Respir. Res. [JOURNAL]
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200 papers
Danthron prevents pulmonary fibrosis through improving mitochondrial function by upregulating carboxylesterase 3.
Li B, Xu R, Zheng H … +6 more , Tian Z, Wang S, Xu S, Yang D, Zhao J, Xie J
Respir Res · 2026 Jun · PMID 42265751 · Full text
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is marked by excessive deposition of extracellular matrix (ECM) and persistent fibroblast activation in the lungs, posing challenges for advancing effective treatment strat...
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is marked by excessive deposition of extracellular matrix (ECM) and persistent fibroblast activation in the lungs, posing challenges for advancing effective treatment strategies. Danthron, a natural anthraquinone derivative extracted from traditional Chinese medicine rhubarb, exhibits antitumor and antioxidant efficacy. METHODS: A bleomycin (BLM)-induced pulmonary fibrosis (PF) mouse model and human precision-cut lung slices (hPCLSs) stimulated with a pro-fibrotic solution were employed. The therapeutic effects of danthron on PF were measured by histological manifestations, immunostaining and expression levels of fibrotic markers. Human fibroblasts (HFs) were utilized to explore the underlying mechanism of danthron on fibroblast function. RESULTS: Our data showed that danthron significantly mitigated BLM-induced PF by reducing collagen deposition and Ashcroft scores in mice. Danthron also suppressed the abundance of fibrotic markers in mouse lungs and hPCLSs. Additionally, danthron impeded the transition of lung fibroblasts to myofibroblasts while promoting their dedifferentiation. Mechanistically, the anti-fibrotic effect of danthron was associated with the upregulation of carboxylesterase 3 (CES3), which consequently enhanced mitochondrial function and mitophagy in fibroblasts. Pharmacological CES3 inhibition (WWL229) reversed these effects, whereas genetic CES3 overexpression potentiated its mitochondrial benefits. Moreover, WWL229 nullified the beneficial effects of danthron in BLM-induced PF. The downregulation of CES3 was identified in IPF patients, which exhibited a negative correlation with fibrotic genes. CONCLUSIONS: This study demonstrated danthron as a valuable experimental tool for identifying relevant targets in preclinical models while underscoring CES3 as a potential therapeutic target for PF.
Targeting IL-33 in COPD: mechanistic lessons from clinical trials and the path forward.
Tancevski I, Sonnweber T
Respir Res · 2026 Jun · PMID 42260523 · Full text
BACKGROUND: Interleukin-33 (IL-33) is a promising therapeutic target in chronic obstructive pulmonary disease (COPD). However, recent clinical trial setbacks have highlighted the complexity of its biology. This review ex...
BACKGROUND: Interleukin-33 (IL-33) is a promising therapeutic target in chronic obstructive pulmonary disease (COPD). However, recent clinical trial setbacks have highlighted the complexity of its biology. This review examines the functions of IL-33 in inflammation, host defense, and tissue remodeling and discusses the potential benefits and harms of targeting this pathway in patients with COPD. METHODS: We synthesize data from clinical trials of anti-IL-33/ST2 agents and integrate these findings with recent molecular and cellular immunology research to elucidate IL-33's dual functionality, induced by the reduced IL-33 and oxidized IL-33 isoforms. Additionally, we highlight the impact of modifying factors, including multimorbidity, exogenous exposures, and microbial pathogens, on the IL-33 cascade. RESULTS: Divergent trial outcomes in patients with COPD treated with anti-IL-33 and anti-ST2 antibodies revealed critical mechanistic insights. Inconsistent efficacy of single-pathway inhibitors likely reflect incomplete targeting of IL-33's dual functionality. While the IL-33red/ST2 pathway drives type 2 inflammation, it is also essential for neutrophil-mediated antibacterial host defense. In contrast, IL-33ox signals through the RAGE/EGFR axis to promote steroid-resistant epithelial remodelling and mucus hypersecretion, a pathway not addressed by ST2-targeted therapies. Experimental data suggesting a potential increase in infection risk associated with anti-IL-33 therapies further underscore the clinical relevance of these mechanistic considerations. CONCLUSIONS: Effective IL-33-targeted therapy in COPD will require a mechanistically comprehensive strategy with precision medicine approaches that address patient heterogeneity, including infection risk and comorbidity burden, and incorporate assessment of IL-33 redox states, soluble ST2, and soluble RAGE.
Genetic and epidemiological evidence linking respiratory and musculoskeletal diseases: shared risk factors and intervention windows.
Murrin O, Voller B, Woodward RM … +17 more , Carrasco-Ribelles LA, Türkmen D, Gu Q, Boddy K, Farmer L, Mancini M, Khalid S, Aveyard N, Fox C, Bowden J, Dudbridge F, Lamb SE, Masoli JAH, Violán C, Pilling LC, Frayling TM, Delgado J
Respir Res · 2026 Jun · PMID 42260503 · Full text
BACKGROUND: We previously identified genetic correlation between pairs of musculoskeletal (MSK) and respiratory conditions. Strategies to prevent or delay their onset remain underexplored in the context of multimorbidity...
