Search Results (574)

Obstructive sleep apnea (OSA) syndrome is a severe, debilitating, and pervasive sleep disorder. OSA mainly affects people with obesity, type 2 diabetes mellitus (T2DM), hypertension, and dyslipidemia and is strongly associated with cardiovascular complications. Based on the bidirectional relationship between T2DM and OSA, the latter represents a risk factor for the former, and, vice versa, people with T2DM have a high risk of OSA. Mechanical and hormonal factors, inflammatory mediators, and a dysregulated autonomic nervous system contribute to the mechanisms underlying the disease. Treatment of OSA is necessary even if the available remedies are not always effective. In addition to traditional treatments, including lifestyle adaptations and bariatric surgery, CPAP equipment, i.e., a breathing device ensuring continuous positive pressure to keep the airways open during sleep, represents the most common treatment tool. More recently, pharmacological research has paved the way to newer seemingly effective therapeutic strategies involving, in particular, two hypoglycemic agent classes, i.e., sodium–glucose co-transporter 2 inhibitors (SGLT2-is) and glucagon-like peptide-1 (GLP-1) receptor agonists (GLP1-ras). This narrative review provides an update on all of the above. Full article

Pediatric asthma is a multifactorial and heterogeneous disease determined by the dynamic interplay of genetic susceptibility, environmental exposures, and immune dysregulation. Recent advances have highlighted the pivotal role of epigenetic mechanisms, in particular, DNA methylation, histone modifications, and non-coding RNAs, in the regulation of inflammatory pathways contributing to asthma phenotypes and endotypes. This review examines the role of respiratory viruses such as respiratory syncytial virus (RSV), rhinovirus (RV), and other bacterial and fungal infections that are mediators of infection-induced epithelial inflammation that drive epithelial homeostatic imbalance and induce persistent epigenetic alterations. These alterations lead to immune dysregulation, remodeling of the airways, and resistance to corticosteroids. A focused analysis of T2-high and T2-low asthma endotypes highlights unique epigenetic landscapes directing cytokines and cellular recruitment and thereby supports phenotype-specific aspects of disease pathogenesis. Additionally, this review also considers the role of miRNAs in the control of post-transcriptional networks that are pivotal in asthma exacerbation and the severity of the disease. We discuss novel and emerging epigenetic therapies, such as DNA methyltransferase inhibitors, histone deacetylase inhibitors, miRNA-based treatments, and immunomodulatory probiotics, that are in preclinical or early clinical development and may support precision medicine in asthma. Collectively, the current findings highlight the translational relevance of including pathogen-related biomarkers and epigenomic data for stratifying pediatric asthma patients and for the personalization of therapeutic regimens. Epigenetic dysregulation has emerged as a novel and potentially transformative approach for mitigating chronic inflammation and long-term morbidity in children with asthma. Full article

Background: Probiotics are live microorganisms known for their health-promoting effects, particularly in modulating immune responses and reducing inflammation within the gastrointestinal tract. Emerging evidence suggests probiotics may also influence respiratory health, prompting investigation into their potential therapeutic application in lung inflammation. Methods: This study examined the anti-inflammatory effects of Ligilactobacillus salivarius (LS01 DSM 22775) and Bifidobacterium breve (B632 DSM 24706) on inflamed pulmonary epithelial cells. Lung carcinoma epithelial cells (A549) and normal bronchial epithelial cells (16HBE) were stimulated with IL-1β and treated with viable and heat-treated probiotics. Results: CCL-2 levels were significantly reduced by up to 40%, in A549 by viable form (10⁵–10⁷ AFU/g), instead of in 16HBE by heat-treated form (10⁷–10⁹ TFU/g). In A549 cells, TNF-α decreased by 20–80% with all formulations; instead, in 16HBE cells, IL-8 was reduced by viable strains (10⁷ AFU/g) by approximately 50%, while heat-treated strains (10⁹ TFU/g) decreased both IL-6 and IL-8 by 50%. All effective treatments completely inhibited IL-4 and eotaxin and suppressed NF-κB activation in both cell lines, with up to 80% reduction in phospho-p65 levels. In A549 cells, heat-treated strains fully blocked PGE2 production; instead, all four probiotics significantly inhibited COX-2 expression by approximately 50%. Conclusions: These findings demonstrate that both viable and heat-treated probiotics can modulate inflammatory responses in pulmonary epithelial cells, suggesting their potential application in inflammatory respiratory diseases. Heat-treated formulations may be particularly suited for local administration via inhalation, offering a promising strategy for targeting airway inflammation directly. Full article

