Next Article in Journal
Thermogenic Adipose Redox Mechanisms: Potential Targets for Metabolic Disease Therapies
Previous Article in Journal
Nootkatone Supplementation Ameliorates Carbon Tetrachloride-Induced Acute Liver Injury via the Inhibition of Oxidative Stress, NF-κB Pathways, and the Activation of Nrf2/HO-1 Pathway
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Antioxidants
Volume 12
Issue 1
10.3390/antiox12010195
antioxidants-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Oxidative Stress and Antioxidants in Chronic Rhinosinusitis with Nasal Polyps

by
Junhu Tai
1,
Jae-Min Shin
1,
Jaehyung Park
1,
Munsoo Han
1,2 and
Tae Hoon Kim
1,2,*
1
Department of Otorhinolaryngology—Head & Neck Surgery, College of Medicine, Korea University, Seoul 02841, Republic of Korea
2
Mucosal Immunology Institute, College of Medicine, Korea University, Seoul 02841, Republic of Korea
*
Author to whom correspondence should be addressed.
Antioxidants 2023, 12(1), 195; https://doi.org/10.3390/antiox12010195
Submission received: 7 December 2022 / Revised: 10 January 2023 / Accepted: 12 January 2023 / Published: 14 January 2023
Browse Figures
Versions Notes

Abstract

:
Oxidative stress results from an imbalance between the production of reactive oxygen species and the body’s antioxidant defense system. It plays an important role in the regulation of the immune response and can be a pathogenic factor in various diseases. Chronic rhinosinusitis (CRS) is a complex and heterogeneous disease with various phenotypes and endotypes. Recently, an increasing number of studies have proposed that oxidative stress (caused by both environmental and intrinsic stimuli) plays an important role in the pathogenesis and persistence of CRS. This has attracted the attention of several researchers. The relationship between the presence of reactive oxygen species composed of free radicals and nasal polyp pathology is a key topic receiving attention. This article reviews the role of oxidative stress in respiratory diseases, particularly CRS, and introduces potential therapeutic antioxidants that may offer targeted treatment for CRS.

1. Introduction

Oxidative stress can be defined as an imbalance between the production and degradation of reactive oxygen species (ROS) [1]. In the process of generating energy through aerobic respiration, humans and other mammals produce a variety of ROS [2], such as hydrogen peroxide and superoxide anions. Excess ROS can be eliminated through the action of various enzymes, including that of superoxide dismutase (SOD), catalase, and other components, to be maintained within the normal range. However, under oxidative stress, excessive ROS levels cause cell damage through interactions with proteins, lipids, and nucleic acids, thereby negatively affecting the function and structure of tissues [3]. Various physiological and pathological conditions have been related to oxidative stress; the failure of the antioxidant system and an increased production of ROS have been linked with obesity, aging, and some mucosal diseases [4]. Recently, the impact of oxidative stress on the human mucosal system has received increasing attention from researchers, especially with regard to respiratory mucosa. Studies have shown that the house dust mite can induce ROS production while inhibiting antioxidant responses in bronchial epithelial cells [5]. In asthma cases, ROS play a key role in the persistence and amplification of airway inflammation and promote mucus hypersecretion, increased vascular permeability, and airway remodeling [6]. In addition to their impact on the lower airway, ROS also have a variety of effects on the nasal mucosa of the upper airway. The nasal submucosal gland is a source of multiple molecules that are important for mucosal host defense [7]. Oxidative stress may play a crucial role in causing the dysfunction or impairment of the nasal epithelial barrier [8]. Chronic sinusitis (CRS) is a disease that stems from a variety of pathogenic factors. Among its common causes are environmental stimuli (such as pollution); viral, fungal, or bacterial infection; smoking; or physiological factors, such as genetic predisposition and immunodeficiency [9]. Patients with CRSwNP suffer from a variety of distressing symptoms, including nasal congestion, decreased or lost sense of smell, rhinorrhea, posterior rhinorrhea, and facial pressure or pain [10]. As a result of the shared type 2 inflammatory pathway, patients with CRSwNP often have comorbid asthma and/or nonsteroidal anti-inflammatory drug-exacerbated respiratory disease, which lead to the need for repeated treatment with corticosteroids and/or sinonasal surgeries to alleviate their uncontrolled symptoms [11,12]. However, the treatment often fails to achieve satisfactory results, which means that it is urgent to find new causes and treatments for CRSwNP. The treatment options of CRSwNP include medical or surgical therapy, and biological agents have been approved or subject to recent clinical trials, but no antioxidant has been approved to treat CRSwNP yet [13]. The antioxidant capacity of the human respiratory mucosa plays an important role in the etiology of CRS, especially CRS with nasal polyps (CRSwNP) [14]. Key factors in the innate defense mechanism of the upper respiratory tract include SOD, peroxiredoxin-2 [15], bactericidal/permeability-increasing fold-containing family A member 1 (BPIFA1) [16], and adenylate-cyclase-activating polypeptide receptor 1 (ADCYAP1) [17,18].
With the implications of ROS being known to the public, people have very high expectations for the provision of antioxidants that can prevent ROS generation. Antioxidant-rich nutrients are generally used as supplements to reduce the damage caused by ROS [19]. Recent studies regarding the role of antioxidants in CRS, especially CRSwNP, have confirmed acceptable results in this regard. For example, a study involving 32 patients with CRS established that local treatment with antioxidants had a better effect on accelerating the recovery of patients’ nasal sinus mucosa after surgery than other conventional topical treatments [20]. This review discusses the role of oxidative stress in respiratory diseases, especially CRS. We also highlight potential antioxidants that may be used to treat CRS as indicated by the latest research.
The study searched PubMed, Web of Science, and Scopus, using a combination of the following search terms (in Title/Abstract): “chronic rhinosinusitis”, “oxidative stress”, and “antioxidant”. This review did not limit the types of research included. Basic research and clinical research are both included. The inclusion criteria include articles exploring the relationship between CRSwNP, oxidative stress, and antioxidants through basic or clinical research published in English between 1992 and 2022. Moreover, there are no restrictions on the types of articles. Article types, such as review, original research, letters, communications, and editorials, are all included in this review, and only some articles for which full text was unavailable were excluded. All selected articles have been imported into EndNote, which will intelligently delete duplicate articles.

