Introduction Asthma is a multifactorial disease influenced by genetic and environmental factors, including diet. The gut microbiome contributes to airway inflammation via the gut-lung axis, partly through production of short chain fatty acids (SCFAs) from bacterial fermentation of dietary fiber. We hypothesized that dietary fiber supplementation could modulate the gut microbiome and increase SCFAs in children with asthma. Methods This is a double-blind, placebo-controlled trial of children who were randomized to consume 12 g of soluble corn fiber (SCF) as a supplement to their usual daily diet (50% the recommended daily fiber intake) or placebo for 4–6 weeks ( clinicaltrials.gov NCT03673618). Dietary surveys, asthma symptom questionnaires, fecal, blood and nasal samples were collected before and after the intervention period to quantify fiber intake, asthma control, nasal and gut microbiome, and serum short chain fatty acids (SCFAs). Results Of the 20 children enrolled, 15 completed the intervention with an average adherence rate of 83%. SCFA concentrations and gut microbiome changes varied by individual and treatment group. No significant differences in gut or nasal alpha or beta diversity were observed between groups post-intervention. However, differential abundance analysis showed a trend toward increased Bifidobacterium in the SCF group compared to placebo (ANCOM-BC p = 0.0004, FDR q = 0.073). Discussion Supplementation of 50% of recommended daily fiber intake had minimal impact on asthma symptoms, the microbiome, or SCFA levels. Future studies should consider higher fiber doses, different fiber types, or targeting individuals with low baseline fiber intake to account for observed variability in microbiome and SCFA responses. Clinical Trial Registration https://clinicaltrials.gov/study/NCT03673618 , identifier NCT03673618.

Asthma is a heterogeneous disease characterized by chronic airway inflammation and reversible airflow obstruction. Particularly in severe asthma, airway mucus plugs can contribute to substantial and persistent airflow obstruction, despite inhaled corticosteroid and bronchodilator treatment. Consequently, it is important that clinicians assess and treat mucus plugs. Increased mucus production and airway eosinophilia caused by type 2 (T2) inflammation contributes to mucus plug formation and persistence. Several biologics are available to target T2 inflammation in asthma and studies have described their effects on airway mucus plugs using mucus plug scoring derived from computed tomography scans. However, the outcomes, designs and populations of the various studies have not been comprehensively summarized. A literature search was performed to identify primary publications examining the effects of biologics on mucus plugs in patients with moderate-to-severe asthma, organizing studies by design and study population. Three placebo-controlled randomized controlled trials (RCTs) were identified; one RCT of tezepelumab in patients across baseline blood eosinophil counts (BECs) and fractional exhaled nitric oxide (FeNO) levels and two RCTs of dupilumab in those with elevated BECs or sputum eosinophils and/or elevated FeNO levels. Across these RCTs, biologic treatment decreased mucus plug scores compared with placebo. In the tezepelumab RCT, greater effects were observed in patients with T2-high asthma, highlighting the association between mucus plugging and T2 inflammation. Among T2-high populations, effects were of a similar magnitude across biologics studied. Other biologics (benralizumab, mepolizumab, omalizumab and reslizumab) were evaluated in observational studies without a placebo control, demonstrating reductions in mucus plug scores after treatment. In several studies, decreases in mucus plugs with biologic treatment were associated with improvements in functional outcomes, including pre-bronchodilator forced expiratory volume in 1 second (pre-BD FEV1), air trapping, ventilation defects assessed by magnetic resonance imaging, asthma control and health-related quality of life. All studies showed residual plugs after biologic intervention, demonstrating a need for further understanding of how best to quantify and characterize mucus plugs to predict their response to treatment and develop optimal, individualised treatment strategies. This review highlights the relevance of assessing and targeting mucus plugs in clinical practice to help optimise patient outcomes.

Background Asthma prevalence increases with age, yet assessment in elderly patients is often limited by difficulties in performing reliable spirometry. Alternative, noninvasive methods such as the Forced Oscillation Technique (FOT) and fractional exhaled nitric oxide (FeNO) measurement may improve evaluation of asthma control in this population. Objective To evaluate asthma control and treatment effectiveness in elderly patients using the Asthma Control Test (ACT), GINA classification, spirometry, FOT, and FeNO, and to compare their clinical usefulness. Methods A total of 105 patients aged ≥65 years with diagnosed bronchial asthma were enrolled. All participants completed the ACT and underwent spirometry (FEV1, FVC, FEV1/FVC), FOT (R5, R20, R5–R20, X5, AX), and FeNO measurement according to ATS/ERS recommendations. Treatment intensity was classified by GINA steps (1–5). Nonparametric tests and Spearman’s rank correlation were used for statistical analysis. Results ACT scores correlated significantly with spirometric, oscillometric, and FeNO parameters. Lower ACT scores were associated with reduced FEV1% predicted and increased airway resistance and reactance (R5, AX), as well as higher FeNO levels (all p < 0.001). Patients treated at higher GINA steps (4–5) exhibited poorer asthma control, higher FeNO, and less favorable FOT indices. Reductions in FeNO following treatment intensification were accompanied by improvements in FEV1 and FOT parameters, particularly AX and R5–R20. Conclusions FOT provides a useful, noninvasive assessment of asthma control in elderly patients and complements spirometry. FeNO adds important information on airway inflammation and treatment response. Their combined use may enhance monitoring of asthma control when spirometry is limited.

Obstructive sleep apnea (OSA) is increasingly recognized as a major comorbidity in chronic respiratory diseases, particularly asthma and chronic obstructive pulmonary disease (COPD). The coexistence of OSA with asthma or COPD significantly complicates the clinical course, leading to poorer disease control, more frequent exacerbations, reduced lung function, impaired sleep quality, and increased cardiovascular and overall mortality. In asthma, OSA exacerbates airway inflammation, enhances bronchial hyperresponsiveness, and decreases responsiveness to standard therapies. In COPD, the "overlap syndrome" is associated with profound nocturnal hypoxemia, chronic hypercapnia, pulmonary hypertension, and a markedly elevated risk of hospitalization and death. Underlying mechanisms include chronic airway inflammation, oxidative stress induced by intermittent hypoxia, instability of ventilatory control (high loop gain), structural upper-airway alterations, and the burden of obesity and metabolic dysfunction. These interactions highlight the urgent need for integrated and proactive management strategies. Thus, we propose an Asthma-COPD-OSA Outpatient Unit (ACOSOU)-a care-delivery model, not a disease entity-designed to integrate systematic screening, diagnosis, treatment initiation, and long-term follow-up of OSA in patients with asthma and COPD. Optimal care requires systematic screening in respiratory outpatient settings, appropriate diagnostic pathways using polysomnography or home sleep apnea testing, and individualized treatment approaches. Continuous positive airway pressure (CPAP) remains the cornerstone therapy for OSA-asthma and OSA-COPD overlap, improving gas exchange, reducing exacerbations, and enhancing disease control. Comprehensive management also includes optimization of inhaled therapies, pulmonary rehabilitation, weight reduction, sleep hygiene, and multidisciplinary collaboration. This review proposes an integrated ACOSOU model to streamline screening, diagnosis, CPAP titration, and long-term follow-up. However, implementation in low- and middle-income countries faces challenges including limited trained sleep-medicine personnel, unequal access to diagnostic tools, and high CPAP costs without insurance coverage. Strengthening infrastructure, training, and policy support will be essential to improve outcomes for patients with chronic respiratory diseases and OSA comorbidity.

Despite improved respiratory symptoms after smoking cessation, patients with chronic obstructive pulmonary disease (COPD) remain susceptible to exacerbations and persistent airway inflammation, wherein the underlying mechanisms for sustained inflammation remain unclear. To address this knowledge gap, we investigated the persistence of airway epithelial barrier dysfunction in ex-smokers with COPD and examined the relationship between goblet cell hyperplasia and barrier dysfunction. We analysed differentiated primary bronchial epithelial cells from never smokers with normal lung function, ex-smokers (> 10-year cessation), and current smokers with COPD using RNA sequencing, ATAC sequencing, and single-cell analyses to examine barrier function and cell differentiation. Genes associated with ciliary formation and motility were progressively downregulated from never smokers to ex-smokers to current smokers with COPD. The expression of junction-associated molecules was decreased in both ex-smokers and current smokers, showing a significant inverse correlation with the proportion of MUC5AC-positive cells. Single-cell analyses revealed distinct alterations in cell differentiation trajectories, particularly persistent goblet cell hyperplasia associated with increased expression of the transcription factor SPDEF, linked to epigenetic changes in the NKX2-1 gene regulatory regions. Epigenetic mechanisms maintain persistent alterations in airway epithelial differentiation after smoking cessation, leading to mucus-producing cell hyperplasia through dysregulation of the NKX2-1/SPDEF axis. This hyperplasia correlates with reduced junction-associated molecule expression and subsequent barrier dysfunction. Therapeutic strategies targeting epithelial barrier restoration and/or normalisation of epigenetic dysregulation may benefit patients with COPD, even after smoking cessation.

Pulmonary iron levels are increased in COPD, possibly due to increased red blood cell leakage from the microvasculature. Neutrophils cause endothelial cell damage which may cause vascular dysfunction and iron dysregulation in COPD. We investigate the relationships between neutrophilic inflammation, iron metabolism and vascular dysfunction in COPD. Using gene and protein analysis, associations between neutrophilic inflammation, iron dysregulation and vascular dysfunction were investigated in two COPD bronchoscopy cohorts: EvA (n=51) and Manchester (n=33). Patients were sub-grouped based on bronchoalveolar lavage (BAL) neutrophil percentage (neutrophilhigh≥3% and neutrophillow<3%). Heme was measured in BAL by LC-MS. BAL cell gene expression of neutrophilic inflammation markers such as C-X-C Motif Chemokine Ligand 8 (CXCL8) and Interleukin 6 Receptor (IL6R) were significantly increased in neutrophilhigh compared to neutrophillow patients in both cohorts; fold change (FC) differences 1.06 - 17. We found increased markers of iron and iron trafficking including Lactoferrin (LTF), Lipocalin-2 (LCN2) and Myoglobin (MB) in neutrophilhigh patients in both cohorts. BAL cell gene expression and BAL fluid protein levels of the vascular dysfunction marker, Vascular Endothelial Growth Factor (VEGF), were significantly higher in neutrophilhigh compared to neutrophillow patients. Fibrinogen and heme were significantly increased in neutrophilhigh BAL fluid. In vitro experiments revealed that blood neutrophils had significantly increased expression of LTF and VEGFA following LPS-stimulation and heme induces endothelial dysfunction. COPD patients with distal lung neutrophilic inflammation have dysregulated iron metabolism which may be a consequence of increased vascular leakage into the airways.

Mycoplasma pneumoniae pneumonia (MPP) is a common respiratory infection characterized by significant inflammatory responses and lung tissue injury. However, the precise immunological mechanisms and temporal dynamics of key cytokines driving pulmonary inflammation in MPP are still unclear. This study aimed to investigate the underlying immunological mechanisms and cytokine dynamics in MPP. We established an acute MPP murine model via intranasal administration of M. pneumoniae. This model recapitulates key features of human MPP, such as robust airway inflammation and cytokine production. Comprehensive analyses were conducted, including histopathology, flow cytometry, and cytokine profiling. Results showed severe inflammatory responses with prominent infiltration of neutrophils and macrophages in lung tissue, whereas monocyte populations were significantly reduced, indicating a shift towards myeloid cell predominance. Notably, 36 cytokines, including pro-inflammatory interleukins (IL-1β, IL-6, IL-17A) and chemokines, were statistically significantly upregulated in bronchoalveolar lavage fluid compared to the normal group, highlighting a cytokine storm associated with lung inflammation and tissue damage. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway analysis further revealed enriched pathways related to cytokine-cytokine receptor interactions and IL-17 signaling, suggesting potential therapeutic targets. In conclusion, this study preclinical provides insights into the innate immune response and cytokine-driven pathology in acute MPP, underscoring the pivotal roles of myeloid cells and pro-inflammatory cytokines. Future research should focus on clinical validation of these findings to assess their translational potential and the exploration of immunomodulatory strategies informed by this model to mitigate MPP severity.

Associations of PM2.5 carbonaceous and ionic constituents with fractional exhaled nitric oxide (FeNO): A panel study with 16 follow-up visits over 4 years.

Epithelial-mesenchymal transition (EMT) is amajor pathological characteristic of airway remodellingin severe asthma. Interleukin (IL)-36 belongs to the IL-1 family and is associated with allergic disease, but the role of IL-36 in airway remodelling in asthma remains unclear. We aimed to explore the effect of IL-36 on EMT and to verify whether blocking IL-36-induced EMT can alleviate the airway remodeling in severe asthma. In this study, BEAS-2B cells were stimulated with IL-36 receptor (IL-36R) agonist. The expression of epithelial‒mesenchymal transition (EMT) markers and the migration capacity of cells were determined. A chronic asthma mouse model was established to evaluate the effects of IL-36 signalling on airway inflammation and remodelling. In vitro, EMT and cell migration in BEAS-2BcellswereinducedbyIL-36. In addition, IL-36 facilitated the phosphorylation of NF-κB and STAT3. In vivo, blocking IL-36R via treatment with an IL-36 receptor antagonist (IL-36Ra) inhibited the infiltration of inflammatory cells, decreased airway hyper-responsiveness (AHR) and alleviated airway remodelling (by inhibiting processes, such as EMT) in asthmatic mice. Compared with the administration of IL-36Ra alone, the coadministration of IL-36R agonist with IL-36Ra restored pathological changes related to airway remodelling. These data indicated that IL-36 signalling may participate in airway remodelling by inducing EMT. IL-36 may be a new therapeutic target for airway remodelling in severe asthma.

CXCR6 as a novel therapeutic target in allergic asthma.

Pediatric asthma, a chronic respiratory disorder characterized by airway inflammation and remodeling, is increasingly linked to epigenetic dysregulation of the airway epithelial barrier. This review explores how DNA methylation, histone modifications, and non-coding RNAs (ncRNAs) impair epithelial integrity, amplify immune responses, and sustain chronic inflammation and tissue remodeling. Aberrant methylation of barrier-related genes (FLGs, CLDNs) disrupts tight junctions and enhances allergen penetration. Methylation abnormalities of immune regulators (IL-13, ALOX12) drive Th2-mediated inflammation, with environmental pollutants such as PM2.5 exacerbating these changes. Elevated H3K27me3 levels and histone deacetylase (HDAC) overactivation suppress immune tolerance genes (e.g., IL-4) and compromise junctional proteins (e.g., occludin), whereas HDAC inhibitors demonstrate preclinical efficacy in restoring barrier function. Dysregulated ncRNAs, such as miR-21 and miR-146, modulate inflammatory pathways, with miR-146a mimics reducing eosinophilic inflammation via NF-κB inhibition. Clinically, epigenetic biomarkers such as ALOX12 hypomethylation have diagnostic potential for asthma phenotypes. Emerging therapies, including DNA methyltransferase inhibitors (5-azacytidine) and HDAC inhibitors (vorinostat), show promise but face challenges such as limited clinical validation and discrepancies between animal models and human disease. Future priorities involve integrating multi-omics approaches to unravel the complexity of asthma, optimizing non-invasive biomarker detection, and developing personalized therapies tailored to epigenetic profiles. By bridging mechanistic insights with clinical innovations, epigenetic strategies may revolutionize precision medicine in pediatric asthma management.

Background: Chronic obstructive pulmonary disease (COPD) is characterized by persistent airway inflammation and recurrent exacerbations that accelerate disease progression. Vitamin D deficiency is highly prevalent in this population and correlates with impaired macrophage function. However, randomized controlled trials regarding supplementation have yielded conflicting results. We hypothesized that efficacy is limited by a ceiling effect, where benefits are strictly restricted to patients with profound baseline deficiency. Methods: We conducted a systematic review and stratified meta-analysis of randomized controlled trials comparing Vitamin D supplementation to placebo in COPD. To ensure methodological homogeneity and avoid data duplication, we strictly included only primary RCTs and excluded aggregate IPD meta-analyses. Studies investigating acute treatment of active exacerbations were also excluded. Data were stratified by baseline serum 25-hydroxyvitamin D [25(OH)D] levels into Severe Deficiency (&lt;10 ng/mL) versus Insufficiency/Sufficiency (≥10 ng/mL). The primary outcome was the risk of moderate-to-severe exacerbations, analyzed using pooled Odds Ratios (OR) with a random-effects model. Results: Five pivotal prevention trials (Lehouck, PRECOVID, ViDA, Hornikx, and Rafiq Pilot) comprising approximately 1,212 participants were included in the quantitative synthesis. In the unstratified analysis, Vitamin D showed no significant benefit (OR 0.78; 95% CI 0.55–1.10). However, stratification revealed a distinct therapeutic window. Patients with severe deficiency (&lt;10 ng/mL) experienced a statistically significant reduction in exacerbation risk (Pooled OR 0.51; 95% CI 0.32–0.87; p=0.012). This effect was driven primarily by trials utilizing high-dose bolus supplementation. Conversely, patients with baseline levels ≥10 ng/mL showed no benefit (OR 0.98; p=0.72), confirming the biological ceiling effect. Conclusion: Vitamin D supplementation confers a significant protective benefit against COPD exacerbations exclusively in patients with severe baseline deficiency (&lt;10 ng/mL). The results support a precision medicine approach—screen, stratify, and target—while cautioning that efficacy appears dependent on correcting profound deficiency, potentially utilizing high-dose intermittent regimens.

Asthma affects an estimated 7.2 million people in the UK and is characterised by airway inflammation, bronchoconstriction and variable airflow obstruction. Emergency nurses frequently encounter adults experiencing an acute asthma attack in the emergency department, making a sound understanding of asthma essential for safe and effective care. This article provides an overview of respiratory anatomy and physiology and of asthma pathophysiology, linking it to clinical presentation and severity classification. It outlines key pharmacological and non-pharmacological interventions used during acute asthma attacks, including bronchodilators, corticosteroids, supplemental oxygen, patient positioning and reassurance. The importance of objective measures of respiratory function, such as peak expiratory flow rate, is discussed. The article also highlights the role of emergency nurses in patient education to support self-management and help prevent future exacerbations.

Asthma prevalence has been increasing, particularly among children and in populations transitioning to Western lifestyle. According to the hygiene hypothesis, early-life exposure to microorganisms may protect against asthma and other allergic conditions. Previous studies demonstrated that Saccharomyces cerevisiae UFMG A-905 reduce bronchial hyperresponsiveness, airway and lung inflammation, and restore IL-10 and IFN-γ. However, the underlying mechanisms remain unclear. To investigate the potential pathways by which S. cerevisiae UFMG A-905 modulates asthma. Wild-type and Il17a⁻/⁻ mice were treated daily with live yeast or its supernatant (postbiotic) by oral gavage, starting ten days before OVA sensitization and maintained during sensitization and challenge. Control groups received saline. Lung tissues were analyzed by flow cytometry to assess dendritic cells and regulatory T cells. Gene expression of TLR-9, NLRP3, Dectin-1, and Mincle was quantified by qPCR. Short-, medium-, and long-chain fatty acids were measured in feces using gas chromatography, while gut cytokine were evaluated by ELISA. Treatment with S. cerevisiae UFMG A-905 led to an increase in CD11c⁺MHCII⁺CD11b⁺CD103⁻ dendritic cells, regulatory T cells (CD4⁺CD25⁺FOXP3⁺), and NLRP3 gene expression in the lung, and the fecal levels of dihomo-γ-linolenic acid. Neither gut cytokines nor OVA specific IgE were affected, and the supernatant did not significantly alter cell counts. The beneficial effects were partially dependent on IL-17A. The effects observed with S. cerevisiae UFMG A-905 correlated with modulation of Th17, dendritic-cell and regulatory T-cell responses, upregulation of NLRP3, and increased fatty acid production, suggesting gut-lung axis involvement.