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease predominantly of the small airways and parenchyma. COPD lungs exhibit an influx of circulating innate immune cells, which, when isolated, display impaired functions, including imbalanced protease secretion. In addition to immune cells, the extracellular matrix (ECM) plays a crucial role in COPD pathology. Remodeling of the ECM can generate ECM fragments, which can be released into circulation and subsequently induce pro-inflammatory responses. COPD is a heterogeneous disease, and serological biomarkers can be used to sub-categorize COPD patients for targeted treatments and optimal recruitment in clinical trials. This study evaluated fragments of calprotectin, collagen type VI, and versican, generated by neutrophil elastase and matrix metalloproteinases (MMP-) 2 and 12, respectively, as potential biomarkers of COPD disease, severity, and endotypes. Lower plasma levels of a neoepitope marker of calprotectin, indicative of activated neutrophils (nordicCPa9-HNETM), were detected in COPD donors compared to controls. CPa9-HNE was associated with milder disease, higher degree of air-trapping, and higher serum levels of MMP-2. Deposition of CPa9-HNE levels in lung tissue revealed no differences between groups. Taken together, CPa9-HNE was found to be a potential marker of mild COPD, but further studies are warranted to validate our findings. Full article

Background/Objectives: Primary malignant lung tumors in children are rare and diagnostically challenging. This study presents a single-center experience in the diagnosis and treatment of these tumors, emphasizing the role of histopathological and genetic profiling in informing individualized therapeutic strategies. Methods: We retrospectively reviewed records of seven pediatric patients (ages 2–18) treated from 2015 to 2025. Diagnostics included laboratory tests, chest CT, bronchoscopy, and histopathological/immunohistochemical analysis. Treatment primarily involved surgical resection, complemented by chemo-, radio-, or targeted therapies when indicated. Results: Inflammatory myofibroblastic tumor (IMT) represented the most commonly diagnosed entity (3/7 cases). The tumors presented with nonspecific symptoms, most frequently dry cough. Tumor type distribution was age-dependent, with aggressive forms such as pleuropulmonary blastoma predominantly affecting younger children, whereas IMT and carcinoid tumors were more common in older patients. Surgical resection remained the mainstay of treatment in the majority of cases. Bronchoscopy served as a valuable adjunct in the initial management of tumors exhibiting intraluminal growth, allowing for direct visualization, tissue sampling, and partial debulking to alleviate airway obstruction. In patients with an initially unresectable IMT harboring specific gene fusion rearrangement (e.g., TFG::ROS1), neoadjuvant targeted therapy with crizotinib enabled adequate tumor shrinkage to allow for subsequent surgical resection. Two patients in the study cohort died as a result of disease progression. Conclusions: A multidisciplinary diagnostic approach—integrating radiologic, bronchoscopic, histopathological, and genetic evaluations—ensures high diagnostic accuracy. While conventional treatments remain curative in many cases, targeted therapies directed at specific molecular alterations may offer essential therapeutic options for selected patients. Full article

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic upper airway disease that may involve different inflammatory endotypes, although in Western populations it is most commonly associated with type 2 inflammation. CRSwNP has a significant impact on the patient’s quality of life. The recommended appropriate medical therapy is effective in controlling CRSwNP symptoms in many patients; however, a subset continues to exhibit persistent type 2 inflammation, evidenced by recurrent nasal polyps, elevated eosinophil counts, or the need for systemic corticosteroids or surgery. Monoclonal antibodies have recently become a novel and personalized treatment that can help refractory patients restore disease control. Objective: The present study aims to evaluate the effectiveness of mepolizumab in real-world settings in a diverse patient population, focusing on assessing the impact of this therapy on patient-reported outcomes after six months of treatment. Methods: This is a multicenter, observational study of CRSwNP patients treated with mepolizumab carried out in five hospitals located in Spain. Adult patients with a diagnosis of uncontrolled CRSwNP were included in the study. The change in the nasal polyp score (NPS) was the main clinical endpoint. Changes in the Sinonasal Outcome Test (SNOT-22), nasal congestion and smell impairment visual analogue scale scores, and blood and nasal polyp tissue eosinophil counts were among other endpoints included. Results: In total, 47 patients were included, and 91% were asthmatic. The nasal polyp score (0–8) was reduced significantly in the cohort (mean change: −2.56, p < 0.0001). The mean SNOT-22 score improved 25.29 points. Nasal congestion (−3.57, p < 0.0001) and smell impairment (−4.0, p < 0.0001) visual analog scale scores (0–10) showed a significant improvement. Blood and tissue eosinophil median counts showed significant reductions versus baseline of 86% and 26%, respectively. Among those patients with asthma, the asthma control test score achieved a median value of 24 points. Conclusions: This study provides real-world evidence supporting the effectiveness of mepolizumab in managing CRSwNP in patients with features suggestive of type 2 inflammation. The observed improvements in patient-reported outcomes, nasal polyp burden, and asthma control suggest that mepolizumab may be a valuable therapeutic option for this patient population. Full article

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide, primarily driven by chronic airway inflammation due to cigarette smoke exposure. Despite its burden, however, current anti-inflammatory therapies offer limited efficacy in preventing disease progression. Plasminogen activator inhibitor-1 (PAI-1), as a key regulator of fibrinolysis, has recently been implicated in structural airway changes and persistent inflammation in patients with COPD. This study aimed to investigate the ability of the PAI-1 inhibitor TM5441 to attenuate airway inflammation and structural lung damage induced by a cigarette smoke extract (CSE) in a mouse model. Mice received intratracheal CSE or vehicle on days 1, 8, and 15, and were sacrificed on day 22. TM5441 (20 mg/kg) was administered orally from days 1 to 22. The CSE significantly increased the mean linear intercept, destructive index, airway resistance, and reductions in dynamic compliance. The CSE also increased the numbers of neutrophils and macrophages in the bronchoalveolar lavage fluid, systemic PAI-1 activity, and neutrophil elastase mRNA and protein expression in the lungs. TM5441 treatment significantly suppressed these changes without affecting coagulation time. These findings suggest that TM5441 may be a novel therapeutic agent for COPD by targeting PAI-1-mediated airway inflammation and emphysema. Full article

Diagnosing and prognosing immune-mediated airway diseases, like hypersensitivity pneumonitis (HP) and sarcoidosis, is complicated due to their overlapping symptoms and the lack of definitive biomarkers. Hence, we wanted to compare bronchoalveolar lavage (BAL) cytokine and chemokine profiles from 92 patients with different immune-mediated and inflammatory airway diseases, namely, HP, sarcoidosis, non-allergic asthma, amiodarone lung, and EGPA. We also compared pulmonary function parameters, BAL’s cellularity, and lymphocyte immunophenotypes. We found significant differences across all measured lung functions (VC, VC%, FEV1, FEV1%, and Tiff%) and in the number of macrophages, lymphocytes, neutrophils, and eosinophils. Furthermore, we showed significant differences in CD4, CD8, and CD4/8 across all included ILDs and OLDs; however, no significant differences were found in CD3, CD19, NK, or NKT. We identified nine biomarkers (IL-1β, IL-6, IL-8, IL-13, VEGF, angiogenin, C4a, RANTES, and MCP-1) that significantly differ in the BAL of patients with HP and sarcoidosis and showed that RANTES and IL-6 are associated with fibrotic outcome. We have demonstrated that interstitial and obstructive lung diseases differ in cytokine and cellular lung imprint, which may, in the future, enable the determination of the disease subtype and thus the identification of targets for the treatment of individuals or subgroups within diseases. Full article

Asthma is defined as a chronic respiratory disease, the processes of which are mainly related to the hyperreactivity of the immune system. Airway hyperresponsiveness and remodeling are other hallmarks of asthma that are strongly involved in the progression of the disease. Moreover, asthma is associated with the occurrence of atopic dermatitis, chronic sinusitis, allergic rhinitis, and a high profile of T2-type cytokines, such as IL-4, IL-5 and IL-13. The hyperresponsiveness of the immune system is a consequence of aberrant levels of alarmins, endogenous molecules that induce pro-inflammatory responses. They are released as a result of a defect or cell death, leading to the initiation of an inflammatory reaction. High-mobility group box 1 (HMGB1), S100 proteins, interleukin-33 (IL-33), thymic stromal lymphopoietin (TSLP), and IL-25 bind to various receptors, influencing the behavior of immune cells, resulting in stimulated migration and activation of these cells. In this review, we will discuss the potential role of alarmins in the pathogenesis of asthma. Full article