BACKGROUND: We previously identified genetic correlation between pairs of musculoskeletal (MSK) and respiratory conditions. Strategies to prevent or delay their onset remain underexplored in the context of multimorbidity. This study investigated whether MSK-respiratory disease pairs show evidence of potential causal relationships, identified modifiable risk factors, and quantified intervention windows to prevent progression to multimorbidity. METHODS: We examined combinations of one respiratory condition (asthma, COPD) and one MSK condition [rheumatoid arthritis (RA), osteoarthritis (OA), polymyalgia rheumatica (PMR), psoriasis]. Two-sample Mendelian randomisation (MR) evaluated potential causal relationships in both directions. Linked electronic health records from CPRD (N = 11,042,985; age ≥ 40 years) were used to assess longitudinal disease trajectories, prognostic consequences, and mediation by potentially modifiable or treatable factors. RESULTS: We found evidence for bidirectional relationships between COPD and RA/OA (ORs 1.10-1.19) and between asthma and RA/OA (ORs 1.03-1.14). COPD genetic liability also increased PMR risk (OR 1.14, 95% CI 1.03-1.25). Psoriasis liability increased risk of COPD (OR 1.04, 95% CI 1.02-1.07) and asthma (OR 1.05, 95% CI 1.03-1.08). Across disease pairs, the median interval between first and second diagnoses was 5-13 years, indicating a substantial window for intervention. Obesity, smoking, hypertension, and thyroid conditions were risk factors common across all studied conditions. Mediation analyses suggested reduced physical activity and lipid changes partially contributed to the onset of respiratory disease following MSK conditions. Colocalisation identified genetic variants causal for specific condition pairs (implicating genes IFIH1, APOE, and CXCR5), highlighting inflammatory and lipid pathways. CONCLUSIONS: MSK and respiratory conditions commonly develop sequentially over many years. Targeted strategies promoting physical function, optimising lipid and cardiovascular risk management may help delay or prevent multimorbidity progression.
Benchtop NMR as a clinical tool for acute respiratory illness: metabolic signatures associated with disease severity.
Alonso-Moreno P, Blasco-Iturri Z, Gotera Rivera C … +11 more , Murillo R, de Benito-Rodríguez LA, Ferruelo A, Pérez-Collar Á, Zambrano Chacón MLÁ, Beraza M, Peces-Barba G, Herrero R, Ruiz-Cabello J, Lorente JA, Izquierdo-Garcia JL
Respir Res · 2026 Jun · PMID 42260468 · Full text
BACKGROUND: Acute respiratory failure remains a major challenge in critical care, and early identification of patients at risk of clinical deterioration is essential. Metabolomics provides a systems-level characterizatio...
BACKGROUND: Acute respiratory failure remains a major challenge in critical care, and early identification of patients at risk of clinical deterioration is essential. Metabolomics provides a systems-level characterization of disease severity but its clinical implementation is limited by the need for high-resolution Nuclear Magnetic Resonance (NMR) infrastructure. Benchtop NMR offers a compact and potentially scalable alternative. This study aimed to identify serum metabolic signatures associated with respiratory severity and evaluate agreement between benchtop and high-resolution NMR platforms. METHODS: Serum samples from COVID-19 patients with acute respiratory failure were classified by respiratory severity (mild, moderate, severe, and very severe). Metabolomic profiling was performed using 500 MHz high-resolution and 80 MHz benchtop NMR systems. Multivariate analyses were used to identify severity-associated metabolic signatures, assess cross-platform agreement, and evaluate associations with clinical variables. RESULTS: Both platforms identified consistent metabolic alterations across severity groups. Supervised models achieved accurate discrimination between hospitalized and non-hospitalized patients and between moderate and very severe cases. Twenty-one metabolites, including glutamine, citrate, lactate, phenylalanine, myo-inositol, glycerol, and trimethylamine N-oxide, contributed to group separation. Altered pathways included carbohydrate metabolism, amino acid turnover, lipid metabolism, and tricarboxylic acid cycle intermediates, consistent with hypoxia and immune activation. Several metabolites correlated with inflammatory markers, immune cell counts, and oxygenation parameters. Importantly, benchtop NMR reproduced the key metabolic patterns observed with high-resolution NMR. CONCLUSIONS: Serum NMR metabolomics identifies metabolic signatures associated with respiratory severity. The agreement between high-resolution and benchtop NMR supports the feasibility of benchtop systems for clinically accessible patient stratification in acute respiratory disease, with potential applicability beyond COVID-19.
Effects of inhaled nitric oxide on ventilation/perfusion mismatch assessed by electrical impedance tomography in intubated patients with moderate-to-severe ARDS: a prospective physiological study.
Yu Y, Tian R, Zhang L … +9 more , Chen Y, Dai Y, Guan J, Wang X, Chen X, Wu J, Pan T, Qu H, Tan R
Respir Res · 2026 Jun · PMID 42251312 · Full text
BACKGROUND: Inhaled nitric oxide (iNO) improves oxygenation in acute respiratory distress syndrome (ARDS), but its precise physiological effects on ventilation-perfusion (V/Q) matching and inflammation over 24 h remain t...
