Respir. Res. [JOURNAL]
Sun
200 papers
COPD in China: the analysis of mortality and burden of disease trends from 2008 to 2021.
Tang C, Fan S, Zhang Y … +3 more , Li Z, Chen H, Liao K
Respir Res · 2026 Apr · PMID 41952222 · Full text
BACKGROUND: To determine basic death situation and assess trends in disease burden, we analyzed the death information of Chronic Obstructive Pulmonary Disease (COPD) among Chinese residents from 2008 to 2021. METHODS: Da...
BACKGROUND: To determine basic death situation and assess trends in disease burden, we analyzed the death information of Chronic Obstructive Pulmonary Disease (COPD) among Chinese residents from 2008 to 2021. METHODS: Data were collected from the Cause-of-Death Surveillance dataset in China. The Crude Mortality Rate (CMR), Age-Standardized Mortality Rate (ASMR), Potential Years of Life Lost (PYLL), and Potential Years of Life Lost Rate (PYLLR) of COPD among Chinese residents from 2008 to 2021 were calculated by Excel 2016. The trends of ASMR and PYLLR were assessed by the average annual percentage change (AAPC), and the difference in mortality was tested by Chi-square tests(χ tests). The age, period, and cohort effects on COPD mortality were analyzed by the Age-Period-Cohort (APC) model. RESULTS: The ASMR of COPD in Chinese residents decreased from 78.84/100,000 in 2008 to 27.81/100,000 in 2021 at an average annual rate of 8.41%, and the PYLLR of COPD in Chinese residents decreased from 1.28‰ in 2008 to 0.53‰ in 2021 at an average annual rate of 6.06%. From 2008 to 2021, the COPD ASMR and PYLLR among Chinese males were higher than females, urban areas were lower than rural areas, western China was higher than central China, and central China was higher than that in eastern China. The decline rate of COPD ASMR and PYLLR was significantly higher in females than males, rural areas than urban areas, and eastern/central regions than western regions. CONCLUSIONS: The mortality and disease burdens of COPD in China decreased yearly and were higher in the elderly, males, rural areas, and western China. The disease burden of COPD decreased more rapidly in women, rural areas, eastern and central China.
Efficacy and safety of telitacicept in patients with progressive interstitial lung disease associated with antisynthetase syndrome, rheumatoid arthritis, or Sjögren's syndrome: a prospective observational study.
Chen X, Sun M, Zhou Y … +4 more , Xiao F, Li M, Yang Y, Dai H
Respir Res · 2026 Apr · PMID 41952216 · Full text
BACKGROUND: Interstitial lung disease (ILD) is a severe complication of antisynthetase syndrome, rheumatoid arthritis, and Sjögren's syndrome, contributing significantly to patient mortality. Standard treatment options r...
BACKGROUND: Interstitial lung disease (ILD) is a severe complication of antisynthetase syndrome, rheumatoid arthritis, and Sjögren's syndrome, contributing significantly to patient mortality. Standard treatment options remain limited. This study evaluated the efficacy and safety of telitacicept, a dual-target inhibitor of B-lymphocyte stimulator and a proliferation-inducing ligand, in patients with these specific ILD subtypes. METHODS: This prospective observational study included 18 patients with ILD associated with antisynthetase syndrome (n = 5), rheumatoid arthritis (n = 5), or Sjögren's syndrome (n = 8). Participants either demonstrated resistance to standard immunosuppressive regimens or presented with other connective tissue diseases (CTDs) and complex multisystemic manifestations. All patients received subcutaneous telitacicept (160 mg weekly) combined with glucocorticoids. Primary outcomes were absolute changes in forced vital capacity percentage (FVC%) and diffusing capacity of the lungs for carbon monoxide percentage (DLCO%) at 24 weeks. Secondary outcomes included exercise capacity (6-minute walk test), radiographic changes (Warrick score), and disease activity indices. Comparisons between baseline and 24 weeks were performed using paired t-tests. RESULTS: After 24 weeks, lung function significantly improved across all groups. FVC% increased by 20.94% in antisynthetase syndrome-ILD, 10.83% in rheumatoid arthritis-ILD, and 12.19% in Sjögren's syndrome-ILD (all P < 0.05). Similarly, DLCO% improved by 30.61%, 8.61%, and 9.73%, respectively (all P < 0.05). Exercise capacity significantly increased, with 6-minute walk distances improving by over 20% in all subtypes. Radiographic assessment showed a significant reduction in lung lesions, with Warrick scores decreasing by 44.73%, 27.04%, and 30.12%, respectively. Systemic disease activity also decreased significantly, and patients successfully reduced their daily prednisone dose to 5-7.5 mg. No adverse reactions were observed during the study period. CONCLUSIONS: Telitacicept demonstrated significant clinical efficacy and a favorable safety profile in patients with ILD associated with antisynthetase syndrome, rheumatoid arthritis, and Sjögren's syndrome. These findings suggest telitacicept may be a promising therapeutic option for refractory or complex connective tissue disease-associated ILD.
Real-world evaluation of adherence to single-inhaler triple therapy in chronic obstructive pulmonary disease: the LIFE Study.
Ogata H, Tsubouchi K, Takano T … +4 more , Maeda M, Oda F, Okamoto I, Fukuda H
Respir Res · 2026 Apr · PMID 41947142 · Full text
BACKGROUND: Adherence and persistence for inhaled maintenance therapy markedly influence outcomes in chronic obstructive pulmonary disease (COPD). However, real-world data for single-inhaler triple therapy (SITT), includ...
BACKGROUND: Adherence and persistence for inhaled maintenance therapy markedly influence outcomes in chronic obstructive pulmonary disease (COPD). However, real-world data for single-inhaler triple therapy (SITT), including the effects of prior controller use and the selected regimen, have been limited. We here aimed to evaluate real-world adherence and persistence for SITT in COPD and to examine differences according to prior controller use and inhaler regimen. METHODS: Using the population-based LIFE Study administrative claims database in Japan, we conducted a retrospective cohort study of patients with COPD who newly initiated budesonide-glycopyrronium-formoterol (BGF) or fluticasone furoate–umeclidinium–vilanterol (FUV) between April 2020 and March 2022. Medication adherence over 12 months was assessed according to the proportion of days covered (PDC), with good adherence defined as a PDC of ≥ 0.80. Multivariable-adjusted risk ratios (RRs) for good adherence were estimated by modified Poisson regression. Treatment persistence was evaluated as time to discontinuation determined by Kaplan-Meier analysis with inverse probability of treatment weighting (IPTW), and differences were quantified as restricted mean survival time (RMST) over 365 days. RESULTS: Among 4077 individuals initiating SITT, only 36.4% achieved good adherence during the 12-month follow-up period. Controller-naïve patients were substantially less likely to achieve good adherence than patients with prior controller use (multivariable-adjusted RR, 0.37; 95% CI, 0.34–0.41). Treatment persistence was also worse for controller-naïve patients, with an IPTW-adjusted RMST that was 3.42 months shorter than that for patients with prior controller use (95% CI, − 3.67 to − 3.15 months). With respect to regimen, FUV was associated with a higher likelihood of good adherence compared with BGF (multivariable-adjusted RR, 1.40; 95% CI, 1.28–1.52) and showed longer treatment persistence (IPTW-adjusted RMST difference of 0.49 months; 95% CI, 0.22–0.76 months). CONCLUSIONS: Adherence and persistence for SITT were suboptimal among patients with COPD in real-world clinical practice, particularly among controller-naïve individuals. Although the once-daily FUV regimen was associated with better adherence and persistence than BGF, substantial gaps in treatment continuity persisted with both regimens. These findings highlight the need for enhanced support at treatment initiation and during early follow-up to optimize long-term SITT use in routine COPD care.
TRPC6 mediates goblet cell differentiation in COPD.
Li H, Hu G, Huang L … +26 more , Yi E, Di N, Li J, Hu C, Che L, Huang Y, Wang J, Wen Q, Yang X, Liu Y, Bai G, Lu X, Cao W, Mei X, Liu X, Li P, Wu F, Hao B, Pu J, Ran X, Sun R, Hong W, Peng Y, Zhou Y, Yin W, Ran P
Respir Res · 2026 Apr · PMID 41943027 · Full text
BACKGROUND: Goblet cell metaplasia is a pathological feature of airway remodelling in chronic obstructive pulmonary disease (COPD). Basal cell clones with goblet cell metaplasia demonstrate high transient receptor potent...
BACKGROUND: Goblet cell metaplasia is a pathological feature of airway remodelling in chronic obstructive pulmonary disease (COPD). Basal cell clones with goblet cell metaplasia demonstrate high transient receptor potential cation channel subfamily C member 6 (TRPC6) expression, but its biological function remains unclear. METHODS: TRPC6 expression was analysed by immunostaining in lung tissues and airway basal cells from patients with COPD, and in the airways of mice exposed to cigarette smoke or interleukin-13. In vitro, the role of TRPC6 was assessed by TRPC6 overexpression and depletion in air–liquid interface cultures of human bronchial epithelial cells. In vivo, TRPC6 function was tested by airway TRPC6 depletion and TRPC6 inhibition in mice exposed to interleukin-13. NOTCH signalling was confirmed as a downstream pathway of TRPC6 by performing rescue experiments. RESULTS: TRPC6 expression was increased in the airway epithelium of patients with COPD and in interleukin-13-exposed mice. TRPC6 overexpression in basal cells from patients without COPD promoted their differentiation into goblet cells, while TRPC6 depletion in basal cells from patients with COPD suppressed goblet cell metaplasia in air–liquid interface cultures. TRPC6 function in suppressed goblet cell metaplasia was confirmed in TRPC6 depletion mice and TRPC6 inhibitor-treated mice. NOTCH signalling increased in interleukin-13-exposed control mice and human bronchial epithelial cell air–liquid interface cultures and decreased after TRPC6 inhibition. CONCLUSIONS: TRPC6 regulated basal cell differentiation, underscoring its potential as a therapeutic target in COPD. The in vivo experiments used mice exposed to interleukin-13, so its clinical potential requires clarification.
Endothelial NEDD4L exacerbates acute lung injury by targeting A20 for ubiquitination degradation.
Huan C, Jia F, Liu P … +2 more , Xu Z, Shi Y
Respir Res · 2026 Apr · PMID 41943017 · Full text
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening critical diseases driven by uncontrolled inflammation and endothelial dysfunction, with limited effective targeted therapies ava...
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening critical diseases driven by uncontrolled inflammation and endothelial dysfunction, with limited effective targeted therapies available. NEDD4L, an E3 ubiquitin ligase, has been linked to ALI pathogenesis, but its role in endothelial cells remains undefined. Here, we explored the function and mechanism of endothelial NEDD4L in ALI. Single-cell RNA sequencing of a sepsis-induced ALI mouse model and in vitro assays revealed marked upregulation of NEDD4L in endothelial cells under ALI-related pathological stimuli (LPS, TNFα, H₂O₂). Endothelial cell-specific NEDD4L knockdown (NEDD4Lᴷᴰ) in mice significantly alleviated LPS-induced lung injury, as evidenced by reduced pathological damage, inflammatory infiltration, cytokine release and improved survival, and similar protective effects were observed in a CLP-induced ALI model. In vitro experiments confirmed that NEDD4L knockdown suppressed TNFα-induced endothelial activation and leukocyte adhesion. Mechanistically, NEDD4L directly bound to the anti-inflammatory protein A20, promoting its polyubiquitination and proteasomal degradation, which impaired A20-mediated inhibition of the JNK/p38/NF-κB pathway and upregulated the expression of pro-inflammatory cytokines and adhesion molecules. Rescue assays verified that A20 overexpression partially reversed NEDD4L induced pro-inflammatory effects. Collectively, our study identifies a novel NEDD4L-A20 axis in endothelial cells that contributes to ALI progression by modulating inflammatory signaling and endothelial dysfunction. Targeting this regulatory axis may provide a potential precise and cell-selective therapeutic strategy for alleviating ALI/ARDS.
KL-6 assisted subtyping of ARDS: from subtype-specific metabolomics to LPCAT1 as a pathogenic target.
