; Yao, H.; Liu, W.; et al. Hydrogen sulfide attenuates cigarette smoke-induced airway remodeling by upregulating SIRT1 signaling pathway. Redox Biol. 2020, 28, 101356. [Google Scholar] [CrossRef]
  303. Bazhanov, N.; Ansar, M.; Ivanciuc, T.; Garofalo, R.P.; Casola, A. Hydrogen Sulfide: A Novel Player in Airway Development, Pathophysiology of Respiratory Diseases, and Antiviral Defenses. Am. J. Respir. Cell Mol. Biol. 2017, 57, 403–410. [Google Scholar] [CrossRef] [PubMed]
  304. Sun, Y.; Wang, K.; Li, M.X.; He, W.; Chang, J.R.; Liao, C.C.; Lin, F.; Qi, Y.F.; Wang, R.; Chen, Y.H. Metabolic changes of H2S in smokers and patients of COPD which might involve in inflammation, oxidative stress and steroid sensitivity. Sci. Rep. 2015, 5, 14971. [Google Scholar] [CrossRef] [PubMed]
  305. Liao, W.; Lim, A.Y.H.; Tan, W.S.D.; Abisheganaden, J.; Wong, W.S.F. Restoration of HDAC2 and Nrf2 by andrographolide overcomes corticosteroid resistance in chronic obstructive pulmonary disease. Br. J. Pharmacol. 2020, 177, 3662–3673. [Google Scholar] [CrossRef] [PubMed]
  306. Li, J.J.; Tay, H.L.; Maltby, S.; Xiang, Y.; Eyers, F.; Hatchwell, L.; Zhou, H.; Toop, H.D.; Morris, J.C.; Nair, P.; et al. MicroRNA-9 regulates steroid-resistant airway hyperresponsiveness by reducing protein phosphatase 2A activity. J. Allergy Clin. Immunol. 2015, 136, 462–473. [Google Scholar] [CrossRef] [PubMed]
  307. Khorasani, N.; Baker, J.; Johnson, M.; Chung, K.F.; Bhavsar, P.K. Reversal of corticosteroid insensitivity by p38 MAPK inhibition in peripheral blood mononuclear cells from COPD. Int. J. Chronic Obstr. Pulm. Dis. 2015, 10, 283–291. [Google Scholar] [CrossRef][Green Version]
Figure 1. Effects of oxidative stress on airway inflammation. Environmental allergens, cigarette smoke, pollution, and pathogens interact with the airway epithelium, leading to increases in exogenous or endogenous reactive oxygen and nitrogen species (RONS) levels and contributing to the pathogenesis of asthma and COPD. In response, the airway epithelium generates superoxide (O2) and nitric oxide (NO) and releases ATP and IL-33. Similarly, airway smooth muscle (ASM) release pro-inflammatory mediators such as CXCL8 and superoxide. In addition to loss in barrier integrity, the airway epithelium exhibits mucous cell metaplasia. ASM becomes hypercontractile and proliferates, leading to hypercontractility and airway thickening. Further, inflammatory cells such as eosinophils and neutrophils release eosinophilic peroxidase (EPO) and myeloperoxidase (MPO), respectively, in response to increased intracellular oxidative stress. EPO and MPO further contribute to increases in airway oxidative stress by generating hydrogen peroxide (H2O2). Increased iNOS activity in macrophages also contributes to RONS and the release of inflammatory mediators. The activity of antioxidant mechanisms, such as the glutathione (GSH) system and superoxide dismutase (SOD), are dysfunctional and are found to be reduced in airway epithelial cells in severe asthma and COPD, further enhancing oxidative stress and airway inflammation. Created with “”. () denotes increased levels and () denotes decreased levels.
Figure 1. Effects of oxidative stress on airway inflammation. Environmental allergens, cigarette smoke, pollution, and pathogens interact with the airway epithelium, leading to increases in exogenous or endogenous reactive oxygen and nitrogen species (RONS) levels and contributing to the pathogenesis of asthma and COPD. In response, the airway epithelium generates superoxide (O2) and nitric oxide (NO) and releases ATP and IL-33. Similarly, airway smooth muscle (ASM) release pro-inflammatory mediators such as CXCL8 and superoxide. In addition to loss in barrier integrity, the airway epithelium exhibits mucous cell metaplasia. ASM becomes hypercontractile and proliferates, leading to hypercontractility and airway thickening. Further, inflammatory cells such as eosinophils and neutrophils release eosinophilic peroxidase (EPO) and myeloperoxidase (MPO), respectively, in response to increased intracellular oxidative stress. EPO and MPO further contribute to increases in airway oxidative stress by generating hydrogen peroxide (H2O2). Increased iNOS activity in macrophages also contributes to RONS and the release of inflammatory mediators. The activity of antioxidant mechanisms, such as the glutathione (GSH) system and superoxide dismutase (SOD), are dysfunctional and are found to be reduced in airway epithelial cells in severe asthma and COPD, further enhancing oxidative stress and airway inflammation. Created with “”. () denotes increased levels and () denotes decreased levels.
Antioxidants 10 01335 g001
Figure 2. Reactive Oxygen Nitrogen Species (RONS) and Glucocorticoid receptor (GR) Signaling. The activation of pro-inflammatory signaling pathways (Tumor necrosis factor Receptor (TNFR), Toll-like Receptor, and Cytokine Receptors) leads to increases in RONS production in mitochondria and cytosol. Posttranslational modification such as acetylation and phosphorylation affect GR and HDAC2 activity, leading to augmented pro-inflammatory responses. Dashed arrows represent decreased activity and function. The figure was adapted from “B Regulatory Cell Surface Receptor Influences IL-10-mediated Immune Tolerance” (2021). Retrieved from (accessed on 27 July 2021).
Figure 2. Reactive Oxygen Nitrogen Species (RONS) and Glucocorticoid receptor (GR) Signaling. The activation of pro-inflammatory signaling pathways (Tumor necrosis factor Receptor (TNFR), Toll-like Receptor, and Cytokine Receptors) leads to increases in RONS production in mitochondria and cytosol. Posttranslational modification such as acetylation and phosphorylation affect GR and HDAC2 activity, leading to augmented pro-inflammatory responses. Dashed arrows represent decreased activity and function. The figure was adapted from “B Regulatory Cell Surface Receptor Influences IL-10-mediated Immune Tolerance” (2021). Retrieved from (accessed on 27 July 2021).
Antioxidants 10 01335 g002
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Lewis, B.W.; Ford, M.L.; Rogers, L.K.; Britt, R.D., Jr. Oxidative Stress Promotes Corticosteroid Insensitivity in Asthma and COPD. Antioxidants 2021, 10, 1335.

AMA Style

Lewis BW, Ford ML, Rogers LK, Britt RD Jr. Oxidative Stress Promotes Corticosteroid Insensitivity in Asthma and COPD. Antioxidants. 2021; 10(9):1335.

Chicago/Turabian Style

Lewis, Brandon W., Maria L. Ford, Lynette K. Rogers, and Rodney D. Britt, Jr. 2021. "Oxidative Stress Promotes Corticosteroid Insensitivity in Asthma and COPD" Antioxidants 10, no. 9: 1335.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop