Respir. Res. [JOURNAL]
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200 papers
Correction: Geospatial and temporal trends of interstitial lung disease subtypes and KL-6 biomarker in China: a nationwide study (2016-2024).
Huang H, Chen Y, Liu C … +8 more , Liu M, Li H, Guo B, Chen X, Zheng P, Fang Y, Guo B, Sun B
Respir Res · 2026 Apr · PMID 42015110 · Full text
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Multi-omics characterises early immune divergence associated with infection-related deterioration after lung transplantation.
Liu Y, Song L, Yang Y … +11 more , Liu J, Guo W, Sun P, Wang K, Su R, Song D, Du J, Li J, Chen J, Wu B, Xie L
Respir Res · 2026 Apr · PMID 42010628 · Full text
BACKGROUND: Early adverse outcomes after lung transplantation often manifest as infection-associated clinical deterioration. Such events are closely intertwined with dysregulated perioperative immune reconstitution and a...
BACKGROUND: Early adverse outcomes after lung transplantation often manifest as infection-associated clinical deterioration. Such events are closely intertwined with dysregulated perioperative immune reconstitution and are influenced by immunosuppressive therapy. A systematic characterisation of the perioperative immune landscape and potentially actionable pathways may facilitate understanding of early trajectory divergence and inform perioperative monitoring and management. METHODS: We conducted longitudinal sampling and immune profiling at predefined perioperative time points in lung transplant recipients. A deeply profiled discovery cohort was constructed using multi-omics approaches including single-cell transcriptomics, B-cell receptor sequencing, plasma proteomics, and flow cytometry, and key findings were externally validated in an independent validation cohort. Healthy donors provided reference baselines for peripheral immune states. RESULTS: Outcome-associated immune divergence was detectable early and became more apparent by post-operative Day 7 (T2). At baseline (T0), recipients who later died tended to show a higher burden of CD177⁺ neutrophils, which may reflect a subclinical inflammatory state and a propensity for NETs-related activity. By T2, the Death group more frequently exhibited persistent inflammatory and infection-related deterioration with features of maladaptive humoral reconstitution, including plasmablast/plasma cell expansion, naïve B-cell depletion, skewed BCR clonality with restricted somatic hypermutation, and heightened BAFF/NETs activity alongside IgA-biased responses. The Live group generally showed a more resolving inflammatory course with relative preservation of B-cell homeostasis. CONCLUSIONS: These data suggest that CD177⁺ neutrophil–linked NETs–BAFF activity may contribute to early adverse trajectories after lung transplantation and may be informative for perioperative risk stratification. A composite assessment at T0 and T2 integrating CD177⁺ neutrophils, BAFF/NETs readouts, B-cell dynamics and immunoglobulin profiles may help identify recipients at risk of infection-related deterioration and nominate the first post-operative week as a potential window for carefully timed immune modulation.
PCSK6 and clinical outcomes in the Pulmonary Fibrosis Foundation Patient Registry.
Berger K, Konkol S, Ma SF … +11 more , Whalen W, Simmons W, Joseph C, Noth I, Huang Y, Oldham J, Moskaluk CA, Lynch D, Humphries S, Kim JS, Podolanczuk AJ
Respir Res · 2026 Apr · PMID 42010571 · Full text
BACKGROUND: Higher plasma proprotein convertase subtilisin/kexin type 6 (PCSK6) concentration has been associated with increased all-cause mortality in idiopathic pulmonary fibrosis (IPF). Its role across the broader spe...
BACKGROUND: Higher plasma proprotein convertase subtilisin/kexin type 6 (PCSK6) concentration has been associated with increased all-cause mortality in idiopathic pulmonary fibrosis (IPF). Its role across the broader spectrum of fibrotic interstitial lung disease (ILDs) remains unclear. We examined associations between PCSK6 and respiratory outcomes in participants with pulmonary fibrosis in the Pulmonary Fibrosis Foundation Patient Registry and evaluated its expression in fibrotic lungs. METHODS: PCSK6 concentration was measured in plasma from 428 participants with fibrotic ILD using ELISA and tested for association with time to death, lung transplant, first respiratory hospitalization, and 10% decline in forced vital capacity (FVC) using adjusted Cox models. Single-cell RNA sequencing (scRNA-seq) data obtained from the IPF Cell Atlas were used to examine expression across disease states. RESULTS: PCSK6 levels were not significantly associated with time to death, lung transplantation, respiratory hospitalization, or 10% FVC decline in the overall cohort, or in the subgroup of participants with usual interstitial pneumonia pattern of fibrosis. Among participants with IPF, higher PCSK6 was associated with reduced survival, consistent with prior findings. scRNA-seq of fibrotic lungs demonstrated high expression in HAS1 + fibroblasts. CONCLUSION: PCSK6 was not associated with worse respiratory outcomes in mixed fibrotic ILD but was associated with reduced survival in IPF. Its enrichment in HAS1 + fibroblasts suggests this pathway may be specific to IPF pathogenesis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12931-026-03642-1.
A syndromic framework for progressive pulmonary fibrosis.
Perrotta F, Luppi F, Sebastiani M … +1 more , Bianco A
Respir Res · 2026 Apr · PMID 41998741 · Full text
Pulmonary fibrosis comprises a heterogeneous group of interstitial lung diseases (ILDs) with diverse aetiologies but often convergent clinical behaviour. Idiopathic pulmonary fibrosis (IPF) represents the prototypical fi...