Wang X, Xue M, Su L … +10 more , Luo X, Li Y, Fan S, Hu Q, Liao H, Jiang C, Chen J, Sun B, Li S, Wang H
Respir Res · 2026 Apr · PMID 41928265 · Full text
BACKGROUND: Acute lung injury (ALI) and the resulting acute respiratory distress syndrome (ARDS) exhibit marked clinical and biological heterogeneity, hindering subtype identification, biomarker discovery, and targeted t...
BACKGROUND: Acute lung injury (ALI) and the resulting acute respiratory distress syndrome (ARDS) exhibit marked clinical and biological heterogeneity, hindering subtype identification, biomarker discovery, and targeted therapy development. We used untargeted metabolomics to identify serum and bronchoalveolar lavage fluid (BALF) biomarkers across ARDS subtypes and potential therapeutic targets. We introduce a KL-6–assisted refinement of the Berlin Definition to separate patients with similar PaO₂/FiO₂ ratios but differing degrees of alveolar epithelial damage. METHODS: We enrolled 166 participants (137 ARDS, 29 controls). Using the Berlin Definition with KL-6–assisted classification, patients were stratified into common and severe subtypes. Serum metabolomes were compared between ARDS and controls and between subtypes; paired serum–BALF profiles characterized systemic vs. pulmonary features. Overlapping metabolites from four comparisons informed target prediction (SwissTargetPrediction, GeneCards), followed by in vitro and in vivo validation in LPS models. RESULTS: Serum profiles and pathway enrichment differed between ARDS and controls and between subtypes. The severe subtype was enriched in fatty-acid oxidation, dicarboxylic acids, and phospholipid remodeling. Three serum metabolites discriminated severe from other less severe ARDS subtypes (AUC > 0.8). This 3-metabolite panel achieved AUC 0.917 in 10-fold cross-validation. Paired analyses showed predominant systemic alterations with subtype-specific BALF signatures; five BALF metabolites were specific to the severe subtype and correlated with KL-6, oxygenation, inflammation, and CT scores. Five shared LysoPCs highlighted LPCAT1 as the top target. LPS upregulated LPCAT1, and this effect was partially reversed by TAK-242, a TLR4 inhibitor. Knockdown of LPCAT1 reduced inflammatory cytokine and MUC1 (KL-6) release in cell culture supernatants. CONCLUSION: KL-6–assisted subtyping reveals distinct systemic and pulmonary metabolic signatures. Three serum metabolites provide evidence that justifies KL-6 as a marker of epithelial-injury–informed ARDS classification, and our results suggest that LPCAT1 is a promising therapeutic target for ARDS.
Longitudinal dynamics and site-specific recovery of the human respiratory microbiome following smoking cessation.
Gschwendtner S, Kovacevic D, Gaede KI … +4 more , Herzmann C, Overmann J, Schloter M, Krauss-Etschmann S
Respir Res · 2026 Apr · PMID 41928236 · Full text
BACKGROUND: The human respiratory tract harbours diverse microbial communities crucial for health, but their dynamics during environmental perturbations like smoking remain poorly understood. While smoking is a major ris...
BACKGROUND: The human respiratory tract harbours diverse microbial communities crucial for health, but their dynamics during environmental perturbations like smoking remain poorly understood. While smoking is a major risk factor for various diseases, its compartment-specific effects on the respiratory microbiome and potential recovery following cessation have not been fully elucidated. Here, we present a longitudinal, multi-site study of respiratory microbiome dynamics in smokers undergoing cessation, benchmarked against healthy never-smokers. METHODS: Using standardized sampling of the anterior nares, oropharynx, and bronchoalveolar lavage (BAL), combined with 16S rRNA gene amplicon sequencing and rigorous contamination controls, we characterized community composition, diversity, inter-individual variability, and microbial interactions across airway compartments. RESULTS: Smokers exhibited pronounced microbiome alterations: nasal richness increased, while lung richness and core taxa were decreased. Smoking-induced changes were compartment-specific and most pronounced in nose and lung. The degree of individual-specific differences in community structure was elevated in smokers and correlated with smoking history. Short-term cessation (6 weeks) led to minor shifts in genus abundance but increased similarity between oropharyngeal and lung communities, whereas long-term cessation (1 year) resulted in partial restoration, particularly in lung and nasal microbiomes. Some genera, including Haemophilus and Prevotella_7, showed persistent alterations, suggesting lasting smoking effects. Network analyses revealed that smoking disrupted microbial co-occurrence and reduced community connectivity, whereas cessation partially restored interaction networks, with central taxa remaining altered and dynamics differing between oropharynx and lung, reflecting different underlying ecological assembly processes. Recovery trajectories were highly individualized, with lung microbiomes influenced by deterministic processes and upper airway microbiomes shaped by stochastic factors, explaining site-specific responses and the persistence of personalized microbial signatures. CONCLUSION: These results provide the first time-resolved, multi-compartment characterization of respiratory microbiome recovery after smoking cessation, revealing that smoking leaves lasting, site-specific imprints on airway microbial communities and interactions. Our findings underscore the need for individual and compartment-specific approaches when designing microbiome-based interventions to support respiratory health.
B cell activating factor (BAFF) levels are associated with failed remission after 12 months of treatment with benralizumab and mepolizumab in severe asthma.
Fischer BC, Drick N, Liu B … +8 more , Riemann L, Habener A, DeLuca D, Dittrich AM, Hoeper MM, Suhling H, Hansen G, Grychtol R
Respir Res · 2026 Apr · PMID 41928209 · Full text
The introduction of biologicals interfering with the interleukin-5 (IL-5) pathway has revolutionized the treatment of severe eosinophilic asthma (SEA), rendering remission an achievable goal even in patients with previou...