Chronic obstructive pulmonary disease (COPD), a disease responsible for early mortality worldwide, is well accepted to be associated with periodontitis epidemiologically. Although both of the diseases are the multi-microbial inflammatory disease, the precise underlying mechanisms by which periodontitis influences the progression of COPD remains largely unknown. Here, we established COPD accompanied with periodontitis mouse models and observed the pronounced progress in pulmonary symptoms and histopathology, characterized by poorer respiratory function, thickened bronchial walls, and increased neutrophils infiltration in lung tissue. Mechanistically, periodontitis pathogen Porphyromonas gingivalis (P. gingivalis) relocated in the lung through the respiratory tract and LPS from P. gingivalis promoted the secretion of chemokines CXCL2 and G-CSF of alveolar epithelial cells through NF-κB and p38 MAPK pathways to recruit neutrophils. Furthermore, exposure to P. gingivalis of infiltrated neutrophils released matrix metallopeptidase-8 (MMP-8) and neutrophil elastase (NE), which aggravated airway inflammation and tissue damage. These findings indicated that periodontitis could exacerbate COPD via its pathogen P. gingivalis, which translocated in the lung and stimulated neutrophil chemotaxis and activation in the lung.

Allergic airway inflammation (AAI), an asthma-like condition, is characterized by Th17/Treg imbalance and PD-1/PD-L1 pathway dysregulation. Yanghe Pingchuan Granules (YP) formulation is clinically used to treat asthma, but its immunomodulatory mechanisms remain unclear. Using an AAI rat model, the effects of YP were assessed. Flow cytometry was carried out to analyze Th17/Treg proportions. Additionally, the expression levels of Foxp3, ROR?t, IL- 10, IL-17, and TGF-1 were measured. PD-L1 siRNA knockdown and overexpression studies were performed to elucidate the role of the pathway. YP treatment restored the Th17/Treg balance by reducing Th17 and increasing Treg cells. It upregulated IL-10 and TGF-1 while downregulating IL-17. YP inhibited the PD-1/PDL1 pathway, correlating with improved immune balance and reduced inflammation. PD-L1 modulation confirmed its role in mediating the effects of YP on cellular and cytokine profiles. The findings indicated that the therapeutic action of YP involves modulation of the Th17/Treg imbalance, likely through inhibition of the PD-1/PD-L1 pathway, thereby shifting thecytokine milieu from a pro- to an anti-inflammatory state. YP alleviates AAI by modulating the PD-1/PD-L1 pathway to restore Th17/Treg balance and suppress inflammation, thereby revealing its potential immunomodulatory mechanism.

ABSTRACTObjectiveIt was found that the levels of antineutrophil cytoplasmic antibodies (ANCA) are elevated and linked to disease severity of bronchiolitis obliterans (BO) in children. This study aims to explore the mechanism of ANCA in the process of BO.MethodsPlasma from BO patients (n = 40) and healthy controls (n = 11) was analyzed for ANCA and neutrophil extracellular traps (NETs) components. Plasma IgG from ANCA‐positive BO children and normal controls were used to stimulate neutrophils, measuring reactive oxygen species (ROS) and NETs production. Small airway epithelial cells (SAECs) were exposed to NETs, assessing viability by CCK8 and cytokine release by ELISA. The IgG treated neutrophils were co‐cultured with SAECs, and cytokines were measured by ELISA.ResultsThe levels of ANCA and NETs components including dsDNA, neutrophil elastase (NE) and myeloperoxidase (MPO) in the plasma of BO children were significantly higher than those of healthy controls. ANCA‐positive IgG induced neutrophils produce ROS and NETs. The cell viability of SAECs was significantly reduced upon treatment with NETs in a concentration‐dependent manner. The levels of IL‐8, IL‐17, TNF‐α, and TGF‐β secreted by SAECs treated with NETs were increased significantly, and the degree of increase was positively correlated with the concentration of NETs. The co‐culture of neutrophils stimulated by ANCA IgG with SAECs significantly increased the expression of cytokines including IL‐8, IL‐17, TNF‐α, and TGF‐β.ConclusionsNETs induced by ANCA may exacerbate airway inflammation in children with BO.

