Daily Respiratory Research Analysis

Chronic obstructive pulmonary disease (COPD), the third leading cause of death worldwide, lacks effective disease-modifying therapies, partly because of complex gene-environment interactions and extensive missing heritability. Here, we applied a multiomics Mendelian randomization (MR) framework-integrating proteome- and transcriptome-wide association analyses (pQTLs/eQTLs) with genome-wide association summary statistics, sensitivity analyses, and colocalization-to assign evidence levels to genes and prioritize those with higher causal likelihoods across diverse cohorts. We identified serpin family G member 1 (SERPING1) as a robust causal candidate, with consistent pQTL associations with COPD (β = -0.038 to -0.006) and with lung function measures, including FEV₁ (β = 0.008 to 0.015) and FEV₁/FVC% (β = 0.014 to 0.026). Longitudinal analyses in the UK Biobank (n = 46,369) and ECOPD cohort (n = 576) revealed that higher circulating SERPING1 protein levels were causally linked to slower FEV₁ decline during early follow-up (UKB: adjusted difference = -22.1 mL/year per standardized unit; ECOPD: -0.73 mL/year per ng/mL), accompanied by marked expression differences between European (higher) and Asian (lower) smokers and COPD patients. In a murine model exposed to cigarette smoke, AAV-mediated SERPING1 overexpression improved lung function, reduced alveolar destruction, and upregulated the expression of fibroblast elastic fiber-related genes. Collectively, these findings identify SERPING1 as a complement pathway regulator that may function both as a short-term biomarker of lung function decline and as a population specific, disease-modifying therapeutic target for COPD.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disorder involving disrupted BMP (bone morphogenetic protein) signaling, pulmonary inflammation, and endothelial-to-mesenchymal transition (EndMT). We hypothesized that IL (interleukin)-33 signaling contributes to PAH progression by inducing EndMT and interacting with BMP9, a key modulator of inflammation and vascular remodeling. METHODS: IL-33 expression was assessed in lung tissues from Sugen/hypoxia and control mice, as well as in pulmonary arterial endothelial cells (PAECs) and lung tissues from patients with PAH and healthy donors. EndMT and signaling pathways were analyzed in PAECs and microvascular endothelial cells (MVECs) exposed to IL-33, BMP9, and sST2 (soluble supression of tumorigenicity 2) using quantitative polymerase chain reaction, Western blotting, ELISA, and immunostaining. Plasma BMP9 and sST2 levels were quantified in patients with PAH. RESULTS: Immunofluorescent analysis revealed elevated IL-33 expression in pulmonary endothelial cells of Sugen/hypoxia mice compared with controls, consistent with findings in PAECs from patients with PAH. BMP9 significantly upregulated sST2 expression in human PAEC and microvascular endothelial cells, inhibited IL-33 target gene expression, and effectively suppressed IL-33-induced EndMT. Notably, BMP9 demonstrated greater efficacy in preventing EndMT compared with rsST2 (recombinant soluble ST2) or ST2L-neutralizing antibodies. Circulating BMP9 and sST2 levels in the plasma of patients with PAH were positively correlated in specific patient groups stratified by sex, age, and New York Heart Association functional class, suggesting a protective role of BMP9 in modulating IL-33-induced EndMT. CONCLUSIONS: BMP9 plays a protective role against IL-33-induced EndMT in PAECs by upregulating sST2 expression and neutralizing IL-33, suggesting that targeting the IL-33 signaling pathway may represent a promising therapeutic strategy to mitigate EndMT in PAH.

BACKGROUND: Clinical guidelines recommend endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) as the initial diagnostic tool for lung cancer staging. However, despite the availability of mediastinal forceps biopsy and cryobiopsy, the optimal diagnostic approaches for other mediastinal conditions remain unclear. METHODS: We searched multiple databases and sources up to February 21, 2025, and employed single-arm, pairwise, and network meta-analytical approaches to comprehensively evaluate EBUS-based biopsies for mediastinal diseases in terms of efficacy and safety. RESULTS: Fifteen prospective studies including 1,316 participants evaluated five EBUS-based mediastinal biopsy strategies (EBUS-TBNA, forceps biopsy, cryobiopsy, and the combinations of EBUS-TBNA with forceps biopsy or cryobiopsy) were involved. Concomitant EBUS-TBNA enhanced the efficacy of both forceps biopsy and cryobiopsy. EBUS-TBNA plus cryobiopsy yielded the best diagnostic outcome, showing significant benefits over EBUS-TBNA (OR 4.01, 95% CrI 3.05-5.33), forceps biopsy (OR 2.75, 95% CrI 1.94-3.92), cryobiopsy (OR 1.80, 95% CrI 1.33-2.45), and EBUS-TBNA plus forceps biopsy (OR 1.81, 95% CrI 1.20-2.72). A similarly favourable safety profile was observed in all EBUS-based biopsy methods. CONCLUSIONS: EBUS-TBNA is the diagnostic cornerstone for mediastinal lesions, with EBUS-TBNA plus cryobiopsy being most effective. All EBUS-guided biopsies demonstrated a favourable safety profile.