The introduction of biologicals interfering with the interleukin-5 (IL-5) pathway has revolutionized the treatment of severe eosinophilic asthma (SEA), rendering remission an achievable goal even in patients with previously uncontrolled disease. This study investigated whether specific plasma biomarkers or clinical features could predict clinical remission in patients treated with an IL-5- (mepolizumab) or IL-5 receptor alpha-antibody (benralizumab) for severe eosinophilic asthma. Clinical remission, defined as sustained symptom control, absence of exacerbations, stable lung function, and no need for systemic corticosteroids, was assessed after 12 months. Plasma levels of 30 cytokines and chemokines were measured at baseline and after three months in 41 patients receiving either mepolizumab or benralizumab. Twelve patients (29%) achieved remission. Clinical characteristics and commonly used biomarkers, including blood eosinophil counts and fractional exhaled nitric oxide, showed no significant association with remission. However, elevated levels of B cell–activating factor (BAFF) at baseline and 3 months follow-up were significantly associated with failure to achieve remission. Logistic regression analyses revealed that plasma BAFF levels were predictive for remission status outperforming conventional eosinophilic inflammation markers. These findings suggest that elevated plasma BAFF may indicate B cell–driven inflammatory in severe eosinophilic asthma, which is not adequately addressed by therapies targeting interleukin-5. BAFF may serve as a valuable biomarker to identify patients less likely to respond to interleukin-5–directed treatments and who may benefit from alternative therapies. Further research is needed to validate these findings and explore the role of BAFF in personalized treatment strategies for severe asthma.
Activation of α7nAChR prevents maladaptive right ventricular remodeling via inhibiting the recruitment of CCR2 macrophages in experimental pulmonary arterial hypertension.
Chen K, Li Z, Lu J … +4 more , Guo Y, Xie H, Wu F, Wu W
Respir Res · 2026 Apr · PMID 41923075 · Full text
BACKGROUND: The transition from adaptive to maladaptive right ventricular (RV) remodeling leads to RV failure (RVF), which is the strongest predictor of mortality in pulmonary arterial hypertension (PAH). However, effect...
BACKGROUND: The transition from adaptive to maladaptive right ventricular (RV) remodeling leads to RV failure (RVF), which is the strongest predictor of mortality in pulmonary arterial hypertension (PAH). However, effective treatments for PAH RVF are currently lacking. Recent studies have implicated C–C chemokine receptor type 2 (CCR2)+ macrophages in promoting PAH RVF. Stimulation of α7 nicotinic acetylcholine receptors (α7nAChR) expressed on macrophages regulates local and systemic inflammation. This study aimed to evaluate the effects of α7nAChR activation on RV remodeling and inflammation in PAH. METHODS: Monocrotaline (MCT)-induced PAH rats were used to mimic the continuum of RV remodeling. The dynamics of RV CCR2+ macrophages, CD43lowHis48high monocytes and inflammatory genes expression were investigated by immunostaining, flow cytometry and real-time polymerase chain reaction. MCT rats were treated with the selective α7nAChR agonist PNU-282987 or the antagonist methyllycaconitine consecutively for 4 weeks, starting 1 week after MCT injection. Echocardiography, hemodynamics and RV pathology were assessed. The abundance, functional phenotype and C–C chemokine ligand 2 (CCL2) secretion of RV CCR2+ macrophages were evaluated. In vitro activation of α7nAChR was performed on bone-marrow derived macrophages. RESULTS: Increased infiltration of RV CCR2+ macrophages and CD43lowHis48high monocytes, and elevated inflammatory gene expression were associated with maladaptive RV remodeling in PAH rats. In vivo, PNU-282987 reduced mortality, prevented maladaptive RV remodeling, and restored RV function. Furthermore, PNU-282987 inhibited the recruitment of RV CCR2+ macrophages by suppressing the CCL2-CCR2 chemotactic axis and enhanced the anti-inflammatory phenotype of RV CCR2+ macrophages. In vitro experiments confirmed these effects of PNU-282987 on CCR2+ macrophages. CONCLUSION: Activation of α7nAChR prevents PAH-induced maladaptive RV remodeling by inhibiting the recruitment of CCR2+ macrophages, thereby offering a novel therapeutic strategy for PAH RVF.
B1 cells drive pulmonary emphysema progression through ADAM10.
Lv R, Li Z, Zhao C … +5 more , Wang M, Shi F, Lu C, Duan J, Xu X
Respir Res · 2026 Mar · PMID 41917947 · Full text
BACKGROUND: The pathogenic role of B cells in pulmonary emphysema remains incompletely understood. This study aimed to delineate the specific B cell subsets and molecular mechanisms driving disease progression. METHODS:...
BACKGROUND: The pathogenic role of B cells in pulmonary emphysema remains incompletely understood. This study aimed to delineate the specific B cell subsets and molecular mechanisms driving disease progression. METHODS: Using single-cell RNA sequencing (scRNA-seq), we characterized lung B cell heterogeneity in a murine model of emphysema induced by porcine pancreatic elastase (PPE). Functional roles were assessed via B cell depletion and pharmacological inhibition of a disintegrin and metalloprotease 10 (ADAM10). RESULTS: Emphysema triggered the formation of pulmonary tertiary lymphoid structures (TLS) enriched with proliferating BAFF⁺ B cells. scRNA-seq revealed a selective expansion of B1 cells, primarily the B1b subset, which was accompanied by increased ICOS expression on lung CD4⁺ T cells. B cell depletion attenuated alveolar destruction, abolished TLS, reduced serum autoantibody levels, and improved lung function. Mechanistically, ADAM10 was specifically upregulated in B1 cells. Functional studies demonstrated that ADAM10, through activation of the Notch signaling pathway, was essential for the proliferation of B1 cells and their capacity to activate CD4+ T cells. Pharmacological inhibition of ADAM10 recapitulated the therapeutic effects, reducing B1 cell numbers, suppressing TLS formation, diminishing ICOS⁺ CD4⁺ T cells and autoantibody titers, and ultimately ameliorating lung pathology and function. CONCLUSION: Our findings identify ADAM10 as a critical regulator of B1 cell-driven immunopathology in emphysema, highlighting the ADAM10-Notch axis in B1 cells as a potential therapeutic target.
FGF21 promotes the resolution of inflammation through the ALOX15/SPM pathway in acute respiratory distress syndrome.