Novel Porphyrin Photosensitizer LD4-PDT Alleviates Asthma Airway Remodeling by Inhibiting EGR1-Dependent TGF-β1/Smad Signaling.

Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder characterized by neutrophil-dominant, corticosteroid-refractory airway inflammation involving the IL-23/IL-17A axis. IL-23 primarily activates the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway through TYK2 and JAK2, whereas IL-17A and other pro-inflammatory cytokines can activate JAK1. However, the contribution of these JAK-dependent pathways to neutrophil-driven inflammation in COPD remains incompletely understood. In this study we investigated how the IL-23/IL-17A axis modulates neutrophil function and evaluated the therapeutic potential of the dual TYK2/JAK1 inhibitor brepocitinib in COPD. Gene expression and flow cytometric analyses revealed increased TYK2 and JAK1 expression and phosphorylation in sputum cells and neutrophils from COPD patients and smokers. IL-23 and IL-17A enhanced neutrophil activation and stimulated IL-8 release from bronchial epithelial cells, effects that were abrogated by brepocitinib. Neutrophils from COPD patients and smokers also exhibited elevated GRβ expression, a mechanism associated with corticosteroid resistance, which was recapitulated by IL-23/IL-17A stimulation and reversed by brepocitinib. In vivo, brepocitinib suppressed neutrophil recruitment induced by IL-23 or LPS in acute inflammation models. Overall, these findings demonstrate that TYK2/JAK1 inhibition mitigates IL-23/IL-17A-induced neutrophil-driven inflammation and GRβ upregulation in COPD. This highlights the JAK/STAT pathway as a promising therapeutic target to overcome severe airway inflammation and restore GRα/GRβ balance in neutrophils.

T helper 1 (T H 1) cells often accompany T H 17 cells across diverse tissues in health and disease, including the lungs. However, roles for the T H 1 effector cytokine, IFN-γ, in T H 17-driven type 3 inflammation is unclear. We devised a reductionistic model to determine the role of IFN-γ in IL-17A-driven inflammation during Streptococcus pneumoniae ( Spn ) infection in vivo. Briefly, intratracheal instillation of Spn along with recombinant TNF-α and IL-17A was used to mimic rapid Spn -specific, T H 17-driven, type 3 inflammation seen in lungs on memory recall infection with Spn . Co-instillation of recombinant IFN-γ was used to probe the role for this T H 1 cell-derived effector cytokine in anti- Spn immune response. Immune cellularity in bronchoalveolar lavage (BAL) was used to determine impacts of IFN-γ on type 3 inflammation in murine airways. Mice sufficient for- or lacking-IFN-γ or STAT1 were used to assess the immunoregulatory functions of IFN-γ in vivo . IFN-γ promptly muted IL-17A-induced inflammatory cell accumulation in Spn -infected airways through a STAT1-dependent mechanism. Both female and male mice demonstrated similar anti-inflammatory effects of IFN-γ on type 3 inflammation. Notably, the impact of IFN-γ was more striking at lower cytokine concentrations. The immunoregulatory effect of IFN-γ against T H 17-driven type 3 inflammation was also evident in physiologically relevant settings: while immunized wildtype (WT) mice controlled lethal Spn infection, immunized IFN-γ knockout mice exhibited even better Spn clearance. This heightened antimicrobial resistance, however, was accompanied by overt airway neutrophilia suggesting risk for immunopathology. Our findings identify a distinct immunoregulatory mechanism that operates within non-lymphoid tissues, where IFN-γ limits IL-17A-mediated type 3 inflammation via STAT1. Thus, the frequent accompaniment of T H 17 cells with T H 1 cells may represent a conserved mechanism that restrains immunopathological potential of T H 17-driven neutrophilic inflammation via STAT1 signaling in non-lymphoid tissues.