Pulmonary fibrosis comprises a heterogeneous group of interstitial lung diseases (ILDs) with diverse aetiologies but often convergent clinical behaviour. Idiopathic pulmonary fibrosis (IPF) represents the prototypical fibrotic ILD; however, a substantial proportion of patients with non-IPF fibrotic ILDs develop a progressive pulmonary fibrosis (PPF) phenotype characterised by irreversible functional decline, worsening symptoms, increased healthcare utilisation, and excess mortality. Although traditionally classified according to underlying cause, accumulating epidemiological, clinical, and biological evidence indicates that once progression emerges, fibrotic ILDs share common trajectories that transcend etiologic boundaries. Across IPF and non-IPF PPF, longitudinal decline in forced vital capacity represents the dominant marker of disease activity and prognosis, with similar rates of deterioration and comparable mortality risk. Shared genetic susceptibility factors—particularly variants affecting telomere maintenance and epithelial integrity—together with convergent fibrotic pathways suggest a common biological vulnerability that may influence disease behaviour beyond the original diagnosis. Clinically, patients with PPF exhibit symptom burden, quality-of-life impairment, risk of acute exacerbations, and need for advanced supportive care that largely overlap with those observed in IPF. Randomised clinical trials further reinforce this convergence, demonstrating that antifibrotic therapies attenuate lung function decline across IPF and PPF populations. Overall, current evidence supports the view that PPF might represent a clinical syndrome characterised by shared disease trajectories, common clinical needs, and comparable responses to antifibrotic therapy.
Proteomic profiling reveals immunologic mediators of endotoxin-related lung function decline: a longitudinal prospective study in textile workers.
Wang H, Goodney G, Zhang F … +8 more , Lai PS, Su L, Gao P, Lim J, Lo S, Liu Z, Christiani DC, Wong JYY
Respir Res · 2026 Apr · PMID 41998673 · Full text
BACKGROUND: Endotoxin is a major pathogenic component of cotton dust in the textile industry. While airborne endotoxin is associated with lung function decline, the underlying molecular mechanisms remain unclear. Proteom...
BACKGROUND: Endotoxin is a major pathogenic component of cotton dust in the textile industry. While airborne endotoxin is associated with lung function decline, the underlying molecular mechanisms remain unclear. Proteomic profiling could provide important insights into the pathways that drive the harmful respiratory effects of endotoxin. METHODS: We conducted serum proteomic profiling of 221 endotoxin-exposed cotton workers and 192 endotoxin-free silk workers from the longitudinal cohort of the Shanghai Textile Worker Study. Using blood samples collected in 2016, proteins were quantified by data-independent acquisition mass spectrometry and genotyping was assessed using low-pass whole genome sequencing. Forced expiratory volume in 1 s (FEV-1) was measured in 2011 and 2016. We used adjusted regression to identify differentially expressed proteins (DEPs) between the exposed and control groups. Causal mediation analyses were performed to identify protein mediators. Mendelian Randomization (MR) analyses provided causal estimates of protein effects on lung function change. RESULTS: Among 2,962 quantified proteins, we identified 224 proteins that were differentially expressed between cotton and silk workers (Bonferroni p < 0.05). Top enriched pathways associated with DEPs were the complement and coagulation cascades (KEGG: hsa04610) and the chemokine signaling pathway (KEGG: hsa04062). Adaptive immune proteins collectively mediated endotoxin-related lung function decline (binomial p = 9.63 × 10⁻⁹⁷). Two immunoglobulin domain proteins significantly (Bonferroni p < 0.05) mediated endotoxin effects on lung function change: Epididymis luminal protein 180 (HEL180) and IGL c3728_light_IGKV4-1_IGKJ1 (IGL c3728), with 46.4% (p = 0.04) and 46.9% (p = 0.05) proportion of the total effect that was mediated. MR estimates demonstrated that every 2-fold decrease in HEL180 and IGL c3728 expression was associated with an FEV-1 decline of 1.90 ml/year (95% CI: [0.79, 3.02]) and 2.36 ml/year (95% CI: [1.68, 3.02]), respectively. CONCLUSION: Using a trans-omic approach, our findings suggest that chronic endotoxin exposure suppresses immunoglobulin domain proteins, weakens adaptive immunity, and accelerates lung function decline. These findings provide greater precision in understanding biological mechanisms underlying endotoxin-related respiratory dysfunction.
MXD4 enhances resistance to KRAS G12C-targeted therapy in lung adenocarcinoma by suppressing ACSL4-mediated ferroptosis.
Yi Y, Hu Y, Ren S … +9 more , Wu Y, Chen X, Lu Y, Yu Q, Zuo D, Bi G, Wang Q, Zhan C, Bian Y
Respir Res · 2026 Apr · PMID 41998662 · Full text
BACKGROUND: KRAS G12C-targeted therapies have transformed the treatment of KRAS G12C-mutant lung adenocarcinoma. However, acquired resistance to these therapies, whose underlying molecular mechanisms are not fully unders...
