The Ninth People's Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, China.
Sci China Life Sci. 2024 May;67(5):970-985. doi: 10.1007/s11427-022-2392-8. Epub 2024 Feb 7.
Emphysema, myofibroblast accumulation and airway remodeling can occur in the lungs due to exposure to atmospheric pollution, especially fine particulate matter (PM), leading to chronic obstructive pulmonary disease (COPD). Specifically, bronchial epithelium-fibroblast communication participates in airway remodeling, which results in COPD. An increasing number of studies are now being conducted on the role of exosome-mediated cell-cell communication in disease pathogenesis. Here, we investigated whether exosomes generated from bronchial epithelial cells could deliver information to normal stromal fibroblasts and provoke cellular responses, resulting in airway obstruction in COPD. We studied the mechanism of exosome-mediated intercellular communication between human bronchial epithelial (HBE) cells and primary lung fibroblasts (pLFs). We found that PM-induced HBE-derived exosomes promoted myofibroblast differentiation in pLFs. Then, the exosomal lncRNA expression profiles derived from PM-treated HBE cells and nontreated HBE cells were investigated using an Agilent Human LncRNA Array. Combining coculture assays and direct exosome treatment, we found that HBE cell-derived exosomal HOTAIRM1 facilitated the myofibroblast differentiation of pLFs. Surprisingly, we discovered that exosomal HOTAIRM1 enhanced pLF proliferation to secrete excessive collagen secretion, leading to airway obstruction by stimulating the TGF-β/SMAD3 signaling pathway. Significantly, PM reduced FEV1/FVC and FEV1 and increased the level of serum exosomal HOTAIRM1 in healthy people; moreover, serum exosomal HOTAIRM1 was associated with PM-related reductions in FEV1/FVC and FVC. These findings show that PM triggers alterations in exosome components and clarify that one of the paracrine mediators of myofibroblast differentiation is bronchial epithelial cell-derived HOTAIRM1, which has the potential to be an effective prevention and therapeutic target for PM-induced COPD.
肺气肿、肌成纤维细胞积累和气道重塑可能由于暴露于大气污染（尤其是细颗粒物[PM]）而发生在肺部，导致慢性阻塞性肺疾病（COPD）。具体而言，支气管上皮细胞-成纤维细胞通讯参与气道重塑，从而导致 COPD。越来越多的研究现在正在研究外泌体介导的细胞间通讯在疾病发病机制中的作用。在这里，我们研究了来自支气管上皮细胞的外泌体是否可以向正常基质成纤维细胞传递信息并引发细胞反应，从而导致 COPD 中的气道阻塞。我们研究了人支气管上皮（HBE）细胞和原代肺成纤维细胞（pLF）之间外泌体介导的细胞间通讯的机制。我们发现 PM 诱导的 HBE 衍生外泌体促进 pLF 中的肌成纤维细胞分化。然后，使用安捷伦人类 lncRNA 阵列研究了来自 PM 处理的 HBE 细胞和未处理的 HBE 细胞的外泌体 lncRNA 表达谱。通过共培养测定和直接外泌体处理，我们发现 HBE 细胞衍生的外泌体 HOTAIRM1 促进了 pLF 的肌成纤维细胞分化。令人惊讶的是，我们发现外泌体 HOTAIRM1 增强了 pLF 的增殖以分泌过多的胶原分泌，通过刺激 TGF-β/SMAD3 信号通路导致气道阻塞。显著的是，PM 降低了 FEV1/FVC 和 FEV1，并增加了健康人群血清外泌体 HOTAIRM1 的水平；此外，血清外泌体 HOTAIRM1 与 PM 相关的 FEV1/FVC 和 FVC 降低有关。这些发现表明 PM 触发了外泌体成分的改变，并阐明了肌成纤维细胞分化的旁分泌介质之一是支气管上皮细胞衍生的 HOTAIRM1，它有可能成为 PM 诱导的 COPD 的有效预防和治疗靶点。