BACKGROUND: Inhaled nitric oxide (iNO) improves oxygenation in acute respiratory distress syndrome (ARDS), but its precise physiological effects on ventilation-perfusion (V/Q) matching and inflammation over 24 h remain to be fully elucidated. To determine the effect of iNO on V/Q matching, gas exchange, and systemic inflammatory response in mechanically ventilated patients with moderate-to-severe ARDS. METHODS: We conducted a prospective, single-center, randomized controlled trial in 40 mechanically ventilated patients with moderate-to-severe ARDS (PaO/FiO ≤ 200 mmHg). Patients were randomized 1:1 to receive either iNO at a clinician-determined dose plus standard mechanical ventilation (iNO group) or standard mechanical ventilation alone (Control group). The primary endpoint was the change in V/Q matching parameters, assessed by electrical impedance tomography (EIT), at 24 hours. RESULTS: Forty patients were randomized (20 per group). At 24 h, the iNO group showed a significantly greater improvement in V/Q matching compared to the control group. The magnitude of reduction in both EIT-measured dead space (between-group difference, P < 0.001) and shunt (between-group difference, P < 0.001 was significantly larger in the iNO group. This physiological improvement was reflected in gas exchange: the median PaO/FiO ratio in the iNO group increased from 114.0 to 240.0 (P < 0.001), an improvement significantly greater than that in the control group (P < 0.001). Similarly, the physiological shunt (Q/Q) decreased more substantially in the iNO group (P < 0.001). iNO treatment also resulted in a greater reduction in pulmonary artery pressure (P < 0.001). No significant between-group differences were observed in inflammatory biomarkers or safety parameters. CONCLUSIONS: In patients with moderate-to-severe ARDS, 24-hour administration of inhaled nitric oxide significantly improves oxygenation by enhancing ventilation-perfusion matching. This effect is driven by a marked reduction in both EIT-measured shunt and dead space. This study provides a direct mechanistic rationale for iNO's physiological effects and supports the potential of using EIT to guide a more personalized therapeutic approach. TRIAL REGISTRATION: Clinicaltrials.gov; Unique identifier: ChiCTR2500113100; Retrospectively registered; Registration date: 25 November 2025.
Editorial Expression of Concern: Role of TNF-α in lung tight junction alteration in mouse model of acute lung inflammation.
Mazzon E, Cuzzocrea S
Respir Res · 2026 Jun · PMID 42243826 · Full text
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Emphysema severity-associated gut microbiota modulates smoke-induced emphysema: evidence from fecal microbiota transplantation.
Kim NH, Lee JH, Oh J … +14 more , Lee S, Jung ES, Suh DH, Kang HJ, Kim B, Kim HS, Kim H, Yun INR, Kim EH, Kim E, Jeong JY, Ji Y, Cho SY, Lee SW
Respir Res · 2026 Jun · PMID 42243780 · Full text
BACKGROUND: Cigarette smoking is the key risk factor for chronic obstructive pulmonary disease, but even similar levels of smoking can result in different disease severity. We hypothesize that differences in gut microbio...
BACKGROUND: Cigarette smoking is the key risk factor for chronic obstructive pulmonary disease, but even similar levels of smoking can result in different disease severity. We hypothesize that differences in gut microbiota and metabolites contribute to differences in emphysema severity through the gut-lung axis. In this study, we compared the microbiome and metabolome among non-emphysema, non-severe emphysema and severe emphysema groups. Additionally, the impact of fecal microbiota transplantation from non-emphysema, non-severe emphysema and severe emphysema groups on emphysema were investigated. METHODS: A total of 78 participants with a smoking history were included in this study and categorized into three groups: non-emphysema, non-severe emphysema, and severe emphysema. Gut microbiota and metabolites were analyzed, and germ-free mice underwent fecal microbiota transplantation with feces from donors representative of each group prior to smoking exposure. RESULTS: Significant differences in gut microbiota and metabolites were observed among the groups, with lower acetic acid levels in patients with severe emphysema, and a greater abundance of Prevotellaceae and Megasphaera in patients without emphysema. Fecal microbiota transplantation from donors with severe emphysema worsened lung pathology in mice subjected to smoking exposure, whereas fecal microbiota transplantation from donors without emphysema attenuated emphysema development. CONCLUSIONS: Gut microbiota and metabolites in participants with a smoking history differ according to the presence of emphysema and its severity, and can affect emphysema development. This suggests a role for gut microbiota in lung disease and provides a foundation for exploring gut microbiota as a potential therapeutic target for chronic obstructive pulmonary disease.
Myeloid-specific Becn1 deficiency elicits spontaneous pulmonary injury and exacerbates acute lung injury.
Liu J, Tan M, Huang S … +6 more , Zhang J, Mao L, Chen C, Fu Y, Jiang X, Zou Z
Respir Res · 2026 Jun · PMID 42231357 · Full text
BACKGROUND: Acute lung injury (ALI) and its severe phenotype, acute respiratory distress syndrome (ARDS), represent devastating and highly lethal respiratory disorders. Hallmarked by unrestrained pulmonary inflammation p...
BACKGROUND: Acute lung injury (ALI) and its severe phenotype, acute respiratory distress syndrome (ARDS), represent devastating and highly lethal respiratory disorders. Hallmarked by unrestrained pulmonary inflammation predominantly driven by myeloid cells, these conditions ultimately culminate in profound disruption of the alveolar-capillary barrier. The reciprocal crosstalk between autophagy and inflammation and its molecular underpinnings in ALI pathogenesis remain incompletely defined. METHODS: The role of myeloid Becn1 in maintaining pulmonary homeostasis and modulating susceptibility to lipopolysaccharide (LPS)-induced ALI was defined, and the potential link between intestinal barrier integrity, gut microbiota, and ALI severity was further interrogated. The expression of BECN1 in bronchoalveolar lavage fluid (BALF) cells from patients with ARDS and in lung tissues of mice with LPS-induced ALI was detected by western blot and immunofluorescence respectively. Myeloid cell-specific Becn1 conditional knockout (cKO) mice were generated. Parallel analyses were performed in both steady-state and LPS-challenged mice, including quantitative lung histopathological analysis, inflammatory cytokine profiling of BALF, bulk RNA sequencing of lung tissue, histological assessment of intestinal architecture and intestinal tight junction integrity, and 16S rRNA gene sequencing of fecal microbiota. RESULTS: Myeloid Becn1 deficiency alone was sufficient to disrupt pulmonary homeostasis, leading to spontaneous lung injury characterized by increased alveolar-capillary permeability, inflammatory cell infiltration, and aberrant activation of immune-inflammatory pathways. When challenged with LPS, these pre-existing inflammatory priming effects translated to exacerbated pulmonary pathology and exaggerated cytokine storm. Beyond the lung, Becn1 cKO mice developed spontaneous intestinal barrier dysfunction and gut microbiota dysbiosis at steady state, including blunted intestinal villi, reduced goblet cells, impaired tight junction integrity, increased mast cell infiltration, and a characteristic microbial shift with depleted Actinobacteria and expanded Alistipes. All these intestinal and microbial perturbations were likely further amplified by LPS challenge, consistent with a potential association between intestinal-microbial dysregulation and exacerbated pulmonary injury. CONCLUSIONS: Myeloid Becn1 governs pulmonary-intestinal immune homeostasis, and its deficiency drives spontaneous lung injury, hyperinflammation, impaired gut-lung crosstalk, and exacerbated acute lung injury, establishing myeloid Becn1 as a critical determinant of acute lung injury severity.