2. Oxidative Stress in Respiratory Diseases

The respiratory system is vulnerable to oxidative stress owing to its complex conductive airways and large alveolar surface area [21,22]. Airway oxidative stress is widely defined as an imbalance between the pro-oxidant and antioxidant processes in the airways [23]. The main pathogenic factors causing diseases comprise infection and inflammation, protease and antiprotease imbalances, and oxidative stress overwhelming the body’s antioxidant defenses [24]. Increased lung oxidative stress in respiratory diseases may occur due to heightened levels of exogenous or endogenous oxidants, or due to a reduction in endogenous antioxidants (Table 1). Exogenous oxidants include air pollution, tobacco smoke, biomass smoke, allergens, particulate matter, and fine particulate matter (<10 μ, <2.5 μ, <0.1 μ in diameter) [25,26]. Endogenous oxidants include hydrogen peroxide, peroxynitrite, xanthine oxidase, superoxide anions, mitochondrial oxidants, and myeloperoxidase [27,28]. Antioxidants that may experience reduced levels in the body include thioredoxin, nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione, forkhead box protein, vitamins, and SOD [29,30]. Oxidative stress drives respiratory diseases through several mechanisms, including activation of the proinflammatory transcription factor nuclear factor-κB (NF-κB) pathway, generation of autoantibodies to carbonylated proteins, reduced expression of sirtuin-1, DNA damage, reduced activity of antiproteases, and increased release of transforming growth factor-beta [31].
The respiratory tract is a direct window of contact with the external environment. Pollutants or toxic substances, such as nitrogen dioxide, sulfur dioxide, and particulate matter in the air, may cause asthma symptoms [32], and these substances are more or less related to oxidative stress. There is evidence that oxidative stress is a prevalent factor in asthma [33,34]. An antioxidative–prooxidative imbalance may lead to pathological changes in the respiratory epithelial cells, and other disease states (such as airway hyperresponsiveness) and defects in the intracellular antioxidant defense system may contribute to asthma development [35]. Methods for detecting oxidative stress-related biomarkers in asthma comprise tests of the exhaled condensate, bronchoalveolar fluid, systemic circulation, and urine as well as experimental detection (Table 2).
Exhaled breath condensates and bronchial fluid detection are airway-related methods for detecting several biomarkers related to oxidative stress [36,37]. It was found that the concentrations of hydrogen ions, hydrogen peroxide, nitric oxide, and 8-isoprostane in the breath of patients with asthma were generally higher than those in healthy controls, and these results were easily detected in patients with severe asthma [38]. A review of 46 studies also revealed that changes in the concentrations of hydrogen ions, hydrogen peroxide, and nitric oxide in exhaled air were related to the deterioration of allergic asthma in children [39]. The level of glutathione determines whether the T helper type-1 (Th1) or type-2 (Th2) immune response mode is dominant, with glutathione depletion being conducive to Th2-related reactions [40]. Acute asthma attacks lead to a decrease in the glutathione levels in children’s exhaled breath condensates, and these levels increase after steroid treatment [41]. A study that analyzed the role of oxidants in human lung injury found that the baseline levels of 3-bromotyrosine in bronchoalveolar fluid proteins from individuals with mild allergic asthma were slightly higher than those in a control group; after exposure to the segmental allergen challenge, the 3-bromotyrosine content in the bronchoalveolar fluid of these individuals increased by more than 10-fold [42]. Catalase enzyme is another key antioxidant. Its activity in the bronchoalveolar lavage fluid of asthmatic patients is lower than that in healthy controls, with a similar observation having been made in animal experiments [43].
One study evaluated the various components of enzymatic and non-enzymatic antioxidants using ELISA to evaluate the levels of glutathione peroxidase and SOD enzymes in patients’ blood and using high-performance liquid chromatography to measure reductions in the levels of glutathione [44]; the glutathione peroxidase and SOD levels were significantly low in children with asthma. Another study involving 57 asthmatic and 38 healthy participants investigated asthma-related markers via noninvasive methods. Urinary levels of bromotyrosine and F2-isoprostane increased in asthmatic patients, indicating that these compounds may be associated with asthma [45]. As for experimental detection, researchers found that a redox thiol/dithiol imbalance alters copper-zinc SOD levels in the cells of asthmatic patients and that copper-zinc SOD was easily inactivated by hydrogen peroxide [46]. In a mouse model of asthma, copper-zinc SOD transgenic mice exhibited less airway inflammation and hyper-reactivity [47].
The inhalation of pollutants increases the oxidative load in individuals with asthma, and oxidative damage of the airway epithelium along with activation of innate immune mechanisms lead to allergic sensitization and inflammation. In addition, the intracellular redox imbalance causes a disruption of signaling cascades and cellular responses, thus increasing the airway inflammation and promoting airway remodeling and hyperresponsiveness [48]. Researchers have used N-acetylcysteine to remove excess ROS and promote endogenous antioxidant mechanisms. It successfully reduced airway inflammation and hyperresponsiveness in animal models of asthma, similarly reducing airway hyperresponsiveness in healthy human subjects and patients exposed to diesel exhaust particles [49,50]. In other studies, however, antioxidant treatments had no effect on asthmatic symptoms. Sulforaphane plays a key role in preventing oxidative stress and inflammation [51]. A double-blind, randomized trial involving 40 adults compared the effects of sulforaphane on airway inflammation and oxidative stress [52]. In contrast to what was expected, the sulforaphane intake did not improve any clinical features of pulmonary inflammation, oxidative stress biomarkers, or asthma atopy. Studying the interaction between currently available asthma and antioxidant treatments (focusing, for example, on the interaction between corticosteroids and ROS) may help in developing novel therapeutic interventions. Corticosteroid treatment is related to a reduction in airway oxidative stress in patients with asthma [53]. However, long-term corticosteroid treatment can lead to mitochondrial dysfunction, which leads to ROS-mediated cardiovascular, metabolic, and other complications [54,55]. Although the treatment of oxidative stress has great potential in assisting with asthma therapy, only a few studies have achieved success in this regard, with most research failing to uncover obvious benefits.
We previously reviewed the effects of oxidative stress and antioxidants on allergic rhinitis, which, similar to asthma, is regarded as a united airways disease. We introduced transcription factors, such as Nrf2 and NF-κB, in a mouse model of allergic rhinitis and in nasal mucosa epithelial cells of patients with allergic rhinitis. Several possible therapeutic antioxidants, such as sulforaphane, resveratrol, and taurine, were also tested, with the latter showing promising results through inhibiting oxidative stress markers [56]. In the following section, we will introduce the role of oxidative stress and antioxidants in CRS, another united airway disease [57].

3. CRS and Oxidative Stress

3.1. Endotype and Phenotype of CRS

CRS can be classified into type 2 and non-type 2 CRS, based on the differences in immune responses between Th1/Th17 and Th2 cells [58]. Previous studies have concluded that CRS without nasal polyps (CRSsNP) shows neutrophilic predominance, whereas CRSwNP exhibits eosinophilic predominance [59]. However, contrary to these findings for European and American patients, most Asian patients with CRSwNP possessed neutrophil predominance, and CRSsNP showed an immune response favoring type 2 CRS and type 1 or 3 inflammation [60]. As illustrated in Figure 1, type 2 CRS is characterized by epithelial cell disorder and elevated levels of Th2 cells (which produce interleukin (IL)-4, IL-5, and IL-13 cytokines), B cells, dendritic cells, and eosinophils [61,62]. The nasal sinus epithelium is the main source of thymic stromal lymphopoietin, which plays a key role in type 2 inflammation by activating Th2 cells and group 2 innate lymphoid cells [63]. IL-5 promotes eosinophil inflammation, whereas IL-4 and IL-13 activate homotypic transformation and mucus production in CRSwNP [61]; B cells produce IgE and other immunoglobulins [62]. It has also been reported that the levels of type 2 inflammatory cytokines IL-25 and IL-33 originating from other epithelial sources are increased in type 2 CRS [64]. Unlike type 2 CRS, non-type 2 CRS is associated with a significant increase in Th1/Th17 cells, corresponding with elevated levels of interferon (IFN)-γ, IL-8, and IL-17 cytokines [65]. IL-6, IL-8, and tumor necrosis factor stimulate the production of IFN- γ and further IL-8 by T cells to strengthen the immune response; IL-8 recruits neutrophils into this region, which release more cytokines, and the epithelial response to environmental stimuli leads to the activation of dendritic cells, thereby inducing the differentiation of Th1 and Th17 cells [66]. According to its phenotype, CRS is currently classified as either expressing or lacking nasal polyps (NPs) [67]. Of the two, CRSwNP is usually accompanied by a dysfunction of the nasal mucosal fibers responsible for mucus transportation and self-cleaning, which leads to the inability of ciliated cells to lubricate the epithelium and remove impurities [68]. This change in the innate defense mechanism of the upper respiratory tract relates to the etiology of CRSwNP, with the antibacterial and antioxidant capacity of the tract showing a gradual decline as CRSwNP progresses [69]. Along with the decline in antioxidant capacity, oxidative stress plays a crucial role in the pathogenesis of CRSwNP [70,71].