Asthma represents a heterogeneous disorder characterized by a dynamic balance between pro-inflammatory and anti-inflammatory forces, with allergic sensitization contributing substantially to airway hyperresponsiveness and remodeling. Central to its pathogenesis are cytokines such as IL-4, IL-5, IL-13, IL-17, and IL-33, which drive recruitment of eosinophils, neutrophils, and other effector cells, thereby precipitating episodic exacerbations in response to viral and environmental triggers. Conventional biomarkers, including blood and sputum eosinophil counts, IgE levels, and fractional exhaled nitric oxide, facilitate phenotypic classification and guide the emerging biologic era. Monoclonal antibodies targeting IgE (omalizumab) and IL-5 (mepolizumab, benralizumab, reslizumab, depemokimab) have demonstrated the ability to reduce exacerbation frequency and improve lung function, with newer agents such as depemokimab offering extended dosing intervals. Itepekimab, an anti-IL-33 antibody, effectively engages its target and mitigates tissue eosinophilia, while CM310-stapokibart, tralokinumab, and lebrikizumab inhibit IL-4/IL-13 signaling with variable efficacy depending on patient biomarkers. Comparative analyses of these biologics, encompassing affinity, dosing regimens, and trial outcomes, underscore the imperative of personalized therapy to optimize disease control in severe asthma. Full article

In chronic respiratory diseases (CRDs), oxidative stress and inflammation are closely linked, driving disease onset, progression, and comorbidities. Oxidative stress activates inflammatory pathways, while chronic inflammation promotes further reactive oxygen species (ROS) production, creating a vicious cycle leading to airway remodeling, reduced lung function, and exacerbations. This review highlights the central roles of inflammation and oxidative stress in chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA). In COPD, chronic hypoxemia associates with emphysema, appearing with disease progression. In OSA, beyond systemic consequences, pulmonary inflammation and oxidative stress contribute to lung injury as well. Although COPD and OSA are distinct conditions, some patients present with “overlap syndrome”, a term used in this review to describe the coexistence of both. This combination poses unique diagnostic and therapeutic challenges. We also examine the role of hypoxia and its transcriptional effects via hypoxia-inducible factors (HIFs) in promoting oxidative stress and inflammation. Finally, we explore how artificial intelligence (AI) offers promising tools to improve diagnosis, monitoring, and management of CRDs and may help elucidate mechanistic links between hypoxia, inflammation, and oxidative stress, contributing to more personalized therapeutic strategies. Full article

Background: The efficacy of EA575 in the treatment of respiratory diseases is described in various clinical studies, improving patients’ disease-related symptoms. However, mechanistic in vivo data proving its beneficial effects are limited. Methods: Focusing on the treatment of acute airway inflammation and accompanying cough, this study aimed to elucidate antitussive and mucoactive properties of EA575, applying two animal models. Animals were treated orally twice daily for 7 days, resulting in 43, 215.2, or 430.5 mg/kg bw/d of EA575. Antitussive effects were investigated within an acute lung inflammation model of bleomycin-treated guinea pigs after citric acid exposure. Hereby, the number of coughs, enhanced pause (penH), and bronchoalveolar lavage fluid (BALF) were investigated. Mucoactivity of EA575 was assessed within a murine model, determining phenol red concentration in BALF. Results: EA575 treatment within the acute lung inflammation model reduced cough events up to 56% while reducing inflammatory cell influx in BALF dose-dependently, e.g., reducing neutrophils in BALF up to 70.9%. This suggests a strong connection between anti-inflammatory and antitussive properties of EA575. Furthermore, penH decreased in a dose-dependent manner, suggesting an ease in respiration. Mucoactivity was shown by a dose-dependent increase in phenol red concentration in BALF up to 38.9%. Notably, EA575/salbutamol co-administration resulted in enhanced phenol red secretion compared to respective single administrations. Conclusions: These data highlight the benefits of EA575 in treating cough-related respiratory diseases, particularly when accompanied by sputum, as EA575 has been shown to obtain mucoactivity. Furthermore, the combinatory effect of EA575/salbutamol treatment provides a foundation for future research in the treatment of chronic respiratory diseases. Full article