Shen C, Cao Y, Wei J … +11 more , Tian X, Zhang C, Wei X, Zeng J, Bao X, Xu J, Tong X, Zhou M, Yan X, Jin S, Wang Q
Respir Res · 2026 Mar · PMID 41913238 · Full text
Acute respiratory distress syndrome (ARDS) is a life-threatening clinical condition associated with high morbidity and mortality, mainly resulting from excessive inflammation and failure of inflammation-resolving mechani...
Acute respiratory distress syndrome (ARDS) is a life-threatening clinical condition associated with high morbidity and mortality, mainly resulting from excessive inflammation and failure of inflammation-resolving mechanisms. Fibroblast growth factor 21 (FGF21) is a metabolic regulator possessing anti-inflammatory properties; however, its role and mechanism in the resolution of inflammation remain unclear. This study showed that FGF21 facilitated the resolution of inflammation by promoting the production of specialized pro-resolving mediators (SPMs) in a mouse model of LPS-induced lung injury. SPMs, generated from arachidonic acid, docosahexaenoic acid, and eicosapentaenoic acid through enzymatic conversion by ALOX15 and related enzymes, exerted anti-inflammatory and pro-resolving effects by binding to their specific receptors. Furthermore, FGF21 was secreted by alveolar macrophages and acted in an autocrine manner to induce their polarization toward the M2 phenotype. Liquid chromatography-mass spectrometry revealed that FGF21 upregulated SPM production during the resolution phase by enhancing the expression of ALOX15 and SPM receptors on M2-polarized resident alveolar macrophages, thereby promoting the resolution of inflammation and attenuating lung injury. These findings provide new mechanistic insights into the resolution of ARDS.
CircATXN2 exacerbates pulmonary arterial hypertension by modulating the miR-138-5p/SMURF1 axis.
Qian Z, Kan J, Chen Y … +5 more , Ye P, Lv Y, Zhu L, Deng Y, Chen S
Respir Res · 2026 Mar · PMID 41913194 · Full text
BACKGROUND: Pulmonary arterial hypertension (PAH) is a chronic disease that is driven by the abnormal proliferation and migration of pulmonary artery smooth muscle cells (PASMCs). Although circular RNAs (circRNAs) have b...
BACKGROUND: Pulmonary arterial hypertension (PAH) is a chronic disease that is driven by the abnormal proliferation and migration of pulmonary artery smooth muscle cells (PASMCs). Although circular RNAs (circRNAs) have been implicated in cardiovascular diseases, their specific roles and mechanisms in pulmonary vascular remodeling remain largely unexplored. METHODS: The expression of circRNAs was evaluated in lung tissues from PAH mice and hypoxia-treated PASMCs. Gain- and loss-of-function experiments were conducted to assess the effects of circATXN2 on PASMC proliferation and migration in vitro and vascular remodeling in vivo. The levels of circATXN2 and miR-138-5p were detected by qRT-PCR, and the expression of SMAD ubiquitination regulatory factor 1 (SMURF1) was quantified using Western Blot. Interactions among circATXN2, miR-138-5p, and SMURF1 were investigated using bioinformatic prediction, RNA immunoprecipitation, luciferase reporter assays, and functional rescue experiments. RESULTS: We identified that circATXN2, derived from Ataxin-2 (ATXN2), was significantly upregulated both in vivo and in vitro. SMURF1 was increased due to the sequestration of miR-138-5p by circATXN2, which in turn enhanced SMAD 1/5/9 degradation and further interfered with the bone morphogenetic protein (BMP) pathway. Downregulation of circATXN2 significantly decreased the proliferation and migration of PASMCs and suppressed the development of PAH in mice. Furthermore, the pathological processes of circATXN2 could be attenuated either through the miR-138-5p elevation or SMURF1 reduction in PASMCs, proving the existence of circATXN2/miR-138-5p/SMURF1 regulatory axis. CONCLUSIONS: Our results demonstrated that circATXN2 promotes hypoxia-induced vascular remodeling via the miR-138-5p/SMURF1 axis, suggesting that targeting this pathway could offer a novel therapeutic strategy for PAH.
A 3-year prospective study to assess clinical characteristics and risk factors for exacerbations in patients with asthma-COPD overlap based on the GINA guideline compared with patients with asthma and COPD.
Ko FWS, Chan KKP, Ng TCC … +8 more , Lo RLP, Ngai JCL, To KW, Yip WH, Ng JKC, Chan C, Lau CHY, Hui DSC
Respir Res · 2026 Mar · PMID 41904521 · Full text
INTRODUCTION: Some patients exhibit characteristics of both asthma and COPD (asthma-COPD overlap [ACO]). There is no gold standard for diagnosing ACO, and limited prospective data exist on the medium-term outcomes of the...
INTRODUCTION: Some patients exhibit characteristics of both asthma and COPD (asthma-COPD overlap [ACO]). There is no gold standard for diagnosing ACO, and limited prospective data exist on the medium-term outcomes of these patients based on the Global Initiative for Asthma (GINA) definition compared to those with asthma or COPD alone. This study assessed the clinical characteristics and risk factors for acute exacerbations (AEs) in ACO patients versus those with COPD or asthma over 3 years. METHODS: Subjects aged over 40 years with a history of asthma and COPD, diagnosed by GINA and Global Obstructive Lung Disease (GOLD) guidelines, were recruited and followed for 3 years. Baseline assessments included a clinical history, symptoms, lung function, a 6-minute walk test (6MWT), blood eosinophil levels, and immunoglobulin E levels. ACO patients were identified per GINA 2017 criteria. AEs were recorded, and risk factors were assessed using Cox regression. RESULTS: Of 538 patients (299 asthma, 239 COPD), 78 (14.5%) were classified as ACO. Post-bronchodilator forced expiratory volume in 1 s (FEV1) % predicted (mean ± SD) was 83.1 ± 19.0% for asthma, 48.0 ± 19.0% for COPD, and 63.0 ± 22.2% for ACO (p < 0.001). Over 3 years, all AEs occurred in 59/272 (21.7%) asthma, 90/188 (47.9%) COPD, and 28/78 (35.9%) ACO patients, while severe AEs requiring hospitalization occurred in 24/272 (8.8%), 79/188 (42.0%), and 20/78 (25.6%), respectively. Compared to asthma patients, ACO patients had a significantly higher risk of first severe AE requiring hospitalization (p < 0.0001) but a lower risk compared to COPD patients (p = 0.014). Risk factors for AEs (all or severe) were: for asthma, prior AE history, shorter 6MWT distance, and lower lung function; for COPD, prior AE history, lower lung function, higher eosinophil count, and being underweight; for ACO, prior AE history and lower lung function. CONCLUSION: In this 3-year prospective study using the GINA definition, ACO patients showed an intermediate risk of severe AEs requiring hospitalization compared to asthma (higher) and COPD (lower), with prior exacerbation history and lower lung function as common risk factors across groups. TRIAL REGISTRATION: gov registration number NCT03272932 (registration date: 9 Jan 2017).