BACKGROUND: KRAS G12C-targeted therapies have transformed the treatment of KRAS G12C-mutant lung adenocarcinoma. However, acquired resistance to these therapies, whose underlying molecular mechanisms are not fully understood, presents a major obstacle to achieving long-term therapeutic success. The purpose of this study was to elucidate the mechanisms of acquired resistance to KRAS G12C inhibitors and identify potential regulators of resistance in lung adenocarcinoma. METHODS: Two lung adenocarcinoma cell lines (H23 and H2122) were exposed to escalating doses of two novel KRAS G12C inhibitors, fulzerasib and garsorasib, to generate resistant variants. Transcriptomic profiling was conducted to identify genes consistently upregulated in resistant cells. CRISPR/Cas9-mediated knockout (MXD4-KO) and siRNA-mediated knockdown of MXD4 were performed to assess its role in drug resistance. Mechanistic investigations employed inhibitors of ferroptosis, apoptosis, and necrosis, along with assays measuring lipid peroxidation and malondialdehyde levels. Further analysis included ferroptosis-related gene expression profiling, lipidomic profiling, ChIP-Seq, ChIP-qPCR, and dual-luciferase reporter assays. The findings were validated in patient-derived organoids (PDOs) and nude mouse models. RESULTS: Transcriptomic profiling identified 11 genes consistently upregulated in resistant cells, with MXD4 emerging as a key resistance regulator. CRISPR/Cas9-mediated knockout of MXD4 restored sensitivity to fulzerasib, garsorasib, sotorasib, and adagrasib, an effect fully reversed upon MXD4 re-overexpression. Similarly, siRNA-mediated knockdown of MXD4 in resistant cells restored drug sensitivity. Mechanistic studies revealed that MXD4 specifically suppresses ferroptosis, rather than apoptotic or necrotic pathways, by repressing ACSL4 expression and blocking its catalytic synthesis of phosphatidylethanolamine-polyunsaturated fatty acids (PE-PUFAs). ACSL4 knockout or overexpression abolished MXD4’s ability to promote ferroptosis suppression and resistance to KRAS G12C inhibitors. ChIP-Seq, ChIP-qPCR, and dual-luciferase reporter assays confirmed that MXD4 directly binds to and represses the ACSL4 promoter. These findings were validated in PDOs and nude mouse models, where MXD4 knockout restored therapeutic sensitivity, while ACSL4 knockout blocked MXD4’s resistance-promoting effects. CONCLUSIONS: This study uncovers a novel resistance mechanism in which MXD4 transcriptionally silences ACSL4 to suppress ferroptosis, enabling cancer cells to evade KRAS G12C inhibitors. Targeting the MXD4-ACSL4 axis represents a promising strategy to overcome therapeutic resistance in KRAS G12C-mutant lung cancer, potentially improving long-term treatment outcomes.
A cross-sectional analysis of Behavioral Risk Factor Surveillance System (BRFSS) data to determine if tobacco and cannabis methods of administration are likely to be consistent across products.
Pebley K, McClure EA, Chen AA … +2 more , Toll BA, Rojewski AM
Respir Res · 2026 Apr · PMID 41998648 · Full text
Cannabis and tobacco co-use has increased over time, but research evaluating co-use risks rarely considers different cannabis or tobacco use modalities (e.g., smoking, vaping). Data were analyzed from 4,071 participants...
Cannabis and tobacco co-use has increased over time, but research evaluating co-use risks rarely considers different cannabis or tobacco use modalities (e.g., smoking, vaping). Data were analyzed from 4,071 participants from the 2022 Behavioral Risk Factor Surveillance System (BRFSS) survey, a nationally representative survey of United States adults, who endorsed past 30-day cannabis use and current cigarette smoking and/or vaping. A weighted multinomial logistic regression was used to determine if current tobacco use (cigarettes, vaping, or dual use; independent variable) was associated with cannabis use modality (only smoking, only vaping, or smoking and vaping cannabis; dependent variable), controlling for race, sex, and education level. Compared to individuals who smoked cigarettes, those vaping (odds ratio [OR] = 7.12, 95% confidence interval [CI]: 4.03, 12.58) or dual using (OR = 5.69, 95% CI: 2.66, 12.19) tobacco were more likely to vape cannabis than smoke cannabis. Additionally, compared to those who smoked cigarettes, individuals vaping (OR = 3.77, 95% CI: 2.73, 5.19) or dual using (OR = 4.62, 95% CI: 3.21, 6.64) tobacco were more likely to smoke and vape cannabis than exclusively smoke cannabis, but were less likely to smoke and vape cannabis than exclusively vape cannabis (OR = 0.53, 95% CI: 0.29, 0.97). Race and education level differences were also found. Results indicated adults co-using tobacco and cannabis may use the same consumption modality for both products (e.g., those smoking tobacco also smoke cannabis, while those vaping tobacco also vape cannabis), which has important implications for health risks.
PROK2 defines a pathogenic neutrophil subset and serves as a clinical indicator of neutrophilic inflammation in COPD.
Li R, Cheng C, Zhao X … +10 more , Xu H, Fei Y, Zhao S, Ma C, Liu Y, Liu P, Pei W, Ye J, Wang X, Zhao D
Respir Res · 2026 Apr · PMID 41998641 · Full text
PURPOSE: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease with progressive airflow limitation. However, the key pathogenic immune cell subset remains unknown. METHODS: A cigarette smoke...
