American Journal of Respiratory Cell and Molecular Biology最新文献

Acute lung injury (ALI) is characterized by exaggerated inflammatory reactions and high clinical mortality rates, but targeted therapeutic interventions are lacking. Warifteine, which is a traditional remedy known for its antiinflammatory properties, has been identified, but its potential effects on ALI remain unexplored. In this study, a murine model of ALI was established by injecting LPS into wild-type (WT) or neutrophil-specific Gsdmd (Gasdermin D)-deficient mice. Pulmonary function was evaluated, and lung samples were collected for immunofluorescence staining and RNA sequencing analysis. Additionally, live imaging of the lungs as well as histological, biochemical, and molecular investigations were performed to assess the progression of LPS-induced ALI in mice. Mouse bone marrow-derived neutrophils were isolated and cultured to investigate the effects of warifteine in vitro. Our findings indicate that warifteine effectively mitigates LPS-induced lung pathology and dysfunction in mice. Mechanistic studies revealed that warifteine protects against ALI by inhibiting neutrophil extracellular trap formation and the resulting cytokine storm. Subsequent research demonstrated that warifteine influences neutrophil extracellular trap formation by inhibiting GSDMD oligomerization through the regulation of reactive oxygen species production by neutrophils. Collectively, these findings reveal a novel role for warifteine in the protection against ALI and suggest that modulating GSDMD oligomerization may be an innovative therapeutic strategy.

Chronic obstructive pulmonary disease (COPD) is a prevalent respiratory disease lacking effective treatment. Focusing on early COPD should help to discover disease modifying therapies. We examined the role of the CXCL12/CXCR4 axis in early COPD using human samples and murine models. Blood samples and lung tissues from both individuals with early COPD and controls were analyzed for CXCL12 and CXCR4 levels. To generate an early-like COPD model, 10-week-old male C57BL/6J mice were exposed to cigarette smoke for 10 weeks and intranasal instillations of polyinosinic-polycytidylic acid (poly(I:C)) for the last 5 weeks to mimic exacerbations. The number of cells expressing CXCR4 was increased in the blood of individuals with COPD, as well as in the blood of exposed mice. Lung CXCL12 expression was higher in both patients with early COPD and exposed mice. Exposed mice presented mild airflow obstruction, peribronchial fibrosis, and right heart thickening. The density of fibrocyte-like cells expressing CXCR4 increased in the bronchial submucosa of these mice. Conditional inactivation of CXCR4, as well as pharmacological inhibition of CXCR4 with plerixafor injections, improved lung function, reduced inflammation, and protected against cigarette smoke and poly(I:C)-induced airway and cardiac remodeling. CXCR4^-/--treated and plerixafor-treated mice also had fewer CXCR4-expressing circulating cells and a lower density of peribronchial fibrocyte-like cells. We demonstrate that targeting CXCR4 has beneficial effects in an animal model mimicking early COPD. Although these preclinical findings are encouraging, further research is needed to explore the potential for transferring these insights into clinical applications, including drug repurposing.

Particulate matter ⩽2.5 μm in aerodynamic diameter (PM_2.5), exposure is closely linked to the exacerbation of asthma. Esrrg (estrogen-related receptor-γ), an orphan nuclear receptor, exerts a crucial role as a transcription factor in various metabolic diseases. Nevertheless, the impacts of Esrrg on PM_2.5-triggered asthma aggravation have not been investigated. Herein, ovalbumin (OVA)-induced asthmatic mice were exposed to PM_2.5 to establish a mouse model of asthma aggravation by PM_2.5. In view of mRNA sequencing, Esrrg was the only member of the nuclear receptor superfamily in the upregulated differentially expressed genes in OVA compared with naive groups as well as OVA + PM_2.5 compared with OVA groups (|log₂ (fold change)| > 1 and P < 0.05). In vivo, adenoassociated virus (AAV) carrying Esrrg shRNA (AAV-shEsrrg) was applied to silence Esrrg. In addition, Esrrg activity was suppressed pharmacologically with an inverse agonist, GSK5182. AAV-shEsrrg or GSK5182 ameliorated airway inflammation in the PM_2.5-aggravated asthmatic mice. In vitro, isolated mouse primary tracheobronchial epithelial cells from mice were identified by detecting cytokeratin 7-positive cells. The treatment of adenovirus vector with shEsrrg or GSK5182 mitigated the cell damage induced by PM_2.5. Notably, Pde3b (phosphodiesterase 3B) expression was decreased by Esrrg inhibition in vivo and in vitro. Dual luciferase reporter and chromatin immunoprecipitation PCR assays showed the binding of Esrrg to the Pde3b promoter. Taken together, these results revealed that Esrrg inhibition alleviated airway inflammation in the PM_2.5-deteriorated asthmatic mouse model and prevented PM_2.5-driven mouse primary tracheobronchial epithelial cell injury through binding to the Pde3b promoter, which might contribute to further study of therapies for PM_2.5-aggravated asthma.