3.2. Oxidative Stress in Chronic Sinusitis with NPs

Exogenous factors that induce oxidative stress in CRS (as they do in other respiratory diseases) include tobacco smoke, allergens, and fine particulate matter [72,73]. These exogenous oxidants can reduce the permeability of airway epithelial cells and destroy the nasal sinus epithelial barrier [74], ultimately inducing oxidative stress (Figure 2). Inflammatory chemokines play a key role in coordinating inflammation [75] and are regulated by redox reactions [76]. Eotaxin-1, a member of the CC chemokine family, induces eosinophil recruitment and activation. One study observed eotaxin immunoreactivity in epithelial and endothelial cells of NPs [77]. Another study showed that eotaxin-1 plays a key role in the selective recruitment of eosinophils in NPs [78]. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase produces ROS that are involved in oxidative stress and signal transduction [79]. A recent study evaluated the expression of the NADPH oxidase subunit p67phox and the oxidative stress marker 4-hydroxy-2-nonenal (4-HNE) in NP tissues of 13 patients with CRSwNP and the nasal mucosae of nine healthy controls. The expression levels of both were significantly higher in NP tissues than those in healthy mucosae [80], confirming that lipid peroxidation occurred in NP tissues. Thioredoxin-interacting protein (TXNIP) is a multifunctional protein that can also increase ROS production and induce oxidative stress by inhibiting the activity of thioredoxin, an antioxidant [81]. One study confirmed that TXNIP expression is upregulated in patients with CRSwNP, indicating the protein’s key role in the pathogenesis of CRSwNP [82]. Heme oxygenase (HO)-1 has been proposed to be a cytoprotective enzyme against oxidative stress in CRSwNP [23]. In a study involving 40 patients with CRSwNP and 20 healthy controls, the expression levels of HO-1 mRNA and proteins were significantly higher in the NPs of the patients than those in the nasal mucosae of controls [83]. Scavenger receptors recognize various wastes and foreign materials invading the human body and usually counteract the generation of ROS induced by environmental toxins [84]. Lectin-like oxidized LDL receptor-1 (LOX-1) is one such scavenger receptor, and its expression is induced by oxidative stress [85]. LOX-1 mRNA expression was significantly higher in patients with CRSwNP than that in healthy controls of one study [86], emphasizing its crucial role in the redox regulation of CRSwNP.
ROS cause neutrophil activation, which can upregulate the expression of genes to release their corresponding proteins. Many of these genes depend on the activation of transcription factors, such as NF-κB, to induce expression. NF-κB activation may be the basis for the effect of pro-inflammatory stimulation of human neutrophil gene expression [87]. The growth of NPs is also closely related to the effects of various cytokines [88], and NF-κB is one of the most important factors related to the production of cytokines during inflammation. One study analyzed the expression of NF-κB, associated inflammatory cytokines, and adhesion molecules in patients with CRSwNP [89]. NPs of a CRSwNP group possessed a significantly higher number of NF-κB p65-positive cells and higher mRNA expression levels of IL-6, IL-8, and eotaxin than uncinate tissues of the control and CRSsNP groups. Nrf2 acts as the key regulator of oxidation and environmental stress by translocating to the cell nucleus and promoting the expression of genes that produce a cell protective response [90]. Nasal sinus mucosal barrier function and tight junctions that had been destroyed by particulate matter could be restored via Nrf2 administration, indicating that activation of the Nrf2 pathway may be a potential therapeutic target for CRS [91]. Another study also showed that the barrier dysfunction of nasal sinus epithelial cells induced by cigarette smoke can be reversed through Nrf2 activation [92].
In addition to the above oxidative stress reactions related to CRSwNP, the following have been noted. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a multi-polymer serine-threonine kinase [93]. The normal activation of CaMKII triggers the exchange of subunits between these holoenzymes, but the increased activation of CaMKII via ROS [94,95] may lead to inflammation and other diseases. The kynurenine/AhR axis mediates mast cell activation through oxidative CaMKII in the pathogenesis of CRSwNP [96]. More in-depth research is needed to clarify the correlation between the kynurenine/AhR axis and CRSwNP-related oxidative stress.
The mucosal surface is protected by many antibacterial factors, such as lactoperoxidase, which creates an inhibitory action on bacteria through the production of ROS [97]. Lactoperoxidase requires H2O2 to oxidize thiocyanate, thus producing hypothiocyanite [98]. Another key process in epithelial defense is the regulation of dual oxygenase (DUOX) expression and function [99]. A study exploring the correlation between DUOX1 expression and inflammatory mediators in CRS [100] found that DUOX1 mRNA levels were significantly increased in patients with CRSwNP compared to those in healthy individuals or patients with CRSsNP. In fact, both the CRSwNP and CRSsNP groups exhibited higher DUOX2 mRNA levels than the control group. The H2O2 content was significantly high in patients with CRSwNP, with H2O2 levels in their nasal secretions being closely related to the expression level of DUOX. These nasal secretions similarly exhibited relatively high levels of cytokines, such as eotaxin, tumor necrosis factor-α, and IL-8. This study demonstrated that ROS generate an overexpression of DUOX1 and DUOX2 in patients with CRSwNP, and the authors postulated that DUOX1 and DUOX2 are key factors in innate defense signal transduction and nasal mucosal inflammation in the human nasal airway epithelium.
Edema is an important histological process in the pathogenesis of CRSwNP. Activated inflammatory cells and their secreted mediators cause tissue inflammation and edema and the waste of this chronic inflammatory process comprises free radicals that cause oxidative stress [101]. However, their exact role and impact on CRSwNP progression remain unclear. A study involving 24 patients with CRSwNP and 20 healthy controls investigated the impact of oxidative status on the severity of CRSwNP and associated quality of life parameters [102]. Oxidative stress level (measured as the total antioxidant status and nitric level) was significantly related to the degree of nasal congestion and disease severity. Another study compared the concentrations of malondialdehyde, SOD, and nitric oxide in healthy and NP tissue samples [70]. Compared to the control tissues, NP samples contained a significantly higher level of malondialdehyde and lower levels of SOD and nitric oxide. Malondialdehyde is the main end product of lipid peroxidation [103], while SOD and nitric oxide are key antioxidants [104]. This demonstrated a close correlation between oxidative stress and the pathogenesis of NPs.
In terms of antioxidant enzymes, the genetic expression of peroxiredoxin-2 (PRDX2), BPIFA1, and ADCYAP1 is crucial to the innate defense mechanism of the upper respiratory tract, in addition to that of SOD [69]. In a study performed in 2006, the levels of ADCAP1, BPIFA1, and SOD proteins were found to be differentially expressed in NPs of Chinese patients with CRSwNP and refractory CRSwNP, suggesting that the reduced expression levels of their genes may be related to the pathogenesis of CRSwNP [105]. In addition, a recent study reported that ADCYAP1, BPIFA1, and PRDX2 were differentially expressed in the nasal mucosa of Caucasian patients with CRSwNP [69], confirming that the differential expression of these genes reduced the antioxidant capacity in patients with CRSwNP. And it has been reported that PRDX2 is related to the severity of asthma, which is the one of the main clinical problems of CRSwNP [106]. Although the same study found that surgery and long-term local corticosteroid treatment can reverse the expression of the above target genes, these procedures can only partially alleviate the decline in the antioxidant capacity of the nasal mucosa, and there are still shortcomings in re-establishing normal SOD homeostasis. Moreover, several surgeries also represent one of the main clinical problems faced by patients with CRSwNP, and surgical treatment should not be a routine choice. It is necessary to determine the specific mechanisms underlying transcriptional and steroid-induced changes that affect the antioxidant capacity of nasal mucosa. There is evidence that the phosphatase and tensin homolog gene (PTEN) can inhibit the activation of phosphoinositide 3-kinase (PI3K), which in turn affects the phosphorylation of protein kinase B (Akt) [107]. The PI3K/PTEN/Akt signaling pathway regulates cell growth, apoptosis, proliferation, and metabolism [108] and is associated with various chronic inflammatory and autoimmune diseases [109]. An in vitro study investigated the role of PTEN in nasal epithelial cells under oxidative stress and the correlation between PTEN and the PI3K/Akt pathway [110]. Mouse nasal epithelial cells were treated with H2O2 to induce oxidative stress and create a cell damage model. In the cells injured by H2O2, oxidative stress was induced due to an increase in ROS levels and corresponding apoptosis, and, notably, this damage was aggravated by PTEN. The studies of oxidative stress and antioxidants related to CRSwNP are summarized in Table 3, and the biomarkers of oxidative stress and antioxidants related to CRSwNP are summarized in Table 4.

3.3. Therapeutic Antioxidants in Chronic Rhinosinusitis with NPs

Oxidative stress plays an important role in the pathogenesis of NPs. High levels of free radical-mediated lipid peroxidation metabolites have been observed in and is related to the severity of NPs [112,113]. Based on the impact of oxidative stress in the occurrence and development of CRSwNP, researchers have explored the feasibility of various antioxidants in the treatment of this disease, including flavones, resveratrol, and terpenoids (Table 5).
Flavones have proven antioxidant and anti-inflammatory effects [119,120]. Hariri et al. [110] found that several flavones such as apigenin inhibit the upregulation of Muc5AC and inducible nitric oxide synthase while also inhibiting the release of cytokines, such as IL-8. These effects resulted in an increase in the ciliary beating and mucociliary clearance of airway cells, supporting the clinical potential of flavones as therapeutic options for CRSwNP. Another candidate is resveratrol, which is a natural product extracted from a Peruvian legume plant that strongly inhibits cyclooxygenase, contributes to cancer prevention, and provides cardiovascular protection, among other beneficial effects [121,122]. Kim et al. used an eosinophilic CRSwNP mouse model to test the therapeutic effect of resveratrol, comparing it to that of triamcinolone acetonide; resveratrol significantly reduced eosinophil infiltration and the degree of subepithelial fibrosis in the nasal mucosa of mice, similar to the effect of triamcinolone acetonide [111]. Moreover, the expression levels of IL-4, IL-5, prostaglandin D synthase, and leukotriene C4 synthase were significantly reduced by resveratrol treatment, and high doses of resveratrol strongly inhibited the production of 5-lipoxygenase. These results demonstrate that resveratrol can prevent and treat eosinophilic CRSwNP through its antioxidant and anti-inflammatory effects. Nitric oxide is released in the nose and sinuses and is related to upper respiratory tract diseases. In allergic rhinitis, CRSsNP, and CRSwNP, the concentration of nitric oxide changes and is considered an indicator of disease severity [123]. Endothelial nitric oxide synthase (eNOS) plays an important role in vascular permeability, edema, and inflammation, and CRSwNP has been shown to increase eNOS phosphorylation [116]. 1,8-Cineol is a natural monoterpene with anti-inflammatory and antioxidant properties [124]. Researchers have found that 1,8-cineol significantly affects eNOS phosphorylation (and thereby, its subsequent activation), indicating that terpenoid antioxidation may have an effect on the treatment of CRSwNP. Quercetin is another bioactive compound with strong antioxidant activity that has been extensively studied [125]. It significantly increases trans-epithelial Cl− transport and ciliary beat frequency in mouse and human nasal airway cells, demonstrating the feasibility of using quercetin for local administration to nasal sinuses [117]. Another treatment option is erdosteine, a drug that has already been approved for the treatment of acute and chronic lung diseases and was originally developed as a mucus-dissolving agent. It has antioxidant, anti-inflammatory, and antibacterial properties and can prevent or reduce the lung tissue damage caused by oxidative stress by regulating ROS production [126]. One study evaluated the efficacy of erdosteine in the treatment of CRSwNP and found that both the endoscopic results and questionnaire survey values of patients with CRSwNP improved after erdosteine treatment, relative to those of a control group. This confirms the feasibility of using erdosteine as an effective substitute for current drugs [118].

4. Conclusions

We reviewed the literature describing the effect of oxidative stress on CRSwNP and summarized several promising antioxidants for the treatment of CRSwNP. However, the current use of antioxidants in patients with CRSwNP is still limited, and there is a lack of evidence. In addition, there are obstacles and limitations in terms of research into antioxidant treatments, such as the small number of clinical cases and short research time. Now, there are many antioxidants for researchers to assess efficacy. The key is that this needs to be carried out in a multi-center, multi-population, and multi-stage study. In a word, further in-depth research is required to prove and support the development of antioxidants for CRS treatment.