Equine asthma is a chronic respiratory disease characterised by neutrophilic inflammation, airway hyperresponsiveness, and impaired pulmonary function. Obesity, increasingly prevalent among domestic horses, has been identified as a potential risk factor for exacerbating inflammatory conditions. This study aimed to explore whether obesity modifies neutrophil metabolism and inflammatory responses in horses affected by asthma. Six asthmatic horses in clinical remission were categorised into two groups: obese and non-obese, based on body condition score. Serum levels of interleukin-1β (IL-1β) and peripheral blood neutrophil counts were significantly higher in obese horses, indicating a heightened systemic inflammatory state. Neutrophils from obese horses displayed a stronger oxidative burst following zymosan stimulation and elevated IL-1β gene expression in response to lipopolysaccharide, suggesting a hyperinflammatory phenotype. Metabolomic profiling of neutrophils identified 139 metabolites, with notable differences in fatty acids, branched-chain amino acids, and tricarboxylic acid (TCA) cycle intermediates. Pathway enrichment analysis revealed significant alterations in fatty acid biosynthesis, amino acid metabolism, and glutathione-related pathways. Elevated levels of itaconate, citraconic acid, and citrate in obese horses indicate profound metabolic reprogramming within neutrophils. These results suggest that obesity promotes a distinct neutrophil phenotype marked by increased metabolic activity and heightened responsiveness to inflammatory stimuli. This altered profile may contribute to the persistence or worsening of airway inflammation in asthmatic horses. The findings underscore the importance of addressing obesity in the clinical management of equine asthma and open avenues for further research into metabolic-targeted therapies in veterinary medicine. Full article

Asthma is a chronic and heterogeneous inflammatory airway disease with diverse clinical endotypes and limited curative treatment options. Recent systems biology analyses identified four potential molecular triggers—AKT1, MAPK13, STAT1, and TLR4—as candidate regulators of asthma-associated signaling pathways. This study aimed to validate the expression of these four proteins and their downstream signaling elements in peripheral blood mononuclear cells (PBMCs) from patients with allergic asthma (AA), nonallergic asthma (NA), and healthy controls (HC), to explore their potential as biomarkers or therapeutic targets. For that, PBMC samples were collected from 45 AA patients, 17 NA patients, and 15 HC subjects. Gene and protein expression of AKT1, MAPK13, STAT1, and TLR4 were quantified using RT-qPCR and Western blotting. Expression patterns were compared across groups and stratified by asthma severity. Correlations with clinical parameters (FEV1, FVC, FeNO, IgE, eosinophil counts) and treatment regimens were also assessed. All four target genes showed significantly reduced expression in asthma patients compared to controls (p < 0.001), with the most marked downregulation in NA patients. At the protein level, MAPK13 and TLR4 showed significant differential expression. Stratification by severity revealed a stepwise reduction in gene expression in AA patients, correlating with disease severity, whereas NA patients showed uniformly low expression regardless of severity. Multiple pathway-related genes, including RELA, SMAD3, NFATC1, and ALOX5, were also downregulated, particularly in NA patients. Notably, differential correlations were observed between gene expression and lung function parameters in AA vs. NA groups. In conclusion, this study supports the potential involvement of AKT1, MAPK13, STAT1, and TLR4 in asthma pathogenesis and highlights differences between allergic and nonallergic asthma at the molecular level. These proteins and their associated pathways may serve as future targets for biomarker development or endotype-specific therapies. Further studies in larger and more diverse cohorts, including functional validation, are warranted. Full article

Asthma is a chronic inflammatory respiratory disease well-known to demonstrate sexual dimorphism in incidence and severity, although the mechanisms causing these differences remain incompletely understood. RPS4X and RPS4Y1 are X and Y-chromosome-linked genes coding ribosomal subunits previously associated with inflammation, airway remodelling and asthma medication efficacy. Particularly, RPS4Y1 has been under-investigated within the context of disease, with little examination of molecular mechanisms and pathways regulated by this gene. The ribosome, a vital cellular machinery, facilitates the translation of mRNA into peptides and then proteins. Imbalance or dysfunction in ribosomal components may lead to malfunctioning proteins. Using CRISPR-Cas9 knockout cellular models for RPS4Y1 and RPS4X, we characterised the function of RPS4Y1 in the context of the asthma-relevant processes, inflammation and fibrosis. No viable RPS4X knockouts could be generated. We highlight novel molecular mechanisms such as specific translation of IL6 and tenascin-C mRNA by RPS4Y1 containing ribosomes. Furthermore, an RPS4Y1-centric gene signature correlates with clinical lung function measurements, specifically in adult male asthma patients. These findings inform the current understanding of sex differences in asthma, as females do not produce the RPS4Y1 protein. Therefore, the pathologically relevant functions of RPS4Y1 may contribute to the complex sexually dimorphic pattern of asthma susceptibility and progression. Full article