The obstructive lung diseases (OLDs), such as asthma and chronic obstructive pulmonary disease (COPD) are characterized by bronchoconstriction and difficulty in breathing. β₂-adrenergic receptor (β₂AR) agonists (β-agonists) represent the most commonly used class of bronchodilators. To enhance their clinical effectiveness, extensive attempts have been made to improve their receptor subtype selectivity and duration of action, resulting in the development of long-acting β-agonists (LABAs) and ultralong-acting β-agonists. Although these drugs effectively alleviate OLD symptoms, concerns have arisen regarding their safety, their reduced therapeutic benefits, and the potential for worsening asthma symptoms. These concerns have led to restrictions on β-agonist use. Recent advances in G protein-coupled receptor (GPCR) pharmacology and biochemistry have introduced new concepts in drug development, such as "biased agonism" and "allosteric modulation." These advancements stem from a deeper understanding of the molecular interactions between β₂ARs and various intracellular proteins (e.g., heterotrimeric G proteins and β-arrestins), which induce a diverse array of functional changes in airway cells. Biased agonism and allosteric modulation offer new avenues for developing the next generation of β-agonists with improved pharmacological properties. This review explores the application of these concepts in developing new β₂AR ligands, including orthosteric and allosteric ligands, that selectively enhance therapeutically beneficial Gs signaling while minimizing harmful β-arrestin-mediated effects in airway cells.

Oxygen supplementation causes an arrest of alveolar formation and a depletion of alveolar epithelial type 2 (AT2) cells in preterm infants, both characteristics of bronchopulmonary dysplasia. BDNF (brain-derived neurotrophic factor) is a key integrator of cell homeostasis and contributes to chronic lung diseases. In this study, 1) wild-type mice were exposed to 85% O₂ or 21% O₂ from birth to postnatal day (P)28, followed by spatiotemporal profiling of pulmonary BDNF signaling on P3-P70; and 2) lung epithelial cells (MLE12), primary murine AT2, and precision-cut lung slices were treated with nonselective Trk inhibitor (K252a), selective TrkB antagonist (Ana12), and TrkB agonist (7,8-dihydroxyflavone). Single-cell transcriptomic profiling revealed an expression of Bdnf in mesenchymal cells but no changes during postnatal development. In contrast, immunofluorescent staining showed a predominant localization of TrkB in AT2 and ACTA2⁺ cells; its expression and phosphorylation were increased at P7-P21. Although hyperoxia induced a 40-fold upregulation of lung Bdnf and a 3-fold elevation of serum BDNF, TrkB abundance and activation decreased by 90%. This was related to a lower Sftpc and increased Acta2 in lungs. Blockade of Trk(B) reduced survival of MLE12 and murine AT2 with a loss of epithelial AT1 and AT2 markers, whereas the TrkB agonist increased survival and regulated AT2 maintenance in precision-cut lung slices after hyperoxia. Our data identified an important functional role of TrkB signaling in AT2 cells, a mechanism that is blocked in neonatal mouse lungs after hyperoxia and may contribute to a lack of regeneration and to arrest of alveolar growth in infants with bronchopulmonary dysplasia.