Vascular-related proteomic signatures in COPD with suspected pulmonary hypertension as predictors of FEV₁ impairment.
Goel K, Ormesher R, Pratte KA … +6 more , Wang Y, Nishino K, Hersh CP, Kechris K, Bowler RP, Petrache I
Respir Res · 2026 Mar · PMID 41904471 · Full text
BACKGROUND: The development of pulmonary hypertension (PH) is a serious complication of chronic obstructive pulmonary disease (COPD). Despite advances in characterizing pulmonary vascular remodeling in COPD-PH, the lack...
BACKGROUND: The development of pulmonary hypertension (PH) is a serious complication of chronic obstructive pulmonary disease (COPD). Despite advances in characterizing pulmonary vascular remodeling in COPD-PH, the lack of targeted therapies limits the routine use of gold-standard invasive diagnostics, highlighting the need for novel biomarkers. The pulmonary vascular endothelium is central to the pathogenesis of both PH and COPD. Since most endothelium-derived modulators of vascular tone and remodeling are targets of endothelial-enriched microRNA-126 (miR-126), a master vascular regulator that is suppressed in COPD, these and related ‘angiocentric molecules’ may be promising biomarkers for COPD-PH. RESEARCH GOAL: To identify angiocentric proteins elevated in individuals with suspected COPD-PH, defined by a pulmonary artery-to-aorta ratio (PA/A) > 1 on thoracic CT, and to evaluate if they are significantly associated with the severity of airflow limitation (FEV₁). STUDY DESIGN: We analyzed plasma proteomic profiles from 1,056 COPDGene Phase-1 participants. Using PA/A > 1 as the outcome, we identified differentially abundant angiocentric proteins. We then assessed the abundance of angiocentric proteins in those with severe airflow obstruction (FEV₁ <50% predicted) among both the COPDGene Phase-1 participants and 188 SPIROMICS Visit-1 participants, and validated the findings in an independent cohort of 363 COPDGene Phase-2 participants. Mediation analyses of multi-omic data examined the relationships between specific miR-126-3p and -p strands levels, their target mRNA and protein levels, and the severity of airflow obstruction. RESULTS: Seventeen angiocentric proteins were increased in participants with PA/A > 1, with interleukin-1 receptor-like 1 (IL1RL1) and platelet-derived growth factor B (PDGFB) showing the most significant elevations. Among those with FEV₁ <50% predicted, eleven angiocentric proteins were increased, including IL1RL1, angiopoietin-2, and peroxiredoxin-5. Mediation analyses supported a contribution of reduced miR-126 levels to lower FEV₁ via select angiocentric molecules, including the direct miR-126 target selenoprotein T. Additionally, LINC01506 and CAPZA1 had a mediation effect on multiple clinical outcomes, including FEV₁, DLCO, and hematocrit. CONCLUSION: In addition to their role in pulmonary vascular remodeling, miR-126–regulated angiocentric proteins are also linked to airflow limitation, highlighting their potential as candidate biomarkers for COPD-associated pulmonary hypertension.
Chronic allergic lung inflammation is associated with brain mast cell-mediated suppression of neuronal activity and behavioral changes in mice.
Trichas M, Kanaya A, Chen K … +5 more , Dantzler K, Hwang J, Emala C, Yang G, Mikami M
Respir Res · 2026 Mar · PMID 41896876 · Full text
BACKGROUND: We have previously observed depressive-like behaviors in mice following the development of chronic allergic lung inflammation that potentially involved brain mast cell activation. However, the specific brain...
BACKGROUND: We have previously observed depressive-like behaviors in mice following the development of chronic allergic lung inflammation that potentially involved brain mast cell activation. However, the specific brain regions that might be responsible for the observed behavioral changes were not identified. The anterior cingulate cortex (ACC) has been implicated in depression, and hypoactivity of this region is seen in the electroencephalogram of patients with depression. In the current study, we tested our hypothesis that chronic allergic lung inflammation causes mast cell activation that affects neuronal activity in the ACC, leading to depressive-like behavioral changes in mice. We further explored whether preventing mast cell activation during allergen administration modulates neuronal activity and attenuates behavioral changes. METHODS: Wild-type C57BL/6 J and Thy1-GCaMP6 mice were sensitized with intranasal house dust mite (HDM) antigen or control PBS for 6 weeks to induce chronic allergic lung inflammation. Intraperitoneal injection of cromolyn sodium was performed during HDM sensitization. Neurocognitive tests were carried out before and after the sensitization. In vivo cortical calcium imaging was performed through cranial windows in head-restrained awake mice, and spontaneous calcium activity was measured. Brain and lung tissues were harvested for assessment of inflammatory changes. RESULTS: Coronal sections of frontal cortex showed that mast cell-derived protease chymase expression was substantially increased in the ACC after 6 weeks of HDM treatment compared with PBS controls. The frequency of somatic calcium activity in ACC pyramidal neurons was reduced in HDM compared with PBS. Intraperitoneal administration of cromolyn sodium, a mast cell stabilizing agent, during HDM sensitization inhibited this frequency reduction observed in HDM sensitized mice. Behavioral changes observed in HDM sensitized mice by open field, light–dark and sucrose preference tests, were attenuated in mice that received cromolyn sodium during HDM sensitization. CONCLUSIONS: Cerebral mast cell degranulation and decreased somatic calcium activity of pyramidal neurons were observed in the ACC of mice with allergic lung inflammation. Co-administration of mast cell stabilizer cromolyn prevented this allergen-induced hypoactivity and behavioral changes. The activation of mast cells in ACC and decreased pyramidal neuronal activity may play a role in the depressive behaviors observed in mice after chronic HDM sensitization.