Author Contributions

Writing—original draft preparation; corrections after review: J.T.; data curation: J.T. and J.-M.S.; methodology: J.P. and M.H.; review and editing: T.H.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Basic Science Research Program of the National Research Foundation, the Ministry of Science and Technology, and the Ministry of Science, ICT, and Future Planning of Korea (grant numbers 2017R1A2B2003575 and NRF-2020R1A2C1006398). The study was supervised by the Institute for Information and Communications Technology Planning and Evaluation and falls under the ICT Creative Consilience program (IITP-2023-2020-0-01819) of the Ministry of Science and ICT, Korea. Our research was further funded by the Korea Health Technology R&D Project (grant numbers HI17C0387 and HR22C1302) through the Korea Health Industry Development Institute, as administered by the Ministry of Health and Welfare. This research was finally funded by a Korea University grant and a grant from the Korea University Medical Center and Anam Hospital in Seoul, Republic of Korea.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Cachofeiro, V.; Goicochea, M.; de Vinuesa, S.G.; Oubiña, P.; Lahera, V.; Luño, J. Oxidative stress and inflammation, a link between chronic kidney disease and cardiovascular disease. Kidney Int. 2008, 74, S4–S9. [Google Scholar] [CrossRef] [Green Version]
  2. Pieczenik, S.R.; Neustadt, J. Mitochondrial dysfunction and molecular pathways of disease. Exp. Mol. Pathol. 2007, 83, 84–92. [Google Scholar] [CrossRef]
  3. Tartaglia, L.A.; Storz, G.; Ames, B.N. Identification and molecular analysis of oxyR-regulated promoters important for the bacterial adaptation to oxidative stress. J. Mol. Biol. 1989, 210, 709–719. [Google Scholar] [CrossRef]
  4. Szewczyk-Golec, K.; Czuczejko, J.; Tylzanowski, P.; Lecka, J. Strategies for Modulating Oxidative Stress under Diverse Physiological and Pathological Conditions. Oxid. Med. Cell. Longev. 2018, 2018, 3987941. [Google Scholar] [CrossRef] [Green Version]
  5. Wang, Y.; Bai, C.; Li, K.; Adler, K.B.; Wang, X. Role of airway epithelial cells in development of asthma and allergic rhinitis. Respir. Med. 2008, 102, 949–955. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Al-Harbi, N.O.; Nadeem, A.; Al-Harbi, M.M.; Ansari, M.A.; AlSharari, S.D.; Bahashwan, S.A.; Attia, S.M.; Al-Hosaini, K.A.; Al Hoshani, A.R.; Ahmad, S.F. Airway oxidative stress causes vascular and hepatic inflammation via upregulation of IL-17A in a murine model of allergic asthma. Int. Immunopharmacol. 2016, 34, 173–182. [Google Scholar] [CrossRef] [PubMed]
  7. Peden, D.B.; Brown, M.E.; Wade, Y.; Raphael, G.D.; Berkebile, C.; Kaliner, M.A. Human nasal glandular secretion of novel antioxidant activity: Cholinergic control. Am. Rev. Respir. Dis. 1991, 143, 545–552. [Google Scholar] [CrossRef] [PubMed]
  8. Hong, Z.; Guo, Z.; Zhang, R.; Xu, J.; Dong, W.; Zhuang, G.; Deng, C. Airborne Fine Particulate Matter Induces Oxidative Stress and Inflammation in Human Nasal Epithelial Cells. Tohoku J. Exp. Med. 2016, 239, 117–125. [Google Scholar] [CrossRef] [Green Version]
  9. Kennedy, D.W. Pathogenesis of chronic rhinosinusitis. Ann. Otol. Rhinol. Laryngol. 2004, 193, 6–9. [Google Scholar] [CrossRef] [PubMed]
  10. Bachert, C.; Bhattacharyya, N.; Desrosiers, M.; Khan, A.H. Burden of Disease in Chronic Rhinosinusitis with Nasal Polyps. J. Asthma Allergy 2021, 14, 127–134. [Google Scholar] [CrossRef]
  11. Fokkens, W.J.; Lund, V.; Bachert, C.; Mullol, J.; Bjermer, L.; Bousquet, J.; Canonica, G.W.; Deneyer, L.; Desrosiers, M.; Diamant, Z.; et al. EUFOREA consensus on biologics for CRSwNP with or without asthma. Allergy 2019, 74, 2312–2319. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Kim, D.W.; Cho, S.H. Emerging Endotypes of Chronic Rhinosinusitis and Its Application to Precision Medicine. Allergy Asthma Immunol. Res. 2017, 9, 299–306. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Tai, J.; Han, M.; Kim, T.H. Therapeutic Strategies of Biologics in Chronic Rhinosinusitis: Current Options and Future Targets. Int. J. Mol. Sci. 2022, 23, 5523. [Google Scholar] [CrossRef]
  14. Kao, S.S.; Bassiouni, A.; Ramezanpour, M.; Finnie, J.; Chegeni, N.; Colella, A.D.; Chataway, T.K.; Wormald, P.J.; Vreugde, S.; Psaltis, A.J. Proteomic analysis of nasal mucus samples of healthy patients and patients with chronic rhinosinusitis. J. Allergy Clin. Immunol. 2021, 147, 168–178. [Google Scholar] [CrossRef] [PubMed]
  15. Lu, W.; Fu, Z.; Wang, H.; Feng, J.; Wei, J.; Guo, J. Peroxiredoxin 2 is upregulated in colorectal cancer and contributes to colorectal cancer cells’ survival by protecting cells from oxidative stress. Mol. Cell. Biochem. 2014, 387, 261–270. [Google Scholar] [CrossRef]
  16. Britto, C.J.; Cohn, L. Bactericidal/Permeability-increasing protein fold-containing family member A1 in airway host protection and respiratory disease. Am. J. Respir. Cell Mol. Biol. 2015, 52, 525–534. [Google Scholar] [CrossRef] [Green Version]
  17. Yim, S.K.; Kim, K.M.; Lee, C.H.; Song, E.K.; Lee, S.O.; Kim, S.W.; Kim, I.H.; Kim, S.H.; Seo, S.Y.; Lee, S.T. The Superoxide Dismutase Mimetic M40403, Improves 5-Fluorouracil-induced Small Intestinal Mucositis in a Mouse Model. In Vivo 2021, 35, 1485–1497. [Google Scholar] [CrossRef]
  18. Bereswill, S.; Escher, U.; Grunau, A.; Kühl, A.A.; Dunay, I.R.; Tamas, A.; Reglodi, D.; Heimesaat, M.M. Pituitary Adenylate Cyclase-Activating Polypeptide-A Neuropeptide as Novel Treatment Option for Subacute Ileitis in Mice Harboring a Human Gut Microbiota. Front. Immunol. 2019, 10, 554. [Google Scholar] [CrossRef]
  19. Seifried, H.E.; Anderson, D.E.; Fisher, E.I.; Milner, J.A. A review of the interaction among dietary antioxidants and reactive oxygen species. J. Nutr. Biochem. 2007, 18, 567–579. [Google Scholar] [CrossRef]
  20. Testa, D.; Marcuccio, G.; Panin, G.; Bianco, A.; Tafuri, D.; Thyrion, F.Z.; Nunziata, M.; Piombino, P.; Guerra, G.; Motta, G. Nasal mucosa healing after endoscopic sinus surgery in chronic rhinosinusitis of elderly patients: Role of topic alpha-tocopherol acetate. Aging Clin. Exp. Res. 2017, 29, 191–195. [Google Scholar] [CrossRef]
  21. Arbex, M.A.; Santos Ude, P.; Martins, L.C.; Saldiva, P.H.; Pereira, L.A.; Braga, A.L. Air pollution and the respiratory system. J. Bras. Pneumol. 2012, 38, 643–655. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Santus, P.; Corsico, A.; Solidoro, P.; Braido, F.; Di Marco, F.; Scichilone, N. Oxidative stress and respiratory system: Pharmacological and clinical reappraisal of N-acetylcysteine. COPD J. Chronic Obstr. Pulm. Dis. 2014, 11, 705–717. [Google Scholar] [CrossRef] [PubMed]
  23. Holguin, F. Oxidative stress in airway diseases. Ann. Am. Thorac. Soc. 2013, 10, S150–S157. [Google Scholar] [CrossRef] [PubMed]
  24. Fischer, B.M.; Voynow, J.A.; Ghio, A.J. COPD: Balancing oxidants and antioxidants. Int. J. Chronic Obstr. Pulm. Dis. 2015, 10, 261–276. [Google Scholar] [CrossRef] [Green Version]
  25. Mehta, P.; Bothiraja, C.; Mahadik, K.; Kadam, S.; Pawar, A. Phytoconstituent based dry powder inhalers as biomedicine for the management of pulmonary diseases. Biomed. Pharmacother. 2018, 108, 828–837. [Google Scholar] [CrossRef]
  26. Gangwar, R.S.; Bevan, G.H.; Palanivel, R.; Das, L.; Rajagopalan, S. Oxidative stress pathways of air pollution mediated toxicity: Recent insights. Redox Biol. 2020, 34, 101545. [Google Scholar] [CrossRef]