Mechanism study of RUNX1/NSUN2 upregulating fatty acid-binding protein 5 through 5-methylcytosine methylation to mediate lipid metabolic reprogramming to promote immunotherapy resistance in non-small cell lung cancer.
He C, Li Y, He H … +8 more , Zhou F, Fu B, Bu J, Wang M, Kong X, Li P, Ni B, Xu S
Respir Res · 2026 Jun · PMID 42231351 · Full text
OBJECTIVE: This study explored the mechanism of RUNX1/NSUN2/FABP5 promoting immunotherapy resistance in non-small cell lung cancer (NSCLC). METHODS: NSCLC patients received anti-programmed cell death protein 1 (PD-1) the...
OBJECTIVE: This study explored the mechanism of RUNX1/NSUN2/FABP5 promoting immunotherapy resistance in non-small cell lung cancer (NSCLC). METHODS: NSCLC patients received anti-programmed cell death protein 1 (PD-1) therapy. In vitro A549 and NCI-H520 cells and in vivo xenograft mouse models were established. RUNX1, NSUN2, FABP5, PD-L1, and lipid metabolic profiles were analyzed using RT-qPCR, Western blot, and biochemical assays. Gain- and loss-of-function experiments were performed to assess the roles of RUNX1, FABP5, and NSUN2 in NSCLC. CD8 T cells in tumor tissues were assessed through flow cytometry. A NSCLC cell-CD8⁺ T cell co-culture system was established, with T cell activation and effector cytokine secretion determined. The mechanism of the RUNX1/NSUN2/FABP5 axis in NSCLC was elucidated by dual-luciferase, ChIP, MeRIP, RIP, and Actinomycin D assays. RESULTS: RUNX1 was highly expressed in immunotherapy-resistant NSCLC. RUNX1 was positively correlated with elevated serum lipids and negatively associated with CD8⁺ T cell activation in tumor tissues. RUNX1 promoted PD-L1 expression and resistance to anti-PD-1 therapy in vivo via FABP5-mediated lipid metabolic reprogramming. RUNX1 regulated FABP5-mediated lipid metabolic reprogramming, enhanced PD-L1 expression, and induced CD8⁺ T cell dysfunction. FABP5 knockdown inhibited lipid metabolism and partially reversed the effects of RUNX1 in NSCLC. RUNX1 promoted NSUN2 transcription, which in turn increased m⁵C methylation of FABP5 and enhanced FABP5 mRNA stability. NSUN2 knockdown partially averted RUNX1's effect in NSCLC. CONCLUSION: RUNX1 alters m⁵C methylation levels by regulating NSUN2 transcription to promote FABP5-mediated lipid metabolic reprogramming, which in turn enhances PD-L1 expression and consequently induces immune resistance in NSCLC.
MyD88 mediates allergic airway inflammation by regulating ILC2s function through inducing the formation of P38/GATA3 complex.
Zhang H, Dai W, Chen X … +9 more , Xi X, Chen Y, Song J, Ge X, Xiang Q, Zhang B, Zhao C, Zhang W, Zhang Y
Respir Res · 2026 Jun · PMID 42226044 · Full text
BACKGROUND: Allergic asthma stands as the predominant asthma phenotype propelled by aberrant type 2 immune response. Type-2 innate lymphoid cells (ILC2s) are significant for generating IL-5 and IL-13 cytokines, highlight...
BACKGROUND: Allergic asthma stands as the predominant asthma phenotype propelled by aberrant type 2 immune response. Type-2 innate lymphoid cells (ILC2s) are significant for generating IL-5 and IL-13 cytokines, highlighting their vital role in triggering and escalating the progression of asthma. Myeloid differentiation primary response protein 88 (MyD88) controls innate and adaptive immune responses by orchestrating inflammatory signals. OBJECTIVE: This work focused on investigating the influence of MyD88 in governing ILC2s-driven allergic airway disease alongside its underlying molecular mechanisms. METHODS: We evaluated the effects of MyD88 in IL-33-induced or allergen-induced airway hyperreactivity (AHR) and airway inflammation. The role and mechanism of MyD88 in regulating ILC2s function were examined in vivo and in vitro by using transcriptome sequencing analysis, flow cytometry, clinical samples, ILC2-specific MyD88 knockout mice, and anti-Thy1.2 antibody against ILC2s in mice. RESULTS: The results showed heightened MyD88 expression in ILC2s sourced from allergic asthmatic patients and asthmatic mice. MyD88 knockout in ILC2s was able to mitigate IL-33-induced airway inflammation, while the MyD88 inhibitor LM8 proves efficacious in attenuating allergen-induced airway inflammation and AHR. After elimination of ILC2s via anti-Thy1.2 antibody, the pharmacological activity of LM8 diminished. Mechanistic studies revealed that MyD88 mediates the activation and proliferation of ILC2s through facilitation of P38-GATA3 complex formation. CONCLUSIONS: The research highlights MyD88 as a critical regulator of ILC2s activation, suggesting its potential utility as a therapeutic target for interventions in allergic asthma.