Update on pulmonary hypertension.
Olschewski H
Respir Res · 2026 Mar · PMID 41888869 · Full text
The hemodynamic definition of pulmonary hypertension including a mean pulmonary arterial pressure > 20 mmHg is evidence based, but the threshold of 15 mmHg for the pulmonary arterial wedge pressure, deciding between pre-...
The hemodynamic definition of pulmonary hypertension including a mean pulmonary arterial pressure > 20 mmHg is evidence based, but the threshold of 15 mmHg for the pulmonary arterial wedge pressure, deciding between pre-and postcapillary PH, is not. Indeed, based on the most recent literature, the normal PAWP is ≤ 13.0 mmHg, raising some interesting questions. The TASK Force on treatment of pulmonary arterial hypertension (PAH) at the latest world symposium for pulmonary hypertension published a new therapeutic algorithm for PAH that looks simpler than the previous algorithm. However, this algorithm exclusively refers to high-quality evidence from pivotal studies. Sildenafil appears to be safe and effective up to 80 mg TID, combination pills including macitentan and tadalafil are available. The activin signaling inhibitor sotatercept has changed our way of thinking about PAH therapy due to unprecedented efficacy. It is highly efficacious not only in WHO FC 2–3 but also in WHO FC 4 PAH. However, according to the recent literature, the long-term effects include systemic and pulmonary microvascular malformations. The serotonin-, tyrosine kinase-, estrogen, and carboanhydrase pathways have successfully been targeted in several PH models and showed excellent safety profiles in early clinical development. However, the approval-oriented clinical studies, published in high-ranking journals, have only met their primary endpoint in case of inhaled seralutinib and inhaled MK5475. Group 3 PH comprises patients which pulmonary hypertension associated to chronic lung diseases or chronic hypoxia. However, there is an overlap between idiopathic PAH with a “lung phenotype” and Group 3 PH. In Europe, PAH targeted therapies have not been approved for group 3 PH. Treatment for COPD PH appears to be more challenging than treatment of ILD PH. However, according to a large retrospective study, sildenafil might provide beneficial effects for COPD PH patients, particularly in those with a strongly elevated PVR and a relatively well-preserved FEV1. For chronic thromboembolic pulmonary disease, pulmonary endarterectomy is therapy of choice. If this is not feasible, balloon pulmonary angioplasty is superior to medical therapy with riociguat. However, among medical therapies, riociguat still appears to be the most reliable medication that is globally approved for CTEPH.
A longitudinal study of quantitative pulmonary dynamic contrast enhanced MRI following COVID-19 infection.
Campbell-Washburn AE, Kanth S, Thurston MD … +9 more , Mancini C, O'Brien KJ, Potersnak A, Wang H, Huapaya J, Regenold D, Baute S, Javed A, Suffredini AF
Respir Res · 2026 Mar · PMID 41888852 · Full text
BACKGROUND: Changes in pulmonary microvascular perfusion after SARS-CoV-2 infection remains poorly characterized due to limitations in longitudinal imaging. To provide a longitudinal evaluation of lung perfusion, we used...
BACKGROUND: Changes in pulmonary microvascular perfusion after SARS-CoV-2 infection remains poorly characterized due to limitations in longitudinal imaging. To provide a longitudinal evaluation of lung perfusion, we used quantitative dynamic contrast enhanced MRI (DCE-MRI) on a 0.55T MRI system in patients following COVID-19. METHODS: In this prospective study, we performed quantitative DCE-MRI to generate perfusion maps on patients with a history of COVID-19 between June 2020 and June 2023. Imaging studies were divided into acute, recovery, convalescent, and extended study phases, collected over 3 years. Median lung perfusion, perfusion heterogeneity, perfusion defect percent, pulmonary transit time, arterial transit time, and transit time defect percent were measured. Perfusion metrics were correlated with pulmonary function tests (PFT), disease severity, cardiorespiratory symptoms, vaccine status, viral variant, and chest CT findings. RESULTS: We included 84 post-COVID-19 patients and 156 separate DCE-MRI exams for analysis, and 10 healthy volunteers. Statistical significance between patients with COVID-19 and healthy volunteers was observed for perfusion defect percent in all study phases (p < 0.01). Five patients had visible perfusion defects. Lower median perfusion was found in patients with low diffusing capacity for carbon monoxide (DLCO) in the recovery phase (p = 0.02), and patients with heterogeneous perfusion maps in the acute phase were more likely to have low DLCO at their final PFT measurements (p = 0.01). During the convalescent phase, patients with residual symptoms had lower median perfusion (p = 0.01), unvaccinated patients had higher transit time defect percent (p = 0.0047), and ground glass opacities on CT were associated with lower median perfusion (p = 0.004). CONCLUSIONS: Pulmonary microvascular perfusion abnormalities are found months after COVID-19, with correlative findings in patients with persistence of pulmonary symptoms and impaired pulmonary function. Our findings further support the utilization of DCE-MRI in a broad range of pulmonary vascular disorders. TRIAL REGISTRATION: clinicaltrials.gov NCT04401449 (registered 2020-05-22) and NCT03331380 (registered 2017-11-02).
Ex vivo allergen specific type 2 immune responses in house dust mite-driven acute airway inflammation in mice depend on allergen extract characteristics.
Verstegen REM, Thijssen S, Kostadinova AI … +4 more , Garssen J, Folkerts G, Hendriks RW, Willemsen LEM
Respir Res · 2026 Mar · PMID 41888808 · Full text
House dust mite (HDM) is frequently used in animal models of allergic airway diseases. HDM extracts differ in allergen concentration and endotoxin contamination, requiring model optimalization for each batch. This study...