  27. Hawkins, C.L.; Davies, M.J. Detection, identification, and quantification of oxidative protein modifications. J. Biol. Chem. 2019, 294, 19683–19708. [Google Scholar] [CrossRef] [Green Version]
  28. Ciencewicki, J.; Trivedi, S.; Kleeberger, S.R. Oxidants and the pathogenesis of lung diseases. J. Allergy Clin. Immunol. 2008, 122, 456–468. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  29. Hwang, J.W.; Rajendrasozhan, S.; Yao, H.; Chung, S.; Sundar, I.K.; Huyck, H.L.; Pryhuber, G.S.; Kinnula, V.L.; Rahman, I. FOXO3 deficiency leads to increased susceptibility to cigarette smoke-induced inflammation, airspace enlargement, and chronic obstructive pulmonary disease. J. Immunol. 2011, 187, 987–998. [Google Scholar] [CrossRef] [Green Version]
  30. Barnes, P.J.; Baker, J.; Donnelly, L.E. Cellular Senescence as a Mechanism and Target in Chronic Lung Diseases. Am. J. Respir. Crit. Care Med. 2019, 200, 556–564. [Google Scholar] [CrossRef]
  31. Barnes, P.J. Oxidative stress-based therapeutics in COPD. Redox Biol. 2020, 33, 101544. [Google Scholar] [CrossRef]
  32. Dozor, A.J. The role of oxidative stress in the pathogenesis and treatment of asthma. Ann. N. Y. Acad. Sci. 2010, 1203, 133–137. [Google Scholar] [CrossRef] [PubMed]
  33. 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] [PubMed]
  34. Dweik, R.A.; Comhair, S.A.; Gaston, B.; Thunnissen, F.B.; Farver, C.; Thomassen, M.J.; Kavuru, M.; Hammel, J.; Abu-Soud, H.M.; Erzurum, S.C. NO chemical events in the human airway during the immediate and late antigen-induced asthmatic response. Proc. Natl. Acad. Sci. USA 2001, 98, 2622–2627. [Google Scholar] [CrossRef] [Green Version]
  35. Kleniewska, P.; Pawliczak, R. The participation of oxidative stress in the pathogenesis of bronchial asthma. Biomed. Pharmacother. 2017, 94, 100–108. [Google Scholar] [CrossRef] [PubMed]
  36. Cepelak, I.; Dodig, S. Exhaled breath condensate: A new method for lung disease diagnosis. Clin. Chem. Lab. Med. 2007, 45, 945–952. [Google Scholar] [CrossRef]
  37. Araneda, O.F.; Carbonell, T.; Tuesta, M. Update on the Mechanisms of Pulmonary Inflammation and Oxidative Imbalance Induced by Exercise. Oxid. Med. Cell. Longev. 2016, 2016, 4868536. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  38. Aldakheel, F.M.; Thomas, P.S.; Bourke, J.E.; Matheson, M.C.; Dharmage, S.C.; Lowe, A.J. Relationships between adult asthma and oxidative stress markers and pH in exhaled breath condensate: A systematic review. Allergy 2016, 71, 741–757. [Google Scholar] [CrossRef] [Green Version]
  39. Thomas, P.S.; Lowe, A.J.; Samarasinghe, P.; Lodge, C.J.; Huang, Y.; Abramson, M.J.; Dharmage, S.C.; Jaffe, A. Exhaled breath condensate in pediatric asthma: Promising new advance or pouring cold water on a lot of hot air? a systematic review. Pediatr. Pulmonol. 2013, 48, 419–442. [Google Scholar] [CrossRef]
  40. Peterson, J.D.; Herzenberg, L.A.; Vasquez, K.; Waltenbaugh, C. Glutathione levels in antigen-presenting cells modulate Th1 versus Th2 response patterns. Proc. Natl. Acad. Sci. USA 1998, 95, 3071–3076. [Google Scholar] [CrossRef]
  41. 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]
  42. 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] [Green Version]
  43. Ghosh, S.; Masri, F.; Comhair, S.; Andreadis, A.; Swaidani, S.; Aronica, M.; Aulak, K.; Erzurum, S. Nitration of proteins in murine model of asthma. Am. J. Respir. Crit. Care Med. 2003, 167, A889. [Google Scholar]
  44. Sackesen, C.; Ercan, H.; Dizdar, E.; Soyer, O.; Gumus, P.; Tosun, B.N.; Büyüktuncer, Z.; Karabulut, E.; Besler, T.; Kalayci, O. A comprehensive evaluation of the enzymatic and nonenzymatic antioxidant systems in childhood asthma. J. Allergy Clin. Immunol. 2008, 122, 78–85. [Google Scholar] [CrossRef]
  45. Wedes, S.H.; Khatri, S.B.; Zhang, R.; Wu, W.; Comhair, S.A.; Wenzel, S.; Teague, W.G.; Israel, E.; Erzurum, S.C.; Hazen, S.L. Noninvasive markers of airway inflammation in asthma. Clin. Transl. Sci. 2009, 2, 112–117. [Google Scholar] [CrossRef]
  46. 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]
  47. Larsen, G.L.; White, C.W.; Takeda, K.; Loader, J.E.; Nguyen, D.D.; Joetham, A.; Groner, Y.; Gelfand, E.W. Mice that overexpress Cu/Zn superoxide dismutase are resistant to allergen-induced changes in airway control. Am. J. Physiol. Lung Cell. Mol. Physiol. 2000, 279, L350–L359. [Google Scholar] [CrossRef]
  48. Michaeloudes, C.; Abubakar-Waziri, H.; Lakhdar, R.; Raby, K.; Dixey, P.; Adcock, I.M.; Mumby, S.; Bhavsar, P.K.; Chung, K.F. Molecular mechanisms of oxidative stress in asthma. Mol. Asp. Med. 2022, 85, 101026. [Google Scholar] [CrossRef]
  49. Shalaby, K.H.; Allard-Coutu, A.; O’Sullivan, M.J.; Nakada, E.; Qureshi, S.T.; Day, B.J.; Martin, J.G. Inhaled birch pollen extract induces airway hyperresponsiveness via oxidative stress but independently of pollen-intrinsic NADPH oxidase activity, or the TLR4-TRIF pathway. J. Immunol. 2013, 191, 922–933. [Google Scholar] [CrossRef] [Green Version]
  50. Carlsten, C.; MacNutt, M.J.; Zhang, Z.; Sava, F.; Pui, M.M. Anti-oxidant N-acetylcysteine diminishes diesel exhaust-induced increased airway responsiveness in person with airway hyper-reactivity. Toxicol. Sci. 2014, 139, 479–487. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  51. Riedl, M.A.; Saxon, A.; Diaz-Sanchez, D. Oral sulforaphane increases Phase II antioxidant enzymes in the human upper airway. Clin. Immunol. 2009, 130, 244–251. [Google Scholar] [CrossRef]
  52. 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]
  53. Teng, Y.; Sun, P.; Zhang, J.; Yu, R.; Bai, J.; Yao, X.; Huang, M.; Adcock, I.M.; Barnes, P.J. Hydrogen peroxide in exhaled breath condensate in patients with asthma: A promising biomarker? Chest 2011, 140, 108–116. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Luan, G.; Li, G.; Ma, X.; Jin, Y.; Hu, N.; Li, J.; Wang, Z.; Wang, H. Dexamethasone-Induced Mitochondrial Dysfunction and Insulin Resistance-Study in 3T3-L1 Adipocytes and Mitochondria Isolated from Mouse Liver. Molecules 2019, 24, 1982. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Kračun, D.; Klop, M.; Knirsch, A.; Petry, A.; Kanchev, I.; Chalupsky, K.; Wolf, C.M.; Görlach, A. NADPH oxidases and HIF1 promote cardiac dysfunction and pulmonary hypertension in response to glucocorticoid excess. Redox Biol. 2020, 34, 101536. [Google Scholar] [CrossRef] [PubMed]
  56. Han, M.; Lee, D.; Lee, S.H.; Kim, T.H. Oxidative Stress and Antioxidant Pathway in Allergic Rhinitis. Antioxidants 2021, 10, 1266. [Google Scholar] [CrossRef]
  57. Klain, A.; Indolfi, C.; Dinardo, G.; Licari, A.; Cardinale, F.; Caffarelli, C.; Manti, S.; Ricci, G.; Pingitore, G.; Tosca, M.; et al. United airway disease. Acta Biomed. 2021, 92, e2021526. [Google Scholar] [CrossRef]
  58. Lee, K.; Tai, J.; Lee, S.H.; Kim, T.H. Advances in the Knowledge of the Underlying Airway Remodeling Mechanisms in Chronic Rhinosinusitis Based on the Endotypes: A Review. Int. J. Mol. Sci. 2021, 22, 910. [Google Scholar] [CrossRef]
  59. Van Zele, T.; Claeys, S.; Gevaert, P.; Van Maele, G.; Holtappels, G.; Van Cauwenberge, P.; Bachert, C. Differentiation of chronic sinus diseases by measurement of inflammatory mediators. Allergy 2006, 61, 1280–1289. [Google Scholar] [CrossRef]
