Respiratory Research最新文献

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.

Background: Silicosis is an incurable occupational lung disease characterized by progressive fibrosis and respiratory failure, imposing a significant global health burden. Surfactant protein A (SP-A) plays a critical role in maintaining pulmonary homeostasis, yet its mechanistic role in silicosis remains unclear.

Methods: SP-A expression was assessed in lung tissues from patients with silicosis and in silica-exposed mice. Sftpa1 gene knockout (Sftpa1^-/-) mice were generated to evaluate the functional role of SP-A in vivo, including lung pathology, collagen deposition, and pulmonary function. RNA sequencing was performed to uncover underlying molecular mechanisms. A549 cells with SP-A silenced by siRNA were employed for in vitro experiments.

Results: SP-A levels were notably reduced in the lung tissue of silicosis patients and in experimental silicosis mice, correlating inversely with disease severity. Sftpa1^⁻/⁻ mice showed markedly exacerbated silica-induced pulmonary fibrosis, extracellular matrix deposition, and functional decline. RNA-seq analysis highlighted activation of intrinsic apoptosis pathways related to pulmonary fibrosis. Mechanistically, SP-A deficiency disrupted the balance of Bcl-2 and Bax, activated Caspase-3, and promoted epithelial apoptosis. Inhibition of the intrinsic apoptosis pathway mitigated the pro-apoptotic effects of SP-A silencing.

Conclusions: These findings demonstrate that SP-A deficiency exacerbates silica-induced pulmonary fibrosis by promoting epithelial apoptosis involving the Bcl-2/Bax/Caspase pathway, highlighting the role of SP-A in fibrogenesis progression and providing a basis for its potential therapeutic target for silicosis.