Faster CYP2A6 increases COPD and lung cancer risk by increasing smoking quantity: a mediated mendelian randomization and observational mediation study.
Giratallah H, Chenoweth MJ, Lerman C … +2 more , Knight J, Tyndale RF
Respir Res · 2026 Jun · PMID 42219484 · Full text
BACKGROUND: Genetic variation in CYP2A6, an enzyme which inactivates nicotine and activates nitrosamines, alters smoking behaviours and was associated with chronic obstructive pulmonary disease (COPD) and lung cancer (LC...
BACKGROUND: Genetic variation in CYP2A6, an enzyme which inactivates nicotine and activates nitrosamines, alters smoking behaviours and was associated with chronic obstructive pulmonary disease (COPD) and lung cancer (LC) in a phenome-wide association study. RESEARCH QUESTIONS: Does smoking quantity mediate the association between CYP2A6 and the risk for COPD and LC? Does the extent of mediation differ between the diseases? METHODS: We implemented two-step two-sample mediated Mendelian Randomization (MR) and observational mediation analyses. CYP2A6 activity was instrumented using a CYP2A6 genetic score. We tested pack-years (chronic smoking exposure), cigarettes per day (CPD; self-reported), and the summation of nicotine's main metabolites, cotinine, and trans-3'-hydroxycotinine (COT+3HC; nicotine intake biomarker) as quantity measures among current smokers. We sourced smoking quantity genetic instruments for MR from genome-wide significant summary statistics. This research was conducted using the UK Biobank Resource. RESULTS: All three smoking quantity measures significantly mediated the effects of CYP2A6 activity on COPD and LC risk in forward mediated MR (p values < 0.05). Given the many assumptions of MR, this provides only a potential direction of effect. Smoking quantity measures mediated a large proportion of the COPD risk but less for LC. In reverse mediated MR (i.e., negative control), CYP2A6 activity did not mediate smoking quantity effects on COPD and LC. INTERPRETATION: Mediated MR and observational mediation analyses together supported a mechanistic role of faster CYP2A6 influencing smoking quantity increase, which increases COPD and LC risk. The observational mediation analyses suggest additional mechanisms may be involved in CYP2A6's impact on LC.
Spatial heterogeneity in the burden of respiratory syncytial virus infection attributable to low and high ambient temperature in Japan: a nationwide time-stratified case-crossover analysis.
Wagatsuma K
Respir Res · 2026 May · PMID 42218525 · Full text
Respiratory syncytial virus (RSV) infection poses a considerable disease burden worldwide. Although multiple studies have estimated the short-term effects of ambient temperature on mortality and morbidity, the burden of...
Respiratory syncytial virus (RSV) infection poses a considerable disease burden worldwide. Although multiple studies have estimated the short-term effects of ambient temperature on mortality and morbidity, the burden of RSV attributable to temperature is poorly characterized. This nationwide study aimed to quantify the total burden of RSV infection in Japan attributable to non-optimum ambient temperature conditions, and to partition this burden into contributions from low and high temperatures and from moderate and extreme components of non-optimum temperature. We collected weekly time-series data on the number of reported RSV cases and meteorological variables (mean temperature, relative humidity, wind speed, and sunshine duration) for all 47 Japanese prefectures from 2006 to 2019. An extended two-stage approach was used: First, a time-stratified case-crossover design fitted with conditional quasi-Poisson regression was used to estimate prefecture-specific associations. Second, multivariate random-effects meta-analysis was used to obtain pooled estimates. The number of attributable cases were estimated for temperatures above and below the optimum minimum morbidity temperature (MMT) and further categorized as moderate or extreme using the 2.5th and 97.5th percentiles as cutpoints. Data on 1,227,012 RSV cases reported during the study period were analyzed. The pooled exposure-response relationship between temperature and RSV incidence was U-shaped, with a higher RSV incidence at both low and high temperature levels. In most prefectures the MMT was between the 40th to 50th percentiles of the local temperature distribution. Overall, 21.32% (95% empirical confidence interval [eCI] 18.93% to 22.78%) of cases were attributable to non-optimum temperature, with marked geographic heterogeneity: from 8.24% (95% eCI: - 9.06-21.12%) in Akita, to 32.63% (95% eCI: 27.86-41.78%) in Kagoshima. A greater share of temperature-attributable cases was due to moderate high temperatures (12.27%, 95% eCI: 10.95-13.19%) than to low temperatures (9.05%, 95% eCI: 7.12-10.36%), whereas the contributions of extremely high and extremely low temperatures were relatively small. High weekly mean ambient temperatures over lag 0-3 weeks were associated with a substantial attributable risk of RSV infection. Public health efforts to reduce the RSV burden should take ambient temperature into account, paying particular attention to the impact of sustained, moderately warm conditions.
The β-hydroxybutyrylation of Zyxin ameliorates pulmonary fibrosis by inhibiting lung fibroblast activation through the PI3K/AKT pathway.