  60. Delemarre, T.; Holtappels, G.; De Ruyck, N.; Zhang, N.; Nauwynck, H.; Bachert, C.; Gevaert, E. Type 2 inflammation in chronic rhinosinusitis without nasal polyps: Another relevant endotype. J. Allergy Clin. Immunol. 2020, 146, 337–343.e6. [Google Scholar] [CrossRef]
  61. Shi, L.L.; Song, J.; Xiong, P.; Cao, P.P.; Liao, B.; Ma, J.; Zhang, Y.N.; Zeng, M.; Liu, Y.; Wang, H.; et al. Disease-specific T-helper cell polarizing function of lesional dendritic cells in different types of chronic rhinosinusitis with nasal polyps. Am. J. Respir. Crit. Care Med. 2014, 190, 628–638. [Google Scholar] [CrossRef]
  62. Klingler, A.I.; Stevens, W.W.; Tan, B.K.; Peters, A.T.; Poposki, J.A.; Grammer, L.C.; Welch, K.C.; Smith, S.S.; Conley, D.B.; Kern, R.C.; et al. Mechanisms and biomarkers of inflammatory endotypes in chronic rhinosinusitis without nasal polyps. J. Allergy Clin. Immunol. 2021, 147, 1306–1317. [Google Scholar] [CrossRef] [PubMed]
  63. Kato, A. Immunopathology of chronic rhinosinusitis. Allergol. Int. 2015, 64, 121–130. [Google Scholar] [CrossRef] [Green Version]
  64. Ogasawara, N.; Klingler, A.I.; Tan, B.K.; Poposki, J.A.; Hulse, K.E.; Stevens, W.W.; Peters, A.T.; Grammer, L.C.; Welch, K.C.; Smith, S.S.; et al. Epithelial activators of type 2 inflammation: Elevation of thymic stromal lymphopoietin, but not IL-25 or IL-33, in chronic rhinosinusitis with nasal polyps in Chicago, Illinois. Allergy 2018, 73, 2251–2254. [Google Scholar] [CrossRef]
  65. Zhang, N.; Van Zele, T.; Perez-Novo, C.; Van Bruaene, N.; Holtappels, G.; DeRuyck, N.; Van Cauwenberge, P.; Bachert, C. Different types of T-effector cells orchestrate mucosal inflammation in chronic sinus disease. J. Allergy Clin. Immunol. 2008, 122, 961–968. [Google Scholar] [CrossRef]
  66. Grayson, J.W.; Hopkins, C.; Mori, E.; Senior, B.; Harvey, R.J. Contemporary Classification of Chronic Rhinosinusitis Beyond Polyps vs No Polyps: A Review. JAMA Otolaryngol. Head Neck Surg. 2020, 146, 831–838. [Google Scholar] [CrossRef]
  67. Cho, S.H.; Hamilos, D.L.; Han, D.H.; Laidlaw, T.M. Phenotypes of Chronic Rhinosinusitis. J. Allergy Clin. Immunol. Pract. 2020, 8, 1505–1511. [Google Scholar] [CrossRef] [PubMed]
  68. Olszewska, A.; Niewiadomski, P.; Olszewski, J. Influence of nasal mucosa irritants on the occurrence of chronic rhinosinusitis without /and with polyps. Otolaryngol. Pol. 2021, 75, 36–44. [Google Scholar] [CrossRef]
  69. Mihalj, H.; Butković, J.; Tokić, S.; Štefanić, M.; Kizivat, T.; Bujak, M.; Baus Lončar, M.; Mihalj, M. Expression of Oxidative Stress and Inflammation-Related Genes in Nasal Mucosa and Nasal Polyps from Patients with Chronic Rhinosinusitis. Int. J. Mol. Sci. 2022, 23, 5521. [Google Scholar] [CrossRef]
  70. Cekin, E.; Ipcioglu, O.M.; Erkul, B.E.; Kapucu, B.; Ozcan, O.; Cincik, H.; Gungor, A. The association of oxidative stress and nasal polyposis. J. Int. Med. Res. 2009, 37, 325–330. [Google Scholar] [CrossRef] [Green Version]
  71. Bozkus, F.; San, I.; Ulas, T.; Iynen, I.; Yesilova, Y.; Guler, Y.; Aksoy, N. Evaluation of total oxidative stress parameters in patients with nasal polyps. Acta Otorhinolaryngol. Ital. 2013, 33, 248–253. [Google Scholar]
  72. Lee, W.H.; Hong, S.N.; Kim, H.J.; Ahn, S.; Rhee, C.S.; Lee, C.H.; Kim, J.W. Effects of cigarette smoking on rhinologic diseases: Korean National Health and Nutrition Examination Survey 2008–2011. Int. Forum Allergy Rhinol. 2015, 5, 937–943. [Google Scholar] [CrossRef]
  73. Mady, L.J.; Schwarzbach, H.L.; Moore, J.A.; Boudreau, R.M.; Tripathy, S.; Kinnee, E.; Dodson, Z.M.; Willson, T.J.; Clougherty, J.E.; Lee, S.E. Air pollutants may be environmental risk factors in chronic rhinosinusitis disease progression. Int. Forum Allergy Rhinol. 2018, 8, 377–384. [Google Scholar] [CrossRef] [PubMed]
  74. Rusznak, C.; Sapsford, R.J.; Devalia, J.L.; Justin John, R.; Hewitt, E.L.; Lamont, A.G.; Wood, A.J.; Shah, S.S.; Davies, R.J.; Lozewicz, S. Cigarette smoke potentiates house dust mite allergen-induced increase in the permeability of human bronchial epithelial cells in vitro. Am. J. Respir. Cell Mol. Biol. 1999, 20, 1238–1250. [Google Scholar] [CrossRef]
  75. Taub, D.D.; Oppenheim, J.J. Review of the chemokine meeting the Third International Symposium of Chemotactic Cytokines. Cytokine 1993, 5, 175–179. [Google Scholar] [CrossRef]
  76. Sozzani, S.; Bosisio, D.; Mantovani, A.; Ghezzi, P. Linking stress, oxidation and the chemokine system. Eur. J. Immunol. 2005, 35, 3095–3098. [Google Scholar] [CrossRef] [PubMed]
  77. Yao, T.; Kojima, Y.; Koyanagi, A.; Yokoi, H.; Saito, T.; Kawano, K.; Furukawa, M.; Kusunoki, T.; Ikeda, K. Eotaxin-1, -2, and -3 immunoreactivity and protein concentration in the nasal polyps of eosinophilic chronic rhinosinusitis patients. Laryngoscope 2009, 119, 1053–1059. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  78. Yoshifuku, K.; Matsune, S.; Ohori, J.; Sagara, Y.; Fukuiwa, T.; Kurono, Y. IL-4 and TNF-alpha increased the secretion of eotaxin from cultured fibroblasts of nasal polyps with eosinophil infiltration. Rhinology 2007, 45, 235–241. [Google Scholar]
  79. Brandes, R.P.; Weissmann, N.; Schröder, K. Nox family NADPH oxidases: Molecular mechanisms of activation. Free Radic. Biol. Med. 2014, 76, 208–226. [Google Scholar] [CrossRef]
  80. Zheng, K.; Hao, J.; Xiao, L.; Wang, M.; Zhao, Y.; Fan, D.; Li, Y.; Wang, X.; Zhang, L. Expression of nicotinamide adenine dinucleotide phosphate oxidase in chronic rhinosinusitis with nasal polyps. Int. Forum Allergy Rhinol. 2020, 10, 646–655. [Google Scholar] [CrossRef]
  81. Alhawiti, N.M.; Al Mahri, S.; Aziz, M.A.; Malik, S.S.; Mohammad, S. TXNIP in Metabolic Regulation: Physiological Role and Therapeutic Outlook. Curr. Drug Targets 2017, 18, 1095–1103. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Lin, H.; Ba, G.; Tang, R.; Li, M.; Li, Z.; Li, D.; Ye, H.; Zhang, W. Increased Expression of TXNIP Facilitates Oxidative Stress in Nasal Epithelial Cells of Patients With Chronic Rhinosinusitis With Nasal Polyps. Am. J. Rhinol. Allergy 2021, 35, 607–614. [Google Scholar] [CrossRef]
  83. Yu, Z.; Wang, Y.; Zhang, J.; Li, L.; Wu, X.; Ma, R.; Han, M.; Xu, G.; Wen, W.; Li, H. Expression of heme oxygenase-1 in eosinophilic and non-eosinophilic chronic rhinosinusitis with nasal polyps: Modulation by cytokines. Int. Forum Allergy Rhinol. 2015, 5, 734–740. [Google Scholar] [CrossRef] [PubMed]
  84. Li, N.; Hao, M.; Phalen, R.F.; Hinds, W.C.; Nel, A.E. Particulate air pollutants and asthma. A paradigm for the role of oxidative stress in PM-induced adverse health effects. Clin. Immunol. 2003, 109, 250–265. [Google Scholar] [CrossRef]
  85. Sawamura, T.; Kume, N.; Aoyama, T.; Moriwaki, H.; Hoshikawa, H.; Aiba, Y.; Tanaka, T.; Miwa, S.; Katsura, Y.; Kita, T.; et al. An endothelial receptor for oxidized low-density lipoprotein. Nature 1997, 386, 73–77. [Google Scholar] [CrossRef] [PubMed]
  86. Nishida, M.; Takeno, S.; Takemoto, K.; Takahara, D.; Hamamoto, T.; Ishino, T.; Kawasumi, T. Increased Tissue Expression of Lectin-Like Oxidized LDL Receptor-1 (LOX-1) Is Associated with Disease Severity in Chronic Rhinosinusitis with Nasal Polyps. Diagnostics 2020, 10, 246. [Google Scholar] [CrossRef] [Green Version]
  87. McDonald, P.P.; Bald, A.; Cassatella, M.A. Activation of the NF-kappaB pathway by inflammatory stimuli in human neutrophils. Blood 1997, 89, 3421–3433. [Google Scholar] [CrossRef] [PubMed]
