Respiratory Research最新文献

Background: Acute lung injury (ALI) can initiate early epithelial remodeling that may precede pulmonary fibrosis, with EMT of alveolar epithelial cells implicated in this acute phase. While mesenchymal stromal cell (MSC)-derived exosomes exhibit repair potential, their conventional culture conditions fail to mimic the hypoxic microenvironment of ALI. Here, we explored the therapeutic effects and regulatory mechanisms of hypoxia-preconditioned bone marrow MSC-derived exosomes (HExos) in LPS-induced ALI with early epithelial remodeling.

Methods: BMSCs were characterized via osteogenic/adipogenic differentiation and flow cytometry. Exosomes derived under normoxia (NExos) and hypoxia (HExos) were isolated and validated using nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), and Western blot. An LPS-induced ALI mouse model was employed to evaluate exosome efficacy. Through integrated miRNA sequencing, luciferase reporter assays, and gain-/loss-of-function experiments, we examined a working model involving the miR-486a-5p/Skp2/GATA4 axis.

Results: HExos markedly alleviated LPS-induced acute lung injury and early-stage collagen deposition. Mechanistically, HExos were enriched with miR-486a-5p, which directly targeted Skp2, thereby reducing Skp2-mediated ubiquitin-proteasome degradation of GATA4 and attenuating EMT-like changes. Notably, miR-486a-5p mimics reversed EMT-like changes in alveolar epithelial cells, while its knockdown abolished the protective effect.

Conclusions: Hypoxia-preconditioned bone marrow-derived mesenchymal stromal cell (BMSC) exosomes demonstrate significant potential to alleviate LPS-induced acute injury and early epithelial remodeling by engaging a miR-486a-5p/Skp2/GATA4 working model, offering a proof-of-concept therapeutic strategy for ALI.

Background: Inherited genomic susceptibility and associated transcriptomic patterns are crucial players in lung cancer etiology. Lung cancer susceptibility is getting rising attention in carcinogenesis. The present study aimed to investigate unique clinical features and transcriptomic profile in patients with familial lung cancer (FLC) in Yunnan-Guizhou Plateau, Wumeng-Mountain area of China.

Methods: 1,823 local lung cancer patients were enrolled (762 FLC, 1061 Sporadic). Clinicopathologic parameters were analyzed and summarized. 43 lung tissue samples (the adjacent nonmalignant tissue) were selected for Transcriptome/RNA-seq, the differential gene expression patterns were analyzed, significant functions and pathways were enriched and studied.

Results: Our FLC cohort showed unique characters: younger age; increased rate of adenocarcinoma, and early-stage cases; unbalance in blood types, anatomic sites and co-existing diseases; highlighted with significantly elevated comorbidity and early-onset of hypertension in FLC + population. Notably, our FLC + group exhibited a higher rate of bilateral lung cancers and multiple pulmonary nodules; beside, were more likely to develop different cysts, polyps, hyperplasia at a younger age. The transcriptome found that immune-related functions & pathways were significantly enriched in the familial cohort. E.g. "immune cells recruitment" with higher Neutrophils/ lower CD4 memory T cells. Collectively, these transcriptomic differences suggested: individuals with FLC may have baseline alterations in immune regulation, which could reflect a compromised immune surveillance or dysregulated inflammatory tone in their normal lung tissue. For the key gene, MUC16 may contribute to this process by influencing the assembly, structure & dynamical functions of pulmonary epithelial cilium; which could potentially impair mucociliary clearance, leading to prolonged retention of pollutants and carcinogens in the lung microenvironment.

Conclusions: Hereditary factors likely contribute to the susceptibility to both lung cancer and hypertension in this population, while chronic exposure to local air pollution may further promote their early-onset and comorbidity. Our findings highlighted the potential significance of MUC16 in familial lung cancer or even early-onset lung cancer; and provided useful data for early screening and personalized treatment strategies for lung cancer.

Thunderstorm asthma (TA) refers to a phenomenon characterized by sudden onset, large-scale outbreaks, and potentially fatal acute exacerbations of asthma. Despite accumulating epidemiological evidence, its cellular and molecular mechanisms remain unclear. Recent studies have proposed a core framework involving "environmental triggers-epithelial barrier damage-immune dysregulation." During thunderstorms, high humidity and strong convection can cause pollen to hydrate and rupture into sub-pollen particles (SPPs) smaller than 2.5 μm, which may further combine with other pollutants such as particulate matter ≤ 2.5 μm(PM_2.5) and ozone (O₃) to form bioaerosols capable of penetrating small airways. These factors can lead to damage of the airway epithelial barrier, with sequential cellular and molecular pathophysiological changes including downregulation of various tight junction proteins in the epithelial barrier, imbalance of mucociliary clearance function, and upregulated secretion of epithelial alarmins such as interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP). This results in increased disease severity through activation of innate and adaptive immunity (e.g., type 2 innate lymphoid cells (ILC2)/T helper 2(Th2) axis activation leading to immunoglobulin E(IgE) upregulation, eosinophil activation, and mast cell degranulation; Th17-mediated neutrophilic inflammation; and toll-like receptor(TLR)-mediated innate immune processes and mucosal inflammation) and enhancement of intrinsic susceptibility factors (e.g., TLR gene polymorphisms and abnormal expression, DNA methylation and histone modifications, as well as microbiome-host interactions). According to research in meteorology, exposomics, and molecular immunology, we believe that airway epithelial barrier dysfunction and immune dysregulation play significant roles in TA. Future translational directions primarily involve establishing a population stratification and early warning system through combinations of meteorological factors with allergens/pollutants, thereby enhancing public protection and health management efforts to improve the early warning, prevention, and clinical management of TA.