PURPOSE: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease with progressive airflow limitation. However, the key pathogenic immune cell subset remains unknown. METHODS: A cigarette smoke-induced COPD mouse model was established. The composition, phenotypic state, and intercellular communication of immune cells in the lungs were characterized using scRNA-seq and flow cytometry. PROK2 and inflammatory mediators were validated by multiplex immunofluorescence and by ELISA in mice and patients with COPD. RESULTS: Chronic cigarette smoke (CS) exposure caused COPD and neutrophil-dominant immune remodeling. Notably, a neutrophil subset, PROK2+ neutrophils (Neu-PROK2), became the dominant neutrophil population, and exhibited elevated expression of matrix metalloproteinases (MMPs), NADPH oxidase components, and neutrophil extracellular traps-related genes, contributing to tissue injury under CS. Multiplex immunofluorescence also revealed PROK2 was primarily localized in alveolar LY6G⁺ neutrophils in CS lungs. Furthermore, Neu-PROK2 comprised an intermediate Ltf lo reservoir and a terminal hyperinflammatory Ltf hi state, forming a CS-driven continuum that progresses from Neu-PROK2 Ltf lo toward Ltf hi, with FOSL1 acting as an upstream driver. Importantly, Serum PROK2 was elevated in stable COPD, correlated positively with neutrophil-associated inflammatory/NET markers, and was inversely associated with eosinophil strata and lung function. CONCLUSION: Our study nominates PROK2⁺ neutrophils as a key pathogenic neutrophil subset in COPD and posits FOSL1 as a putative upstream driver. These findings suggest that PROK2 may serve as a candidate circulating biomarker associated with neutrophil-related inflammatory activity in COPD.
Quantitative computed tomography body composition analysis for risk stratification in bronchiectasis.
Semenzato U, Santello V, Fichera G … +12 more , Previtero D, Contin C, Rastelli A, Valvason R, Zuffellato M, Ferrari A, Micelli A, Giraudo C, Sattin A, Cattelan A, Spagnolo P, Tinè M
Respir Res · 2026 Apr · PMID 41998633 · Full text
BACKGROUND: Nutritional status and sarcopenia are established contributors to morbidity and mortality in chronic respiratory diseases. This study aimed to assess the prevalence and impact of body composition features ext...
BACKGROUND: Nutritional status and sarcopenia are established contributors to morbidity and mortality in chronic respiratory diseases. This study aimed to assess the prevalence and impact of body composition features extracted from computed tomography (CT) in patients with non-CF bronchiectasis. METHODS: We analysed data from 112 patients. Muscle and subcutaneous fat area and density were assessed by semi-automatic segmentation at the level of the 12th thoracic vertebra using the mediastinal window of routine chest CT scans. Clinical and functional features were compared between patients with and without body composition abnormalities. Associations between CT-derived body composition parameters and clinical outcomes were explored. RESULTS: The majority of patients were female (86/112, 77%) and the median age was 66 years (56–74). Myosteatosis (low muscle density) affected 75 of 112 (66%) patients. Patients with myosteatosis (MSp) were older than those without (wMSp), median age 70 (61–77) vs. 58 (45–69) years (p < 0.001), and had lower FEV1, 81 (69–95) vs. 89 (78–101) % pred. (p = 0.038) and MEF50, 48 (25–66) vs. 61 (44–74) % pred. (p = 0.043). The incidence of non-tuberculous mycobacteria (NTM) pulmonary disease was higher in MSp compared to wMSp (19% vs. 3%; p = 0.043). Muscular density negatively correlated with the Bronchiectasis Severity Index (r = − 0.32; p = 0.012), FACED (r = − 0.38; p = 0.03) and E-FACED (r = − 0.35; p = 0.007) scores. Myosteatosis was not related to gender, radiological extension of bronchiectasis, bacterial colonization or laboratory data. CONCLUSIONS: Myosteatosis is highly prevalent in patients with bronchiectasis and is associated with worse airflow obstruction, higher disease severity, and increased frequency of NTM pulmonary disease, independently from BMI. Abnormal body composition as defined by CT assessment may provide clinically relevant information beyond traditional anthropometrics and complement existing severity scores for risk stratification in patients with bronchiectasis.
Multiomic and functional validation of ACSL3, a regulator of fatty acid metabolism, as a lymph node metastasis-associated gene in lung adenocarcinoma.
Liang Y, Liang L, Du M … +3 more , Lei Y, Gao Y, Li S
Respir Res · 2026 Apr · PMID 41998631 · Full text
BACKGROUND: This study investigates the role of fatty acid metabolism (FAM)-related genes in lymph node metastasis (LNM) and prognosis of lung adenocarcinoma (LUAD) and elucidates the underlying mechanisms. METHODS: Tran...
BACKGROUND: This study investigates the role of fatty acid metabolism (FAM)-related genes in lymph node metastasis (LNM) and prognosis of lung adenocarcinoma (LUAD) and elucidates the underlying mechanisms. METHODS: Transcriptomic and single-cell RNA-seq data from TCGA and GEO were integrated to identify FAM-related genes. Non-negative matrix factorization clustering and univariate Cox regression were applied to develop a FAM-based prognostic risk model (FScore). Associations of FScore with gene mutations and tumor microenvironment features were analyzed. Immunohistochemistry, and functional assays were performed to alidate the role of ACSL3 in LUAD malignancy and lymphangiogenesis. RESULTS: A five-gene FAM-related risk signature (ACSL3, MCAT, NDUFAB1, OLAH, ACSL4) was identified. The derived FScore stratified patient prognosis across multiple independent cohorts, with high FScore linked to significantly worse overall survival. FScore increased progressively with nodal stage (N0 < N1 < N2) and correlated with an immunosuppressive “cold” tumor microenvironment and specific mutation patterns (e.g., low FLG mutation). Single-cell and spatial transcriptomics revealed cell-type–specific FAM activity, predominantly in epithelial, mast, and myeloid cells. ACSL3 was overexpressed in LUAD tissues and served as an independent poor prognostic factor. ACSL3 overexpression elevated intracellular triglyceride and phospholipid levels, upregulated key FAM enzymes (FASN, ACC, ACLY) and the c-Myc/VEGFC axis, promoted proliferation, migration, invasion, and lymphangiogenesis, while suppressing apoptosis. CONCLUSIONS: The FScore serves as a robust predictor of LNM and poor prognosis in LUAD. ACSL3 drives lymphatic metastasis via the c-Myc/VEGFC axis, positioning ACSL3 as a potential therapeutic target to suppress LNM in LUAD.