  88. Frączek, M.; Rostkowska-Nadolska, B.; Kapral, M.; Szota, J.; Kręcicki, T.; Mazurek, U. Microarray analysis of NF-κB-dependent genes in chronic rhinosinusitis with nasal polyps. Adv. Clin. Exp. Med. 2013, 22, 209–217. [Google Scholar]
  89. Jung, H.J.; Zhang, Y.L.; Kim, D.K.; Rhee, C.S.; Kim, D.Y. The Role of NF-κB in Chronic Rhinosinusitis With Nasal Polyps. Allergy Asthma Immunol. Res. 2019, 11, 806–817. [Google Scholar] [CrossRef] [PubMed]
  90. Sajadimajd, S.; Khazaei, M. Oxidative Stress and Cancer: The Role of Nrf2. Curr. Cancer Drug Targets 2018, 18, 538–557. [Google Scholar] [CrossRef]
  91. London, N.R., Jr.; Tharakan, A.; Rule, A.M.; Lane, A.P.; Biswal, S.; Ramanathan, M., Jr. Air pollutant-mediated disruption of sinonasal epithelial cell barrier function is reversed by activation of the Nrf2 pathway. J. Allergy Clin. Immunol. 2016, 138, 1736–1738.e4. [Google Scholar] [CrossRef] [Green Version]
  92. Tharakan, A.; Halderman, A.A.; Lane, A.P.; Biswal, S.; Ramanathan, M., Jr. Reversal of cigarette smoke extract-induced sinonasal epithelial cell barrier dysfunction through Nrf2 Activation. Int. Forum Allergy Rhinol. 2016, 6, 1145–1150. [Google Scholar] [CrossRef] [Green Version]
  93. Hudmon, A.; Schulman, H. Structure-function of the multifunctional Ca2+/calmodulin-dependent protein kinase II. Biochem. J. 2002, 364, 593–611. [Google Scholar] [CrossRef]
  94. Stratton, M.; Lee, I.H.; Bhattacharyya, M.; Christensen, S.M.; Chao, L.H.; Schulman, H.; Groves, J.T.; Kuriyan, J. Activation-triggered subunit exchange between CaMKII holoenzymes facilitates the spread of kinase activity. Elife 2014, 3, e01610. [Google Scholar] [CrossRef]
  95. Erickson, J.R.; Joiner, M.L.; Guan, X.; Kutschke, W.; Yang, J.; Oddis, C.V.; Bartlett, R.K.; Lowe, J.S.; O’Donnell, S.E.; Aykin-Burns, N.; et al. A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation. Cell 2008, 133, 462–474. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. Qu, J.; Mei, Q.; Niu, R. Oxidative CaMKII as a potential target for inflammatory disease (Review). Mol. Med. Rep. 2019, 20, 863–870. [Google Scholar] [CrossRef] [PubMed]
  97. Reiter, B.; Perraudin, J.P. The antibacterial activity of lactoferrin and neonatal E. coli infections. A selective and critical review. Adv. Exp. Med. Biol. 1998, 443, 175–188. [Google Scholar] [CrossRef]
  98. Gattas, M.V.; Forteza, R.; Fragoso, M.A.; Fregien, N.; Salas, P.; Salathe, M.; Conner, G.E. Oxidative epithelial host defense is regulated by infectious and inflammatory stimuli. Free Radic. Biol. Med. 2009, 47, 1450–1458. [Google Scholar] [CrossRef] [Green Version]
  99. El Hassani, R.A.; Benfares, N.; Caillou, B.; Talbot, M.; Sabourin, J.C.; Belotte, V.; Morand, S.; Gnidehou, S.; Agnandji, D.; Ohayon, R.; et al. Dual oxidase2 is expressed all along the digestive tract. Am. J. Physiol. Gastrointest. Liver Physiol. 2005, 288, G933–G942. [Google Scholar] [CrossRef]
  100. Cho, D.Y.; Nayak, J.V.; Bravo, D.T.; Le, W.; Nguyen, A.; Edward, J.A.; Hwang, P.H.; Illek, B.; Fischer, H. Expression of dual oxidases and secreted cytokines in chronic rhinosinusitis. Int. Forum Allergy Rhinol. 2013, 3, 376–383. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  101. Takabayashi, T.; Schleimer, R.P. Formation of nasal polyps: The roles of innate type 2 inflammation and deposition of fibrin. J. Allergy Clin. Immunol. 2020, 145, 740–750. [Google Scholar] [CrossRef] [Green Version]
  102. Topal, O.; Kulaksızoglu, S.; Erbek, S.S. Oxidative stress and nasal polyposis: Does it affect the severity of the disease? Am. J. Rhinol. Allergy 2014, 28, e1–e4. [Google Scholar] [CrossRef] [PubMed]
  103. Ayala, A.; Muñoz, M.F.; Argüelles, S. Lipid peroxidation: Production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxidative Med. Cell. Longev. 2014, 2014, 360438. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Schiffrin, E.L. Oxidative stress, nitric oxide synthase, and superoxide dismutase: A matter of imbalance underlies endothelial dysfunction in the human coronary circulation. Hypertension 2008, 51, 31–32. [Google Scholar] [CrossRef]
  105. Wu, M.M.; Sun, H.; He, G.X.; Wang, T.S.; Xiao, Z.Q.; Feng, X.P. Determination of differentially expressed proteins and it’s significance among chronic sinusitis, nasal polyps and normal nasal mucosa. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2006, 41, 171–175. [Google Scholar] [PubMed]
  106. Kwon, H.S.; Bae, Y.J.; Moon, K.A.; Lee, Y.S.; Lee, T.; Lee, K.Y.; Kim, T.B.; Park, C.S.; Moon, H.B.; Cho, Y.S. Hyperoxidized peroxiredoxins in peripheral blood mononuclear cells of asthma patients is associated with asthma severity. Life Sci. 2012, 90, 502–508. [Google Scholar] [CrossRef]
  107. Carnero, A.; Blanco-Aparicio, C.; Renner, O.; Link, W.; Leal, J.F. The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications. Curr. Cancer Drug Targets 2008, 8, 187–198. [Google Scholar] [CrossRef] [PubMed]
  108. Tanaka, Y.; Hosoyama, T.; Mikamo, A.; Kurazumi, H.; Nishimoto, A.; Ueno, K.; Shirasawa, B.; Hamano, K. Hypoxic preconditioning of human cardiosphere-derived cell sheets enhances cellular functions via activation of the PI3K/Akt/mTOR/HIF-1α pathway. Am. J. Transl. Res. 2017, 9, 664–673. [Google Scholar]
  109. Yadav, U.C.; Naura, A.S.; Aguilera-Aguirre, L.; Boldogh, I.; Boulares, H.A.; Calhoun, W.J.; Ramana, K.V.; Srivastava, S.K. Aldose reductase inhibition prevents allergic airway remodeling through PI3K/AKT/GSK3β pathway in mice. PLoS ONE 2013, 8, e57442. [Google Scholar] [CrossRef]
  110. Jia, M.; Chen, X.; Liu, J.; Chen, J. PTEN promotes apoptosis of H2O2-injured rat nasal epithelial cells through PI3K/Akt and other pathways. Mol. Med. Rep. 2018, 17, 571–579. [Google Scholar] [CrossRef] [Green Version]
  111. Wu, M.M.; Chen, T.; Xiong, W.; Huang, C.J.; Shi, Z.Q.; Pu, H.J. The role of PACAP protein in chronic sinusitis with or without nasal polyps. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2016, 30, 1608–1611. [Google Scholar] [CrossRef]
  112. Dagli, M.; Eryilmaz, A.; Besler, T.; Akmansu, H.; Acar, A.; Korkmaz, H. Role of free radicals and antioxidants in nasal polyps. Laryngoscope 2004, 114, 1200–1203. [Google Scholar] [CrossRef]
  113. Cheng, Y.K.; Tsai, M.H.; Lin, C.D.; Hwang, G.Y.; Hang, L.W.; Tseng, G.C.; Shen, P.S.; Chang, W.C. Oxidative stress in nonallergic nasal polyps associated with bronchial hyperresponsiveness. Allergy 2006, 61, 1290–1298. [Google Scholar] [CrossRef] [PubMed]
  114. Hariri, B.M.; McMahon, D.B.; Chen, B.; Freund, J.R.; Mansfield, C.J.; Doghramji, L.J.; Adappa, N.D.; Palmer, J.N.; Kennedy, D.W.; Reed, D.R.; et al. Flavones modulate respiratory epithelial innate immunity: Anti-inflammatory effects and activation of the T2R14 receptor. J. Biol. Chem. 2017, 292, 8484–8497. [Google Scholar] [CrossRef] [Green Version]
  115. Kim, S.W.; Kim, D.W.; Khalmuratova, R.; Kim, J.H.; Jung, M.H.; Chang, D.Y.; Shin, E.C.; Lee, H.K.; Shin, H.W.; Rhee, C.S.; et al. Resveratrol prevents development of eosinophilic rhinosinusitis with nasal polyps in a mouse model. Allergy 2013, 68, 862–869. [Google Scholar] [CrossRef] [PubMed]
  116. Koennecke, M.; Benecke, F.; Masche, A.; Linke, R.; Bruchhage, K.L.; Pries, R.; Klimek, L.; Wollenberg, B. Increased phosphorylation of eNOS in nasal polyps of chronic rhinosinusitis patients can be diminished by 1,8-cineol. Nitric Oxide 2018, 78, 89–94. [Google Scholar] [CrossRef] [PubMed]