House dust mite (HDM) is frequently used in animal models of allergic airway diseases. HDM extracts differ in allergen concentration and endotoxin contamination, requiring model optimalization for each batch. This study aimed to refine and validate our murine model of HDM-driven acute allergic airway inflammation with a new batch of HDM extract and comparing different administration doses.We evaluated three HDM extracts, HDM1 (old batch), HDM2 and HDM3, containing varying Der p1 concentrations (33.7, 71.4 and 9.0 mg/g protein) and endotoxin levels (94.8, 53.9 and 24.7 EU/g protein). Male BALB/c mice were intranasally sensitized (day 0) with 1 µg (HDMlow) or 5 µg (HDMhigh), and challenged (day 7–11) with 10 µg (HDMlow) or 15 µg (HDMhigh) of the same HDM extract. Bronchoalveolar lavage fluid (BALF), lung tissue and serum were collected on day 14.High doses of all extracts significantly increased BALF total cell influx, including eosinophils and lymphocytes, and elevated lung Th2 and CD69 + Th2 cell frequencies. Eosinophils and lymphocytes induction varied across extracts (6–17 × 104 and 3–8 × 104 cells respectively). HDM3high tended (p < 0.1) to increase serum HDM-specific IgE. Upon ex-vivo HDM-restimulation of lung cells comparing HDM3 high with HDM2 high, only cells of HDM3high-treated mice showed increased IL-5 and IL-13 production.Overall, the high dose protocol most effectively induced HDM-driven acute allergic airway inflammation, based on BALF eosinophil and lymphocyte influx. Even though having low Der p1 and endotoxin levels, only HDM3high enhanced cytokine production upon ex-vivo HDM-restimulation, indicating the value of this functional assay to discriminate between HDM batches.
Expression of complement pathway genes is associated with progression of idiopathic pulmonary fibrosis.
Swaminathan AC, Mulder H, Neely ML … +5 more , Schmid R, Belperio JA, Patel NM, Palmer SM, Todd JL
Respir Res · 2026 Mar · PMID 41882705 · Full text
BACKGROUND: Studies suggest that the complement pathway may play a role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). We evaluated associations between complement pathway gene expression and clinical outcom...
BACKGROUND: Studies suggest that the complement pathway may play a role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). We evaluated associations between complement pathway gene expression and clinical outcomes in patients with IPF. METHODS: RNA was extracted from blood samples collected at enrollment into the IPF-PRO Registry. Patients were divided into discovery (n = 261) and validation (n = 609) cohorts. Patients were followed prospectively while receiving usual care. Using Cox proportional hazards models, we evaluated associations between expression of 45 complement pathway genes and three clinical outcomes. Analyses were unadjusted and adjusted for clinical variables at enrollment. RESULTS: Eight complement pathway genes (CR1, CD59, C2, C1QTNF6, ITGB3, C1QBP, CD55, CR2) were associated with ≥ 1 outcome in the discovery cohort and evaluated in the validation cohort. In the discovery cohort, in unadjusted analyses, higher expression of the membrane-bound complement regulators CR1, CD55, and CD59 was associated with increased risk (hazard ratios [HRs]: 1.75 [95% CI 1.27, 2.41], 1.40 [1.06, 1.85] and 1.62 [1.17, 2.23], respectively), and higher expression of complement pathway component C2 with a decreased risk (HR 0.75 [0.61, 0.91]), of disease progression (absolute decline in forced vital capacity % predicted ≥ 10%, death, or lung transplant). Associations of CR1, CD55 and C2 with disease progression persisted in the validation cohort in adjusted analyses. In the discovery cohort, in unadjusted analyses, higher expression of CR1 and CD55 was associated with increased risk (HRs 2.66 [1.68, 4.23] and 1.90 [1.24, 2.93], respectively), and higher expression of C2 with a decreased risk (HR 0.61 [0.46, 0.80]), of respiratory death; associations with CR1, CD55, and C2 persisted in the validation cohort in adjusted analyses. In the validation cohort, increased expression of C2 was associated with reduced risk of respiratory hospitalization in adjusted analyses (HR 0.65 [0.50, 0.83]). Principal component analysis identified a composite score including complement components and regulators that was associated with increased risk of disease progression and respiratory death in both cohorts. CONCLUSIONS: Higher expression of complement regulators and lower expression of complement components, individually and in combination, may be biomarkers of progression of IPF. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01915511). Registered 5 August 2013, https://clinicaltrials.gov/ct2/show/NCT01915511 .
Compartmental analysis of the pulmonary proteome reveals novel functions of the aryl hydrocarbon receptor.
Wilson ET, Heimbach NS, Gorgani R … +4 more , Rijnbout-St James W, Aloufi N, Eidelman DH, Baglole CJ
Respir Res · 2026 Mar · PMID 41882680 · Full text
UNLABELLED: As a barrier organ, the lungs are continuously exposed to environmental stimuli and rely on molecular sensors to detect and respond to these external cues. One such sensor is the aryl hydrocarbon receptor (Ah...
UNLABELLED: As a barrier organ, the lungs are continuously exposed to environmental stimuli and rely on molecular sensors to detect and respond to these external cues. One such sensor is the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor traditionally recognized for its role in xenobiotic metabolism. However, this function is a relatively recent evolutionary adaptation of the AhR. Beyond its detoxification role, AhR has been implicated in developmental and homeostatic processes, as evidenced by defects in AhR-deficient mice. Despite this, the contribution of endogenous AhR activity to pulmonary homeostasis remains poorly defined. To address this gap, we leveraged high-resolution proteomics from lung tissue, bronchoalveolar lavage fluid (BALF), and extracellular vesicles (EVs) of AhR-expressing and AhR-knockout mice to define the role of AhR in shaping the pulmonary proteomic landscape. Our analysis reveals that each compartment exhibits a distinct proteomic signature and that AhR plays a central role dictating that composition within each compartment. Notably, AhR regulates proteins involved in epithelial barrier function, alveolar macrophage lipid handling, and the selective packaging of bioactive cargo into EVs. These findings identify AhR as a key regulator of structural and immune balance in the lung and uncover new functions of this receptor in maintaining pulmonary homeostasis. Furthermore, our work highlights the potential of EVs as sensitive indicators of AhR activity and offers new insight into therapeutic strategies targeting AhR signaling in respiratory disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12931-026-03593-7.
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