Comment: Increased exacerbations and hospitalizations among Pi*MZ compared to Pi*MM individuals?
Fromme M, Remih K, Strnad P
Respir Res · 2026 Apr · PMID 41998569 · Full text
Abstract loading — click title to view on PubMed.
Increasing propellant gas emissions from pressurized metered-dose inhalers in obstructive lung diseases in France over 11 years.
Mahé J, Muller G, Roche N … +4 more , Bourdin A, Grimaldi D, Patout M, Zysman M
Respir Res · 2026 Apr · PMID 41992276 · Full text
INTRODUCTION: Management of chronic obstructive respiratory diseases involves the use of inhaled therapies, including pressurized metered-dose inhalers (pMDIs) that contain hydrofluoroalkane (HFA). These propellant gases...
INTRODUCTION: Management of chronic obstructive respiratory diseases involves the use of inhaled therapies, including pressurized metered-dose inhalers (pMDIs) that contain hydrofluoroalkane (HFA). These propellant gases contribute to greenhouse gas emissions (GHG) due to their infrared radiation absorption capacity, resulting in a high Global Warming Potential, far higher than carbon dioxide (CO), contributing to climate change. The aim of this study was to estimate the carbon footprint of the propellant gases contained in all pressurized metered-dose inhalers prescribed in France, over an 11-year period. METHODS: Data were extracted from the French Health System Open Medic Database, covering 2014 to 2024. Gas quantities were obtained from the French Theriaque Database and, when unavailable, from pharmaceutical companies. Emissions were expressed as CO equivalents based on their corresponding Global Warming Potential values. RESULTS: Over the past decade, 500 million inhalers were dispensed, pressurized metered-dose inhalers representing 44% of them. Gas quantity data was available for 83% of the units. Over the 11-year period, total emissions reached 4.5 million MtCOeq. The mean annual emission was 409 ktCOeq, representing a 38,7% increase, particularly pronounced since 2021. DISCUSSION: This exhaustive national study shows that pressurized metered-dose inhalers emitted more than 4,5 MtCOeq in 11 years, increasing annually. These findings highlight the substantial carbon footprint associated with current inhalers containing high Global Warming Potential propellant gases and underline the need to promote lower-impact therapeutic alternatives.
Fibroblast activation protein inhibitor (FAPI) PET imaging in pulmonary fibrosis: pathophysiology, clinical utility, and emerging theranostic applications.
Al-Waqeerah A, He H, Bashah A … +3 more , Ghaleb E, Wang N, Gao L
Respir Res · 2026 Apr · PMID 41981646 · Full text
Pulmonary fibrosis arises from a dysregulated wound-healing response in which activated fibroblasts drive excessive extracellular matrix deposition and irreversible lung architectural distortion. Conventional high-resolu...
Pulmonary fibrosis arises from a dysregulated wound-healing response in which activated fibroblasts drive excessive extracellular matrix deposition and irreversible lung architectural distortion. Conventional high-resolution computed tomography (HRCT) detects largely established structural damage, limiting opportunities for early intervention. The fibroblast activation protein (FAP), a membrane-bound serine protease expressed on activated fibroblasts, presents a potential molecular target for imaging active fibrogenesis. The advent of fibroblast activation protein inhibitor (FAPI)–based radiotracers for positron emission tomography (PET) has been developed to visualize FAP expression in vivo. This review traces the translational continuum from FAP biology through radiotracer development to clinical application of FAPI-PET/CT in interstitial lung diseases, summarising preclinical and emerging human studies investigating FAPI PET/CT in interstitial lung diseases, highlighting preliminary evidence for the detection of early fibroblast activation, potential risk stratification, and monitoring of therapy response. We also discuss the functional heterogeneity of FAP-expressing fibroblast subsets and the interpretive challenges this poses for FAPI imaging. The review also considers early translational work on FAPI-based theranostics, combining diagnostic imaging with fibroblast-targeted radioligand approaches. While FAPI-PET/CT shows promise as a tool for characterizing fibrogenic activity, current evidence remains limited, and prospective studies are needed to clarify its clinical utility and potential role in guiding personalized interventions.
Short-term effects of air pollutants on asthma hospitalizations in a megacity in North China (2016-2021): a time-series study.
Niu W, Huang J, Hu Y … +2 more , Tang G, Wang G
Respir Res · 2026 Apr · PMID 41981581 · Full text
BACKGROUND: Asthma remains a major global health challenge, with air pollution triggering severe exacerbations. Current studies have reported inconsistent results due to limited pollutant coverage, small sample size, or...