  117. Zhang, S.; Smith, N.; Schuster, D.; Azbell, C.; Sorscher, E.J.; Rowe, S.M.; Woodworth, B.A. Quercetin increases cystic fibrosis transmembrane conductance regulator-mediated chloride transport and ciliary beat frequency: Therapeutic implications for chronic rhinosinusitis. Am. J. Rhinol. Allergy 2011, 25, 307–312. [Google Scholar] [CrossRef] [Green Version]
  118. Hoza, J.; Salzman, R.; Starek, I.; Schalek, P.; Kellnerova, R. Efficacy and safety of erdosteine in the treatment of chronic rhinosinusitis with nasal polyposis-a pilot study. Rhinology 2013, 51, 323–327. [Google Scholar] [CrossRef]
  119. Martens, S.; Mithöfer, A. Flavones and flavone synthases. Phytochemistry 2005, 66, 2399–2407. [Google Scholar] [CrossRef]
  120. Sato, Y.; Shibata, H.; Arai, T.; Yamamoto, A.; Okimura, Y.; Arakaki, N.; Higuti, T. Variation in synergistic activity by flavone and its related compounds on the increased susceptibility of various strains of methicillin-resistant Staphylococcus aureus to beta-lactam antibiotics. Int. J. Antimicrob. Agents 2004, 24, 226–233. [Google Scholar] [CrossRef]
  121. Pezzuto, J.M. The phenomenon of resveratrol: Redefining the virtues of promiscuity. Ann. N. Y. Acad. Sci. 2011, 1215, 123–130. [Google Scholar] [CrossRef] [PubMed]
  122. Csiszar, A. Anti-inflammatory effects of resveratrol: Possible role in prevention of age-related cardiovascular disease. Ann. N. Y. Acad. Sci. 2011, 1215, 117–122. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  123. Serrano, C.; Valero, A.; Picado, C. Nasal nitric oxide. Arch. Bronconeumol. 2004, 40, 222–230. [Google Scholar] [CrossRef] [PubMed]
  124. Juergens, U.R. Anti-inflammatory properties of the monoterpene 1.8-cineole: Current evidence for co-medication in inflammatory airway diseases. Drug Res. 2014, 64, 638–646. [Google Scholar] [CrossRef] [PubMed]
  125. Xu, D.; Hu, M.J.; Wang, Y.Q.; Cui, Y.L. Antioxidant Activities of Quercetin and Its Complexes for Medicinal Application. Molecules 2019, 24, 1123. [Google Scholar] [CrossRef] [PubMed]
  126. Cazzola, M.; Page, C.; Rogliani, P.; Calzetta, L.; Matera, M.G. Multifaceted Beneficial Effects of Erdosteine: More than a Mucolytic Agent. Drugs 2020, 80, 1799–1809. [Google Scholar] [CrossRef]
Antioxidants 12 00195 g001 550
Figure 1. The type 2 and non-type 2 endotypes of CRS.
Figure 1. The type 2 and non-type 2 endotypes of CRS.
Antioxidants 12 00195 g001
Antioxidants 12 00195 g002 550
Figure 2. Role of oxidative stress in CRSwNP.
Figure 2. Role of oxidative stress in CRSwNP.
Antioxidants 12 00195 g002
Table
Table 1. Sources of oxidative stress in respiratory diseases.
Table 1. Sources of oxidative stress in respiratory diseases.
Exogenous OxidantsEndogenous OxidantsReduced Antioxidants
Air pollutionHydrogen peroxideThioredoxin
Tobacco smokePeroxynitriteNrf2
Biomass smokeXanthine oxidaseGlutathione
Allergens Superoxide anionsForkhead box protein
Particulate matterMitochondrial oxidantsVitamins
PM2.5 (<10 μ, <2.5 μ, <0.1 μ)MyeloperoxidaseSOD
Table
Table 2. Biological targets and biomarkers of oxidative stress in asthma.
Table 2. Biological targets and biomarkers of oxidative stress in asthma.
TargetsBiomarkers
Exhaled breath condensateHydrogen ions
Hydrogen peroxide
Nitric oxide
Oxides of nitrogen
8-Isoprostanes
Glutathione
Bronchoalveolar fluid3-Bromotyrosine
Catalase
Systemic circulationReduced glutathione
Ascorbic acid
α-Tocopherol
Lycopene
β-Carotene
UrineBromotyrosine
F2-isoprostane
Experimental detectionCopper-zinc SOD
Manganese SOD
Table
Table 3. Summary of studies of oxidative stress and antioxidants related to CRSwNP.
Table 3. Summary of studies of oxidative stress and antioxidants related to CRSwNP.
Research TypeKey Findings of Basic Research Study and General Information of Clinical TrialReference
Basic research studiesEotaxin immunoreactivity in endothelial cells of NPsYao et al. [77]
Eotaxin-1 plays a key role in the selective recruitment of eosinophils in NPsYoshifuku et al. [78]
Expression of p67phox and 4-HNE were higher in NP tissues than healthy mucosaeZheng et al. [80]
TXNIP expression is upregulated in CRSwNPLin et al. [82]
Expression of HO-1 mRNA and proteins was higher in the NPs than that in controlYu et al. [83]
LOX-1 mRNA expression was higher in CRSwNP than that in healthy controlsNishida et al. [86]
CRSwNP group possessed a higher number of NF-κB p65-positive cells and higher mRNA expression levels of IL-6, IL-8, and eotaxin than control groupJung et al. [89]
The barrier dysfunction of nasal sinus epithelial cells can be reversed through Nrf2 activationTharakan et al. [92]
DUOX1 mRNA levels were increased in CRSwNP compared to those in controlCho et al. [100]
Oxidative stress level was related to the nasal congestion and disease severityTopal et al. [102]
Compared to the control tis-sues, NP samples contained a higher level of malondialde-hyde and lower levels of SOD and nitric oxideCekin et al. [70]
Clinical trial25 Caucasian patients (10 females and 15 males, aged 51–62 years). Moderate to high preoperative Malm endoscopy and Lund–Mackay CT scores. The treatment lasted for 6 monthsMihalj et al. [69]
Table
Table 4. Biomarkers of oxidative stress and antioxidants in the CRSwNP.
Table 4. Biomarkers of oxidative stress and antioxidants in the CRSwNP.
Biomarkers of Oxidative StressBiomarkers of Antioxidants
Eotaxin-1 [77,78]HO-1 [23,83]
NADPH [79,80]LOX-1 [85,86]
TXNIP [81,82]Nrf2 [90,91,92]
NF-κB [87,88,89]SOD [70,102,104]
Lactoperoxidase [97,98]PRDX2 [69,111]
DUOX1, DUOX2 [99,100]BPIFA1 [69,111]
Malondialdehyde [70,102,103]ADCYAP1 [69,111]
PTEN, PI3K, Akt [107,108,109,110]
Table
Table 5. Potential antioxidants for use in the treatment of CRS.
Table 5. Potential antioxidants for use in the treatment of CRS.
AntioxidantsRoles in the Nasal Mucosa and NPsReference
Several representative flavones (apigenin, wogonin, chrysin, tangeritin)Inhibits the upregulation of Muc5AC and inducible nitric oxide synthase, as well as the release of cytokines (e.g., IL-8)Hariri et al. [114]
ResveratrolDecreases the degree of eosinophilic infiltration and subepithelial fibrosis, as well as levels of IL-4, IL-5, prostaglandin D synthase, and leukotriene C4 synthaseKim et al. [115]
TerpenoidsMonoterpene oxide 1,8-cineol decreases the excessive eNOS phosphorylation typically found in NPsKoennecke et al. [116]
QuercetinIncreases transepithelial Cl− transport and ciliary beat frequency in culture models of sinonasal epitheliumZhang et al. [117]
ErdosteineThis study compared patients with CRSwNP treated with Erdosteine alone or Erdosteine in combination with nasal corticosteroid spray and found that the response was significantly better in the Erdosteine-only groupHoza et al. [118]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Tai, J.; Shin, J.-M.; Park, J.; Han, M.; Kim, T.H. Oxidative Stress and Antioxidants in Chronic Rhinosinusitis with Nasal Polyps. Antioxidants 2023, 12, 195. https://doi.org/10.3390/antiox12010195

AMA Style

Tai J, Shin J-M, Park J, Han M, Kim TH. Oxidative Stress and Antioxidants in Chronic Rhinosinusitis with Nasal Polyps. Antioxidants. 2023; 12(1):195. https://doi.org/10.3390/antiox12010195

Chicago/Turabian Style

Tai, Junhu, Jae-Min Shin, Jaehyung Park, Munsoo Han, and Tae Hoon Kim. 2023. "Oxidative Stress and Antioxidants in Chronic Rhinosinusitis with Nasal Polyps" Antioxidants 12, no. 1: 195. https://doi.org/10.3390/antiox12010195

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