Respiratory Research最新文献

Background: Runt-related transcription factor 2 (Runx2), a transcription factor of the RUNX family, is involved in various inflammatory diseases. However, the role of Runx2 was unclear in chronic obstructive pulmonary disease (COPD).

Methods: Pulmonary Runx2 level was compared in COPD patients and control subjects via a case-control study. Runx2 expression was detected in lung tissues of COPD mice and human bronchial epithelial (BEAS-2B) cells simulated with cigarette smoke extracts (CSE).

Results: Pulmonary Runx2 expression was upregulated, and inversely associated with pulmonary function and positively correlated with inflammatory cytokines in COPD patients. Mechanistically, Runx2 activation facilitated the transcription of CDK8, a co-regulator of nuclear factor-κB (NF-κB), and inflammatory cytokines production. Luciferase report gene assay confirmed that CDK8 was the downstream target gene of Runx2. Further analysis found that CSE inhibited Runx2 ubiquitination and proteasomal degradation. Besides, CSE elevated nicotinamide adenine dinucleotide (NAD⁺) consumes and Sirtuin 3 (Sirt3) depletion. Additionally, Runx2 acetylation was increased in CSE-exposed BEAS-2B cells, lungs tissues from COPD mice and patients. Interestingly, Sirt3 overexpression or supplementation with Nicotinamide Riboside (NR), the precursor of NAD⁺, abolished CSE-induced Runx2 acetylation and Runx2-CDK8 axis activation. In vivo experiment further confirmed NR supplementation evidently mitigated cigarette smoke-induced a COPD-like phenotype in mice.

Conclusions: These results indicated that Sirt3 depletion-induced Runx2 acetylation contributes to CDK8 activation and pulmonary inflammation in the progression of COPD.

Background: The impact of wildfire smoke (WFS) on air quality across the contiguous US has become geographically widespread. However, the effects of WFS exposure on psychometric measures of mental and physical health remain largely unknown.

Objectives: To assess the associations between WFS PM_2.5 and black carbon (BC) exposure and psychometric health measures.

Methods: The St. George's Respiratory Questionnaire (SGRQ) and the 36-Item Short Form Survey (SF-36) were administered to participants in the Lovelace Smokers Cohort in New Mexico to assess psychometric health measures in the past 4 weeks. WFS estimates were calculated against Albuquerque metropolitan area for 7-, 15-, 30-, and 60-d prior to questionnaire completion. The associations between exposure and health measures were assessed using linear models.

Results: Associations were observed for all psychometric measures with WFS PM_2.5 and BC exposures estimated for 7-day prior to questionnaire completion. These associations remained for WFS exposure estimated up to 30-day prior to questionnaire completion for all SGRQ subdomains and physical health measures of SF-36, whereas associations with the mental health component were more transient and primarily evident within one week. Additionally, WFS PM_2.5 exhibited stronger potency than total ambient PM_2.5. Male participants, individuals with less than a college education, and those exposed to woodsmoke demonstrated stronger associations with WFS exposure.

Conclusions: Exposure to WFS was associated with worse SGRQ and SF-36 scores, with notable differences in temporal patterns between mental and physical health measures. Our findings also underscore the importance of source-specific risk assessment for air pollution.

Background: Bronchiectasis is a common feature in idiopathic pulmonary fibrosis (IPF) and rheumatoid arthritis-associated interstitial lung disease (RA-ILD). While these so-called traction bronchiectasis are often considered a secondary phenomenon in fibrosing ILD, their prognostic significance and relationship to respiratory pathogen detection and outcomes remain unclear.

Methods: We conducted a retrospective, single-center cohort study in IPF or fibrosing RA-ILD patients with available high-resolution computed tomography (HRCT) and lower-respiratory tract microbial samples between 2014 and 2024. Bronchiectasis was assessed using the bronchiectasis subscore of the Brody score; fibrosis was quantified by deep-learning-based automated HRCT analysis. Primary outcome was 5-year transplant-free survival; secondary outcomes included isolation of pathogens per CDC criteria, PFT trajectories, bronchiectasis-associated symptoms, and hospitalization. Statistical methods included Cox regression, linear mixed-effects modeling and correlation analysis.