BACKGROUND: Asthma remains a major global health challenge, with air pollution triggering severe exacerbations. Current studies have reported inconsistent results due to limited pollutant coverage, small sample size, or focus on mild cases. Beijing, with extreme air pollution, clear seasons, and dense population, provides an ideal setting to examine pollution-hospitalization relationships for asthma. METHODS: Using 2016–2021 data from 12 Beijing monitoring stations, we analyzed daily particulate matter ≤ 2.5 μm (PM₂.₅), particulate matter ≤ 10 μm (PM₁₀), sulfur dioxide (SO₂), nitrogen dioxide (NO₂) and carbon monoxide (CO) levels. A generalized additive time-series model with a Poisson distribution was used to investigate relative risks (RRs) and 95% confidence intervals (CIs) for asthma hospitalizations, stratified by sex, age, atopic status and season. RESULTS: All five air pollutants were significantly associated with the risk of asthma hospitalization, and each exhibited lagged effects. Per interquartile range (IQR) increase in pollutant concentration, RRs were: PM₂.₅ 1.018 (95% CI: 1.005–1.031), PM₁₀ 1.012 (1.003–1.021), SO₂ 1.019 (1.010–1.028), NO₂ 1.059 (1.041–1.077), and CO 1.025 (1.014–1.036). Strongest associations occurred in winter. Females, the elderly, and non-atopic individuals were most vulnerable. CONCLUSION: Short-term exposure to air pollutants increased asthma hospitalization risks, with amplified effects in females, the elderly, and non-atopic individuals. These findings highlight critical exposure windows and vulnerable populations, guiding targeted interventions. The registration number of this study in China’s National Medical Research Registration and Filing Information System is MR-11-23-009586.
Elarekibep, an inhaled anti-IL-4 receptor alpha Anticalin, in moderate-to-severe asthma: a randomized, placebo-controlled phase 2a study (APATURA).
Hugo T, Harper AR, Leander J … +14 more , Gardiner P, Palmér R, Lundin P, Bock D, Zhou XH, Bondarenko I, Burns S, Wiegert E, Fitzgerald MF, Close DR, Keeling DJ, Pandya H, Belvisi MG, O'Byrne PM
Respir Res · 2026 Apr · PMID 41981420 · Full text
BACKGROUND : The pro-inflammatory cytokines interleukin (IL)-4 and IL-13 and their cognate receptor IL-4 receptor-alpha are key targets for asthma therapy. Elarekibep is an inhaled Anticalin protein developed to inhibit...
BACKGROUND : The pro-inflammatory cytokines interleukin (IL)-4 and IL-13 and their cognate receptor IL-4 receptor-alpha are key targets for asthma therapy. Elarekibep is an inhaled Anticalin protein developed to inhibit IL-4 receptor-alpha signalling in patients with moderate-to-severe asthma not controlled with standard-of-care therapies. APATURA was a phase 2a study (NCT04643158) investigating the efficacy and safety of elarekibep in patients with moderate-to-severe asthma. METHODS : This was a randomized, placebo-controlled, double-blinded, multicentre, two-part study investigating elarekibep administered via dry powder inhaler twice daily for 4 weeks. Part 1 evaluated the safety and pharmacokinetics of elarekibep in patients with controlled moderate asthma, and part 2 evaluated the efficacy of elarekibep compared with placebo in those with uncontrolled moderate-to-severe asthma. RESULTS : In total, 72 patients were included (part 1: n = 50; part 2: n = 22) in the study. In part 1, approximately half of the patients receiving elarekibep (n = 20; 58.8%) or placebo (n = 8; 50.0%) experienced at least one treatment-emergent adverse event. Most of the treatment-emergent adverse events reported were of mild intensity. Elarekibep was steadily absorbed, with a median time to peak drug concentration of approximately 3–4 hours post-dose. In part 2, there was a mean increase from baseline in pre-bronchodilator forced expiratory volume in 1 second of 196 mL with elarekibep 3 mg compared with placebo (95% confidence interval: 14.3, 378; p = 0.035 vs placebo) at week 4. Improvements in Asthma Control Questionnaire-6 scores at week 4 were numerically superior with elarekibep 1 mg and 3 mg than with placebo. CONCLUSION : Elarekibep was clinically well tolerated with no identified short-term safety concerns. Development of elarekibep was terminated due to lung pathology findings in a 13-week non-human primate inhalation toxicology study, which were considered to be adverse and relevant for chronic clinical dosing. Nonetheless, the overall data demonstrate that there remains potential for the development of inhaled biologic therapies for patients with asthma that may offer advantages over systemically administered biologics. TRIAL REGISTRATION: NCT04643158 (ClinicalTrials.gov). Registered 23 November 2020.
Epoxyeicosatrienoic acids protect airway epithelial mitochondria by activating the cAMP/PKA-DRP1 Ser637 axis in cigarette smoke-induced lung injury.
Li Y, Yang A, Zhao R … +10 more , Wu B, Xu B, Lin F, Hu X, Liu S, Li X, Liu C, Fu L, Yan F, Yu G
Respir Res · 2026 Apr · PMID 41965679 · Full text
BACKGROUND: Cigarette smoke–induced airway epithelial injury is a central pathological feature of chronic obstructive pulmonary disease (COPD) and is closely associated with mitochondrial dysfunction. Excessive dynamin-r...