Qiu L, Huang H, Li S … +2 more , Chen H, Wang X
Respir Res · 2026 May · PMID 42218444 · Full text
Idiopathic pulmonary fibrosis (IPF) is a lethal interstitial lung disease with poorly understood pathogenesis. Here, we identify reduced lysine β-hydroxybutyrylation (Kbhb) of the focal adhesion protein Zyxin in bleomyci...
Idiopathic pulmonary fibrosis (IPF) is a lethal interstitial lung disease with poorly understood pathogenesis. Here, we identify reduced lysine β-hydroxybutyrylation (Kbhb) of the focal adhesion protein Zyxin in bleomycin (BLM)-induced pulmonary fibrosis in mice. In a BLM-induced mouse model, we observe a significant reduction in lung tissue Kbhb levels, while β-hydroxybutyrate (β-OHB) supplementation restores Kbhb modification, there by mitigating fibrosis. Transcriptome profiling suggests that β-OHB exerts anti-fibrotic effects by modulating the PI3K/AKT pathway. Proteomic analysis further reveals a decrease in Kbhb modification at the K263 site of Zyxin in IPF mice. In vivo experiments demonstrate that Zyxin knockout or β-OHB treatment markedly alleviates fibrotic pathology and reduces collagen deposition as well as mouse mortality. This study is the first to elucidate the mechanism by which Zyxin Kbhb modification suppresses pulmonary fibrosis via the PI3K/AKT pathway, offering a novel metabolic modification-based therapeutic strategy for IPF.
Clinical phenotypes of difficult-to-treat and mild asthma defined by cluster analysis.
Leily M, Mistry H, Zhang H … +19 more , Larsson M, Varkonyi-Sepp J, Ainsworth B, Wei L, Eames C, Hudson-Colby JJ, Lewis A, Freeman A, Haitchi HM, Dennison P, Djukanovic R, La Mata SH, Seumois G, Vijayanand P, Kyyaly MA, Vorobeva E, Dabrio-Reina E, Arshad SH, Kurukulaaratchy RJ
Respir Res · 2026 May · PMID 42216135 · Full text
BACKGROUND: Cluster modelling has demonstrated asthma heterogeneity across disease severities, but contemporary data integrating difficult-to-treat and mild asthma with systematic assessment of comorbidity-focused treata...
BACKGROUND: Cluster modelling has demonstrated asthma heterogeneity across disease severities, but contemporary data integrating difficult-to-treat and mild asthma with systematic assessment of comorbidity-focused treatable traits remain limited. OBJECTIVE: To identify and characterise difficult-to-treat and mild asthma clusters in two UK cohorts: Wessex AsThma CoHort of Difficult Asthma (WATCH-DA) and a mild-asthma cohort from the Epigenetics of Severe Asthma study (EOSA-MA). METHODS: Separate K-means clustering was applied to WATCH-DA (n = 498; 11 variables) and EOSA-MA (n = 67; 12 variables). Post-hoc comparisons evaluated demographic, inflammatory, physiological, comorbidity and patient-reported outcome profiles. RESULTS: Six difficult-to-treat and two mild asthma clusters were identified respectively, all Type-2 (T2)-predominant. Difficult-to-treat asthma clusters differed by sex, age of asthma-onset, body mass index (BMI) and comorbidities. Two clinically controlled clusters, cluster-1 (Early-onset atopic controlled) and cluster-4 (Late-adult-onset non-atopic controlled), showed distinct comorbidity patterns despite lower overall morbidity. Three severe, exacerbation-prone, adult-onset, female predominant difficult-to-treat clusters (Adult-onset eosinophilic exacerbator [cluster-2], Young-adult-onset high-risk exacerbator [cluster-5], Adult-onset obese multimorbid symptomatic [cluster-6]) varied by blood eosinophil counts (BEC), spirometry, BMI, treatment needs, comorbidities, and quality of life. An Adolescent-onset obese atopic obstructive (cluster-3) showed fewer exacerbations but high BEC with worst spirometry and poor asthma control. In mild asthma, cluster-1 (Early-onset atopic mild) showed worse pathophysiological indices and asthma control than cluster-2 (Adolescent-onset mild) but similarly high comorbidity prevalence. CONCLUSION: Characterisation of difficult-to-treat and mild asthma clusters reveals diverse associated clinical traits and outcomes across the asthma severity spectrum. Recognition of these clusters and their associated comorbidities should prompt early personalised asthma management to address both airway-centric and comorbid disease aspects.
Radiological diversity in rheumatoid arthritis associated with usual interstitial pneumonia (RA-UIP) and its therapeutic implications: towards a generalizable framework of interstitial lung disease treatment.
Yamakawa H, Yamano Y, Tsuboi H … +3 more , Makino S, Takemura T, Ogura T
Respir Res · 2026 May · PMID 42216000 · Full text
Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a major extra-articular manifestation of rheumatoid arthritis and a key determinant of patient outcomes. Among its radiologic subtypes, the usual inte...
Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a major extra-articular manifestation of rheumatoid arthritis and a key determinant of patient outcomes. Among its radiologic subtypes, the usual interstitial pneumonia (UIP) pattern is the most frequent and clinically important; however, the definition and conceptual use of "RA-UIP" differ among disciplines and across countries, reflecting variations in how radiologic and pathologic features are integrated into clinical practice. RA-UIP shares several features with idiopathic pulmonary fibrosis (IPF) but also differs in pathogenesis, imaging characteristics, and clinical behavior, resulting in more heterogeneous prognoses and therapeutic responses. Although a recent international update proposed a unified classification encompassing both idiopathic and secondary interstitial pneumonias, secondary UIPs such as RA-UIP often show overlapping or combined morphologies that remain challenging to categorize and manage. This review emphasizes the dynamic interplay between joint and lung disease activity in RA-ILD conceptualized as a "virtuous" or "vicious" cycle. Stable control of arthritis can promote pulmonary stability, whereas uncontrolled systemic inflammation and treatment limitations-often complicated by infection-can destabilize both. While antifibrotic therapy can slow fibrotic progression, sustained inflammatory control remains essential for maintaining a favorable cycle. Integrating these dual perspectives, we outline a conceptual clinical-radiologic framework for interpreting UIP-like patterns in RA-ILD in relation to the balance between inflammation and fibrosis. Rather than serving as an evidence-based treatment algorithm, this flexible, patient-centered framework is intended to organize radiologic heterogeneity, support multidisciplinary therapeutic discussion, and generate hypotheses for future validation across autoimmune and other fibrosing ILDs.
The gut-lung axis in ARDS: beyond microbial translocation.
Li X, Zhang X, Yuan S … +1 more , Zhang J
Respir Res · 2026 May · PMID 42215979 · Full text
The gut-lung axis has emerged as a pivotal pathway in the pathogenesis of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Disruption of the intestinal barrier, a common event in critical illness,...
The gut-lung axis has emerged as a pivotal pathway in the pathogenesis of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Disruption of the intestinal barrier, a common event in critical illness, facilitates the systemic dissemination of live microbiota, their pathogen-associated molecular patterns (PAMPs), and bioactive metabolites. This process critically depends on the integrity of the gut vascular barrier (GVB). The GVB is the endothelial layer underlying the gut epithelium. It serves as the final gatekeeper, restricting microbial products from entering the systemic circulation. Concurrently, intestinal immune cells, such as γδ T cells and innate lymphoid cells (ILCs), migrate to the lungs and amplify the inflammatory cascade. Emerging evidence links regulated cell death, especially pyroptosis, necroptosis, and ferroptosis, to disruption of both gut and lung barriers, fueling a self-amplifying cycle of organ injury. This review synthesizes current evidence on the cellular, molecular, and metabolic mechanisms underlying gut-derived lung injury. Furthermore, we critically evaluate several emerging gut-targeted therapeutic strategies aimed at restoring microbial homeostasis and mitigating ALI/ARDS, including fecal microbiota transplantation (FMT), probiotics, synbiotics, and mesenchymal stem cell (MSC) therapy. Deciphering the gut-lung dialogue holds promise for developing novel treatments for this devastating condition.
Relevant insights from personalized inhaled carbon monoxide dosing in a safety study in pneumonia and ARDS.
Baron RM, Arciniegas A, Sullivan S … +7 more , Courchaine M, Thompson BT, Stenzler A, Choi ME, Choi AMK, Perrella MA, Winkler T
Respir Res · 2026 May · PMID 42210269 · Full text
BACKGROUND: Low-dose inhaled carbon monoxide (iCO) has demonstrated significant therapeutic potential in preclinical studies, and its safety has been established in human studies. However, the safety of delivering person...
BACKGROUND: Low-dose inhaled carbon monoxide (iCO) has demonstrated significant therapeutic potential in preclinical studies, and its safety has been established in human studies. However, the safety of delivering personalized iCO concentrations of 200 to 500 ppm in ventilated patients with pneumonia and ARDS, targeting 7% HbCO at 90 min of exposure, remains unknown. METHODS: Personalized iCO concentrations needed to reach a plasma HbCO of 7% at 90 min were determined using a Coburn-Forster-Kane (CFK) calculator, utilizing baseline and 20-minute (20-min) arterial HbCO measurements at an iCO test concentration of 200 ppm. The personalized iCO concentration was administered for the remainder of the 90 min with HbCO measurements performed at 60-, 75-, and 90-minutes. RESULTS: There were no safety incidents observed during the study, and all exposed subjects were alive and well at 6-month follow-up. Surprisingly, we found significant deviations between measured and predicted HbCO levels at 90 min for individualized exposures with iCO of 220 to 425 ppm (p < 0.001), which were more discrepant at higher iCO doses. However, fitting the CFK model to the 20- to 90-minute HbCO measurements confirmed the validity of the CFK model and revealed significant deviations for baseline HbCO (p < 0.001), suggesting pulmonary vascular responses to iCO during the 20-min test exposure, confirmed by observed changes in DLCO. CONCLUSIONS: Pulmonary vasodilation in response to iCO can affect early HbCO kinetics, which is relevant to refining protocols for reliable, personalized iCO administration that optimize pulmonary iCO concentrations, thereby increasing the benefits of therapeutic iCO administration in lung diseases.
Asthma exacerbation risk after short-term air pollution exposure varies by age, sex, severity, and eosinophil count: East London cohort study.
Hajmohammadi H, Pfeffer PE, Mudway IS … +1 more , Griffiths CJ
Respir Res · 2026 May · PMID 42210238 · Full text
BACKGROUND: Air pollution is associated with asthma mortality and hospital admissions, yet few studies have focused on exacerbations managed in the community or which subgroups of asthma patients are most vulnerable. Ide...