Results: 267 IPF and 56 RA-ILD patients were included. Median modified Brody score was 11.5 (IQR 7-16; max possible range 0-72). Higher Brody scores strongly correlated with fibrotic extent (R = 0.6, P < 0.001). Higher scores had significantly lower baseline FVC and DLCO (P < 0.001), but no differences in PFT trajectories over time. In multivariable Cox regression, higher bronchiectasis scores were independently associated with mortality (HR 1.03 per point [95%CI 1.01-1.06], P = 0.003); fibrosis extent showed similar results (HR 1.02, CI 1.00-1.03, P = 0.017). Pathogens were found at a median of 3 months after baseline in 50.9% (IPF) and 46.4% (RA-ILD), without association with survival, symptoms or Brody scores. Staphylococcus aureus was most common (28.9%); Pseudomonas aeruginosa was rare (1.9%).

Conclusion: In both IPF and RA-ILD, higher bronchiectasis scores were associated with fibrosis extent and mortality, but not classical clinical bronchiectasis features. This supports traction bronchiectasis as a marker of fibrotic remodeling rather than a distinct syndrome.

Trial registration: Not applicable.

Background: While the renin-angiotensin-aldosterone system (RAAS) is critically involved in pathomechanisms related to SARS-CoV-2 infection, the role of ongoing therapy with angiotensin-converting enzyme 1 inhibitors (ACEi) or Angiotensin-II type 1 receptor (AT₁R) blockers (ARB) is much less clear. We evaluated the effects of the ACEi enalapril (ENA) and the ARB losartan (LOS) on SARS-CoV-2 infection in human ex vivo-cultured, precision-cut lung slices (PCLS) obtained from normal human lung tissue.

Methods: PCLS were pre-treated for 5d with vehicle, LOS or ENA (300 µM), followed by mock infection or infection with SARS-CoV-2 and incubation with vehicle, LOS or ENA for 1d or 2d. Thereafter, PCLS were harvested for analysis of viral replication, inflammatory responses, endoplasmic reticulum (ER) stress and apoptosis pathways.

Results: Both LOS and ENA significantly reduced viral replication in PCLS, with ENA being more potent. LOS was more efficient than ENA in reducing the expression of IL1B, CCL2, CXCL2 and TNFA, but not of IL6, whereas ENA preferentially caused a reduction of IL6 and CCL2 in SARS-CoV-2-infected PCLS. Further, ENA, but not LOS, significantly decreased the expression of viral entry factors, ACE2 and transmembrane serine protease 2 (TMPRSS2), in infected PCLS. Importantly, LOS or ENA did not exert cytotoxic effects.

Conclusions: RAAS-antagonizing drugs do not seem to exert detrimental effects during SARS-CoV-2 infection. In opposite, in an ex-vivo model of human PCLS, such treatment was found to dampen SARS-CoV-2 infection and consecutive inflammation.

Bronchioalveolar stem cells (BASCs), located at the bronchioalveolar duct junction (BADJ), contribute to adult lung regeneration after injury, yet their role during postnatal lung morphogenesis remains poorly characterized. In this study, we showed that BASCs first emerged at birth and persisted throughout the postnatal saccular stage with stable localization and abundance. To trace their fate, we generated a Sftpc^DreER knock-in mouse and combined it with Scgb1a1^CreER and dual-reporter H11^{LSL - ZsG_RSR-tdT} mice to establish a dual recombinase-mediated lineage tracing system (BASC-Tracer). Using this system, we observed that BASCs expanded postnatally and migrated into both alveolar and airway compartments. In the alveoli, they lost SCGB1A1 expression and differentiated into AT2 and AT1 cells to drive alveolar maturation, whereas in the airways, they lost SFTPC expression and gave rise to club cells. Furthermore, we employed a hyperoxia-induced bronchopulmonary dysplasia model to assess the injury response of BASCs during lung development. We found that hyperoxic exposure markedly suppresses BASC regenerative capacity. Finally, spatial transcriptomic analysis revealed that BASCs reside within a distinct BADJ-associated niche, characterized by a unique repertoire of signaling ligands that distinguishes this niche from those of AT2 and club cells. Together, these findings delineate the dynamic behavior of BASCs during lung development and provide spatial characterization of their niche.