BACKGROUND: Cigarette smoke–induced airway epithelial injury is a central pathological feature of chronic obstructive pulmonary disease (COPD) and is closely associated with mitochondrial dysfunction. Excessive dynamin-related protein 1 (DRP1)–mediated mitochondrial fission contributes to epithelial oxidative stress and apoptosis; however, the endogenous regulatory mechanisms limiting aberrant DRP1 activation in the airway epithelium remain poorly understood. Epoxyeicosatrienoic acids (EETs), lipid mediators metabolized by soluble epoxide hydrolase (EPHX2), have been implicated in lung protection, but their role in regulating mitochondrial dynamics in cigarette smoke–exposed airway epithelium has not been established. METHODS: Wild-type and EPHX2-/- mice were exposed to chronic cigarette smoke to evaluate mitochondrial morphology, oxidative stress, epithelial apoptosis, and lung mechanics. In vitro, BEAS-2B airway epithelial cells were exposed to cigarette smoke extract (CSE) with pharmacological or genetic modulation of EET signaling. Mitochondrial structure and function, including reactive oxygen species production, mitochondrial membrane potential, and DRP1 phosphorylation status, were assessed using confocal microscopy, transmission electron microscopy, and immunoblotting. RESULTS: Chronic cigarette smoke exposure induced marked mitochondrial fragmentation, increased oxidative stress, and epithelial apoptosis, accompanied by enhanced DRP1 activation. Genetic deletion of EPHX2 or exogenous EET supplementation preserved mitochondrial network integrity and significantly attenuated DRP1-mediated mitochondrial fission in both in vivo and in vitro models. In vivo, restoration of inhibitory DRP1 Ser637 phosphorylation was associated with reduced mitochondrial fragmentation, whereas in vitro EETs promoted inhibitory DRP1 Ser637 phosphorylation via activation of the cAMP/PKA signaling pathway, thereby limiting pathological mitochondrial fission and mitigating epithelial cell injury. CONCLUSIONS: EETs act as endogenous modulators of mitochondrial dynamics in airway epithelial cells. By restraining DRP1-mediated mitochondrial fission, EET signaling protects against cigarette smoke–induced mitochondrial dysfunction and epithelial injury, supporting the EPHX2–EET axis as a mechanistically and clinically relevant pathway for further translational investigation in COPD.
Enhanced CCL2-CCR2 signalling promotes recruitment of monocyte-derived macrophages in progressive fibrosing hypersensitivity pneumonitis.
Santos RF, Cardoso CG, Pinto A … +23 more , Oliveira L, Coelho DB, Gonçalves M, Alexandre AT, Melo N, Mota PC, Neves I, Cardoso V, Guimarães S, Moura CS, Carvalho A, Flores L, Friões F, Fernandes P, Coelho A, Sokhatska O, Beltrão M, Delgado L, Vasques-Nóvoa F, Moreira AL, Morais A, Saraiva M, Bastos HN
Respir Res · 2026 Apr · PMID 41963948 · Full text
BACKGROUND: Hypersensitivity pneumonitis is characterized by immune dysregulation that often leads to irreversible lung tissue scarring. While elevated monocytes play a key role in idiopathic pulmonary fibrosis, their co...
BACKGROUND: Hypersensitivity pneumonitis is characterized by immune dysregulation that often leads to irreversible lung tissue scarring. While elevated monocytes play a key role in idiopathic pulmonary fibrosis, their contribution in progressive fibrotic hypersensitivity pneumonitis, along with the role of the CCL2 chemoattractant, requires clarification. METHODS: Immune characterization of circulating and lung markers of 71 patients with fibrotic hypersensitivity pneumonitis with median follow-up time of 35.8 months (57.7% progressed, 31% exacerbated), comparing with controls, non-fibrotic cases and idiopathic pulmonary fibrosis. RESULTS: Elevated serum CCL2 strongly associated with disease progression and acute exacerbations, with baseline levels above 1080 pg/mL predicting progression and shorter survival. Despite significant variability in CCL2 levels over time, their elevation near progression was consistent, suggesting a role for this chemokine in the fibrotic cascade. Moreover, classical monocytes from patients with progressive disease displayed higher CCR2 expression, and peripheral blood mononuclear cells from these patients showed enhanced CCL2-driven chemotaxis. Bronchoalveolar lavage immunophenotyping identified enriched CCR2 + monocyte-derived precursors in fibrotic hypersensitivity pneumonitis, implicating this cellular population in disease severity. Genetic analysis of CCL2/CCR2 revealed no association between their expression and known polymorphisms. Mechanistically, elevated CCL2 may drive disease progression by recruiting CCR2 + monocytes, contributing to the profibrotic microenvironment. CONCLUSIONS: These findings underscore the CCL2/CCR2 axis as a promising biomarker pathway for disease monitoring in fibrotic hypersensitivity pneumonitis, which could guide therapeutic interventions and stratification of high-risk patients.
Multidisciplinary management of interstitial lung disease in autoimmune rheumatic diseases: an Italian Delphi consensus.
Sebastiani M, Bargagli E, Cerri S … +6 more , Guiducci S, Manfredi A, Sgalla G, Vancheri C, Zanatta E, Luppi F
Respir Res · 2026 Apr · PMID 41963897 · Full text
BACKGROUND: Although guidelines recommend a multidisciplinary team (MDT) approach for the diagnosis and management of systemic autoimmune rheumatic disease-associated interstitial lung disease (SARD-ILD), they lack guida...