BACKGROUND: Air pollution is associated with asthma mortality and hospital admissions, yet few studies have focused on exacerbations managed in the community or which subgroups of asthma patients are most vulnerable. Identifying these groups is crucial for targeted public health interventions and clinical guidance. METHODS: We developed Poisson generalised regression models examining associations between short-term exposure to air pollutants (NO, PM and PM, and O) and courses of oral corticosteroids (OCS) prescribed in primary care for exacerbations in a cohort of asthma-registered adults (18-80 years) in East London, between March 2019-February 2023. We analysed three time frames: pre-, during, and post-COVID-19 pandemic, and performed stratified analyses by gender, age, asthma management step, and blood eosinophil levels. RESULTS: For every interquartile range (IQR) increase in the preceding week's average exposure, the risk of OCS prescription increased by 5% for NO, 2% for PM, and 2% for PM. Risk for OCS prescriptions were 2% lower during the COVID-19 period and 28% higher post-COVID-19 compared to pre-COVID-19. Stratified analyses showed that male and older adults had higher risks for NO associated exacerbations with same-day exposure but lower risks for one-week exposure, compared to females and younger adults. Risks were also slightly higher in patients on step 4/5 asthma medications and in those with eosinophilia, with similar patterns observed for PM and PM. CONCLUSION: Short-term exposure to NO, PM, and PM increases the risk of mild asthma exacerbations, however risk and lag were affected by age, gender, and patient subgroups, emphasizing the need for tailored public health strategies.
Evaluation of 2-methyl-4-isothiazolin-3-one-induced human pulmonary toxicity using integrated air-liquid-interface and a lung-on-chip.
Park S, de Maddalena LL, Schmid S … +4 more , Sengupta A, Woo CG, Hobi N, Cho YJ
Respir Res · 2026 May · PMID 42204607 · Full text
A 3:1 disinfectant composed of 5-chloro-2-methyl-4-isothiazolin-3-one (CMIT) and 2-methyl-4-isothiazolin-3-one (MIT) has been widely used in water-based household products such as detergents, toothpaste, and cosmetic app...
A 3:1 disinfectant composed of 5-chloro-2-methyl-4-isothiazolin-3-one (CMIT) and 2-methyl-4-isothiazolin-3-one (MIT) has been widely used in water-based household products such as detergents, toothpaste, and cosmetic applications. In the United States, it was classified as a pesticide in 1998 and designated as a Category 2 dermal-toxicity substance for cosmetics. Several studies in the Republic of Korea have reported that components of humidifier disinfectants (HDs) such as polyhexamethylene guanidine (PHMG), CMIT, and MIT cause chronic pulmonary conditions. However, its toxicity is still controversial because of the discrepant results between human cases and animal experiments. We recapitulate the in vivo characteristics of the pulmonary epithelial cells and introduce an air-liquid interface (ALI) system to replicate acute inhalation injury. To assess compound-specific toxicity in the human airway, NHBE cells were first differentiated under ALI conditions and then exposed to MIT under submerged conditions. In parallel, Barrier-on-Chip (AlveoliX AG) technology integrated with the Cloud α AX12 (Vitrocell Systems GmbH) allowed us to mimic human lung physiology more realistically. In this study, this inhalation platform was utilized to nebulize MIT onto primary cell-derived immortalized alveolar epithelial cells (iAECs) co-cultured with human lung microvascular endothelial cells (hLMVECs) seeded onto the AX12. Additionally, PHMG was used as a positive control to compare MIT toxicity levels. Using this approach, significant barrier disruption and cytotoxicity were observed when MIT was introduced into the alveolar lung-on-chip. Overall, we confirmed MIT-induced toxicity in both bronchial and alveolar epithelial models, highlighting the importance of multiscale in vitro systems for inhalation toxicology.
Plasma metabolomic signatures associated with inhaled corticosteroid requirements in clinically stable asthma: a prospective cross-sectional study.
Lee HW, Pyung YJ, Oh S … +4 more , Lee JK, Heo EY, Yun CH, Kim DK
Respir Res · 2026 May · PMID 42192512 · Full text
BACKGROUND: Despite substantial clinical and biological heterogeneity, asthma severity is often classified by treatment intensity, which may inadequately reflect underlying pathobiology. We aimed to characterize plasma m...
BACKGROUND: Despite substantial clinical and biological heterogeneity, asthma severity is often classified by treatment intensity, which may inadequately reflect underlying pathobiology. We aimed to characterize plasma metabolomic profiles associated with treatment-defined severity among patients with clinically well-controlled asthma receiving guidance-based inhaled corticosteroid (ICS) therapy. METHODS: In this prospective cross-sectional study, patients with well-controlled asthma, defined by Asthma Control Test scores > 20 and consistent ICS use without recent exacerbations, were enrolled. Plasma samples were analyzed using proton nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry. After asthma severity was defined by ICS dose requirement, metabolomic differences were evaluated between severe and non-severe asthma. The significant metabolites were identified through elastic net-assisted variable selection and Firth's penalized logistic regression adjusting for clinical covariates. Probabilistic relationships among these metabolites and severity were further explored using Bayesian network modeling. RESULTS: Fifty-five patients were included. Lactate and pyruvate levels were significantly elevated in the severe asthma group. In multivariable analyses adjusting for clinical covariates, pyruvate (adjusted odds ratio (aOR) = 10.239 [95% CI = 1.320-19480.301], P-value = 0.025) and dimethylamine (aOR = 12.693 [95% CI = 1.292-628.175], P-value = 0.028) were associated with treatment-defined severity. Bayesian network analysis further supported the direct probabilistic associations of these metabolites with asthma severity. Subgroup analyses confirmed consistent trends across clinical strata, suggesting that distinct metabolic states may underlie higher ICS requirements despite stable symptom control. CONCLUSION: In clinically stable asthma, elevated pyruvate and dimethylamine were associated with greater ICS requirements, suggesting that metabolomic profiling may aid in refining endotypes and personalizing anti-inflammatory therapy beyond symptom-based assessment.
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