Background: Disruption of parasympathetic pulmonary nerves, which release acetylcholine and trigger airway smooth muscle constriction, has been shown to improve lung function and alleviate symptoms in patients with chronic obstructive pulmonary disease (COPD). However, the current targeted lung denervation (TLD) mono-polar radiofrequency (RF) ablation system has the potential for structural improvement to enhance the generalizability and safety of the TLD procedure.

Objective: To develop a novel TLD multi-polar RF ablation for COPD treatment and evaluate its feasibility, safety, and efficacy.

Methods: In the preclinical study, we performed TLD in vitro (porcine lung and liver model) to validate its feasibility and in vivo (dogs and sheep) to ensure its safety and preliminary efficacy. Subsequently, we conducted a first-in-man study to evaluate TLD in patients with COPD forced expiratory volume in 1 s (FEV₁)/forced vital capacity (FVC) (FEV₁/FVC < 0.70; FEV₁ 20%-60% predicted) with three energy settings (12 W, 14 W, and 16 W). The primary safety endpoint was the occurrence of any adverse events or serious adverse events deemed related to the TLD device or the procedure. The efficacy endpoints included the instrument and technical success rates of the TLD procedures, as well as changes in lung function, exercise capacity assessments, and health-related quality of life.

Results: In vitro experiments demonstrated that using ice-cold saline irrigation reduced the temperature at the ablation point compared to room-temperature saline (44 °C vs. 63 °C). The ablation range was 6-8 mm when the single electrode power was 12-16 W, coinciding with the distribution of peribronchial nerves. In the in vivo experiments, we confirmed the feasibility of performing TLD in dogs without causing esophageal injury. In sheep, the bronchoscopy and histological examinations showed airway epithelial restitution within a one-year follow-up. Postprocedural pulmonary airway resistance was reduced by approximately 30% with a sustained 30% decrease in axonal staining. In the first-in-man study, the nine patients included reported good tolerance with a success instrument rate of 100% and a technical success rate of 88.9%. FEV₁ increased by 160 ± 120 mL at 6 months post-TLD and 80 ± 150 mL at 12 months post-TLD from baseline. The patients' motor ability and quality of life scores showed improvement but returned to baseline levels by the twelfth month.

Conclusion: This study demonstrated the feasibility of the novel TLD multi-polar RF ablation system in COPD patients. Its safety and clinical efficacy require further validation in larger patient cohorts.

Clinical trial number: ChiCTR2100047843 ( http://www.chictr.org.cn/ ). Registration date: 27 June, 2021.

Background: Exposure to particulate matter (PM) is a significant public health concern associated with respiratory, cardiovascular, and metabolic diseases. Oxidative stress is a key biological mechanism mediating the harmful effects of PM exposure. However, a comprehensive review of relating PM exposure to omics layers of oxidative stress has been lacking. We aimed to systematically review the current evidence on the associations between PM exposure and the multi-omics signatures of oxidative stress.

Methods: We conducted a systematic review of studies published between January 2021 and March 2024 in PubMed and Web of Science, following a registered protocol (PROSPERO ID: CRD42024617742). Eligible studies assessed the impact of PM exposure on oxidative stress-related omics in adult human populations. Data on exposure assessment, study characteristics, and omics outcomes were extracted, and the risk of bias was evaluated using the Newcastle-Ottawa Scale and Cochrane's.

Results: Seventy-seven studies were included. PM exposure was consistently associated with oxidative stress markers across multiple omics platforms. Studies on the analytes showed that PM was associated with an increase in oxidative markers. Metabolomics studies revealed alterations in pro-oxidant metabolites (e.g., eicosanoids, ceramides) and disruptions in antioxidant pathways (e.g., glutathione, vitamin C, and E metabolism). PM exposure was also linked to changes in energy metabolism, fatty acid oxidation, and detoxification pathways. Genomics studies reported differential methylation in genes involved in oxidative stress and inflammation. Microbiome studies suggest that PM exposure alters the composition of gut and nasal microbiota, favoring a pro-oxidative profile. However, some studies reported no significant associations, highlighting heterogeneity in findings.

Conclusion: Our systematic review demonstrates that PM exposure affects multiple molecular pathways related to oxidative stress across diverse omics platforms. These findings highlight the complex responses to PM, underscoring the need for integrative multi-omics approaches to fully understand the health impacts of air pollution.