BACKGROUND: Although guidelines recommend a multidisciplinary team (MDT) approach for the diagnosis and management of systemic autoimmune rheumatic disease-associated interstitial lung disease (SARD-ILD), they lack guidance on MDT composition and function. This Delphi consensus project aimed to define a shared MDT model for managing patients with SARD-ILD. METHODS: A questionnaire was circulated to an expert panel of 77 Italian pulmonologists, rheumatologists, immunologists, and internal medicine specialists, with statements rated over two voting rounds using a 5-point Likert scale. RESULTS: Response rates were 73% and 95% for the first and second rounds, respectively, after which consensus (≥ 66.6% agreement) was achieved for all the statements. Consensus statements and recommendations address the responsibilities of healthcare professionals involved in an MDT, including organization, referrals, management, and standard outcomes. CONCLUSION: Although limited to Italy, the current consensus project is the first attempt to define shared rules for MDTs in the context of SARD-ILD, but further work is needed to achieve international consensus on this topic.
Diet-induced obesity alleviates epithelial damage in hyperoxic acute lung injury (HALI) in mice.
Kampelmann M, Pich A, Mühlfeld C … +1 more , Schipke J
Respir Res · 2026 Apr · PMID 41957652 · Full text
BACKGROUND: Oxygen therapy is often lifesaving for critically ill patients with acute respiratory distress syndrome (ARDS). However, high oxygen doses may cause hyperoxic acute lung injury (HALI). In line with the obesit...
BACKGROUND: Oxygen therapy is often lifesaving for critically ill patients with acute respiratory distress syndrome (ARDS). However, high oxygen doses may cause hyperoxic acute lung injury (HALI). In line with the obesity pandemic, numbers of ARDS patients with obesity are rising. Epidemiological data suggest higher morbidity but lower mortality in obese ARDS patients. However, it is currently unclear whether there is a biological basis for this “obesity paradox”. This study used a controlled animal model to investigate influences of diet-induced obesity on HALI-associated structural, molecular and functional changes of the lung. METHODS: Male C57BL/6N mice were fed either control diet (CD) or high fat diet (HFD) for 30 weeks. A subset of the animals was additionally exposed to normobaric hyperoxia (FiO2: 90%; Hyper) for 72 h. RESULTS: Hyperoxia was associated with reduced blood oxygenation and mechanical alterations indicative of pulmonary stiffening. Body fat depots were depleted in CD-Hyper, but not in HFD-Hyper groups. Morphological hallmarks of HALI including fragmentation and loss of epithelial cells as well as septal edema were significantly alleviated in hyperoxic obese mice. Diet-group specific changes in protein abundances suggested regulation of cellular stress response in CD-Hyper, whereas in HFD-Hyper predominantly metabolic and cell adaptive processes were altered. CONCLUSIONS: Diet-induced obesity did not influence functional measures in the acute phase of hyperoxia but prevented depletion of body fat reserves and mitigated structural lung damage indicating a beneficial impact on regeneration. This supports a biological basis for an obesity paradox in ARDS, and should be taken into account for future individualized prevention and therapy in obese patients.
Outcomes of patients with acute exacerbations of idiopathic pulmonary fibrosis treated with corticosteroids: a systematic review and meta-analysis.
Mondoni M, Albrici C, Puci MV … +8 more , Nalesso G, Cefalo J, Muresu N, Tirelli C, Belmonte LA, Ferranti G, Zava M, Sotgiu G
Respir Res · 2026 Apr · PMID 41957608 · Full text
BACKGROUND: Acute exacerbation of idiopathic pulmonary fibrosis (IPF) is the most severe complication and one of the main causes of death in these patients. No proven effective therapies have been reported until now but...
BACKGROUND: Acute exacerbation of idiopathic pulmonary fibrosis (IPF) is the most severe complication and one of the main causes of death in these patients. No proven effective therapies have been reported until now but high-dose corticosteroids are suggested by the international guidelines. METHODS: A search of the scientific evidence was carried out using PubMed, Embase, and Scopus. Observational and experimental studies describing clinical outcomes in adult patients with acute exacerbations of IPF treated with corticosteroids were included. RESULTS: 32 studies were selected for the qualitative and quantitative analysis. In patients treated only with corticosteroids, the pooled 90-day and in-hospital mortality rate was 42% (95% CI = 19-67%) and 43% (95% CI = 30-56%), respectively. Pooled 90-day mortality in patients treated with methylprednisolone at doses of 1000 mg/day was higher than in those treated with 500-1000 mg/day (i.e. 10 mg/kg/day) (54% (95% CI = 11-94%) VS. 39% (95% CI = 12 to 71%)). In patients with background antifibrotic therapy, the pooled 90-days mortality was of 39% (95% CI = 25-54%) while in those without was of 49% (95% CI = 10-89%). The 90-day and in -hospital mortality for patients receiving concomitant immunosuppressive therapy was 37% (95% CI = 29-46%) and 35% (95% CI = 12-62%), respectively. The overall 1-year mortality was 43% (95%CI = 30-56%). CONCLUSIONS: Patients with acute exacerbation of IPF treated with corticosteroids show a high short- and long-term mortality. Those treated with lower steroid doses and with background antifibrotic therapy show the highest short-term survival rates.
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