Chabot Andréanne, Meus Marc-Andre, Naud Patrice, Hertig Vanessa, Dupuis Jocelyn, Villeneuve Louis, El Khoury Nabel, Fiset Celine, Nattel Stanley, Jasmin Jean-Francois, Calderone Angelino
Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada; Département de Physiologie, Université de Montréal, Montréal, Québec, Canada.
J Cell Physiol. 2015 Jan;230(1):170-9. doi: 10.1002/jcp.24696.
Upregulation of the intermediate filament protein nestin was identified in a subpopulation of fibroblasts during reactive and reparative fibrosis and directly contributed to the enhanced proliferative phenotype. The present study tested the hypothesis that nestin was expressed in lung fibroblasts and the pattern of expression represented a distinct marker of pulmonary remodeling secondary to myocardial infarction and type I diabetes. Nestin((+)) fibroblasts were detected in rat lungs and a subpopulation exhibited a myofibroblast phenotype delineated by the co-expression of smooth muscle α-actin. In the lungs of myocardial infarcted rats, interstitial collagen content and nestin mRNA/protein levels were significantly increased despite the absence of secondary pulmonary hypertension, whereas smooth muscle α-actin protein expression was unchanged. Exposure of rat pulmonary fibroblasts to pro-fibrotic stimuli angiotensin II and transforming growth factor-β significantly increased nestin protein levels. In the lungs of type I diabetic rats, the absence of a reactive fibrotic response was associated with a significant downregulation of nestin mRNA/protein expression. Nestin was reported a target of miR-125b, albeit miR-125b levels were unchanged in pulmonary fibroblasts treated with pro-fibrotic stimuli. Nestin((+)) cells lacking smooth muscle α-actin/collagen staining were also identified in rodent lungs and a transgenic approach revealed that expression of the intermediate filament protein was driven by intron 2 of the nestin gene. The disparate regulation of nestin characterized a distinct pattern of pulmonary remodeling secondary to myocardial infarction and type I diabetes and upregulation of the intermediate filament protein in lung fibroblasts may have facilitated in part the reactive fibrotic response.
在反应性和修复性纤维化过程中，在成纤维细胞亚群中发现中间丝蛋白巢蛋白上调，这直接导致增殖表型增强。本研究检验了以下假设：巢蛋白在肺成纤维细胞中表达，且其表达模式代表心肌梗死和I型糖尿病继发的肺重塑的独特标志物。在大鼠肺中检测到巢蛋白（+）成纤维细胞，并且一个亚群表现出由平滑肌α-肌动蛋白共表达所描绘的肌成纤维细胞表型。在心肌梗死大鼠的肺中，尽管没有继发性肺动脉高压，但间质胶原含量和巢蛋白mRNA/蛋白水平显著增加，而平滑肌α-肌动蛋白蛋白表达未改变。将大鼠肺成纤维细胞暴露于促纤维化刺激物血管紧张素II和转化生长因子-β可显著增加巢蛋白蛋白水平。在I型糖尿病大鼠的肺中，无反应性纤维化反应与巢蛋白mRNA/蛋白表达的显著下调有关。巢蛋白被报道为miR-125b的靶标，尽管在用促纤维化刺激物处理的肺成纤维细胞中miR-125b水平未改变。在啮齿动物肺中也鉴定出缺乏平滑肌α-肌动蛋白/胶原染色的巢蛋白（+）细胞，并且转基因方法显示中间丝蛋白的表达由巢蛋白基因的内含子2驱动。巢蛋白的不同调节特征化了心肌梗死和I型糖尿病继发的肺重塑的独特模式，并且肺成纤维细胞中中间丝蛋白的上调可能部分促进了反应性纤维化反应。
