State Key Laboratory of Respiratory disease, Department of Physiology, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, RP China.
Ecotoxicol Environ Saf. 2024 May;276:116309. doi: 10.1016/j.ecoenv.2024.116309. Epub 2024 Apr 10.
Emerging evidence has suggested that exposure to PM is a significant contributing factor to the development of chronic obstructive pulmonary disease (COPD). However, the underlying biological effects and mechanisms of PM in COPD pathology remain elusive. In this study, we aimed to investigate the implication and regulatory effect of biomass fuels related-PM (BRPM) concerning the pathological process of fibroblast-to-myofibroblast transition (FMT) in the context of COPD. In vivo experimentation revealed that exposure to biofuel smoke was associated with airway inflammation in rats. After 4 weeks of exposure, there was inflammation in the small airways, but no significant structural changes in the airway walls. However, after 24 weeks, airway remodeling occurred due to increased collagen deposition, myofibroblast proliferation, and tracheal wall thickness. In vitro, cellular immunofluorescence results showed that with stimulation of BRPM for 72 h, the cell morphology of fibroblasts changed significantly, most of the cells changed from spindle-shaped to star-shaped irregular, α-SMA stress fibers appeared in the cytoplasm and the synthesis of type I collagen increased. The collagen gel contraction experiment showed that the contractility of fibroblasts was enhanced. The expression level of TRPC1 in fibroblasts was increased. Specific siRNA-TRPC1 blocked BRPM-induced FMT and reduced cell contractility. Additionally, specific siRNA-TRPC1 resulted in a decrease in the augment of intracellular Ca concentration ([Ca]) induced by BRPM. Notably, it was found that the PI3K inhibitor, LY294002, inhibited enhancement of AKT phosphorylation level, FMT occurrence, and elevation of TRPC1 protein expression induced by BRPM. The findings indicated that BRPM is capable of inducing the FMT, with the possibility of mediation by PI3K/AKT/TRPC1. These results hold potential implications for the understanding of the molecular mechanisms involved in BRPM-induced COPD and may aid in the development of novel therapeutic strategies for pathological conditions characterized by fibrosis.
新的证据表明，暴露于 PM 是慢性阻塞性肺疾病（COPD）发展的一个重要因素。然而，PM 在 COPD 病理中的潜在生物学效应和机制仍不清楚。在这项研究中，我们旨在探讨生物质燃料相关 PM（BRPM）在 COPD 背景下与成纤维细胞向肌成纤维细胞转化（FMT）病理过程相关的意义和调节作用。体内实验表明，暴露于生物燃料烟雾与大鼠气道炎症有关。暴露 4 周后，小气道出现炎症，但气道壁无明显结构改变。然而，24 周后，由于胶原蛋白沉积增加、肌成纤维细胞增殖和气管壁厚度增加，发生了气道重塑。在体外，细胞免疫荧光结果表明，BRPM 刺激 72 小时后，成纤维细胞的细胞形态发生明显变化，大多数细胞由梭形变为星状不规则，细胞质中出现α-SMA 应激纤维，I 型胶原合成增加。胶原凝胶收缩实验表明，成纤维细胞的收缩性增强。成纤维细胞中 TRPC1 的表达水平增加。特异性 siRNA-TRPC1 阻断 BRPM 诱导的 FMT 并降低细胞收缩性。此外，特异性 siRNA-TRPC1 导致 BRPM 诱导的细胞内 Ca 浓度 ([Ca]) 增加减少。值得注意的是，发现 PI3K 抑制剂 LY294002 抑制了 BRPM 诱导的 AKT 磷酸化水平增强、FMT 发生和 TRPC1 蛋白表达升高。这些结果表明 BRPM 能够诱导 FMT，其可能通过 PI3K/AKT/TRPC1 介导。这些结果对理解 BRPM 诱导的 COPD 中涉及的分子机制具有重要意义，并可能为纤维化特征的病理状况的新型治疗策略的发展提供帮助。
