Hogan Taryn B, Tiwari Nivedita, Nagaraja M R, Shetty Shwetha K, Fan Liang, Shetty Rashmi S, Bhandary Yashodhar P, Shetty Sreerama
Texas Lung Injury Institute, Department of Medicine, University of Texas Health Science Center at Tyler, 11937 US Highway 271, Tyler, TX 75708, USA.
Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
iScience. 2022 Mar 3;25(4):104022. doi: 10.1016/j.isci.2022.104022. eCollection 2022 Apr 15.
Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease resulting from dysregulated repair responses to lung injury. Excessive extracellular matrix deposition by expanding myofibroblasts and fibrotic lung fibroblasts (fLfs) has been implicated in the pathogenesis of PF, including IPF. We explored fLfs' microRNA-34a (miR-34a) expression from IPF tissues. Basal miR-34a levels were decreased with reduced binding of p53 to the promoter DNA and 3'UTR mRNA sequences. Overexpression of miR-34a in fLfs increased p53, PAI-1, and reduced pro-fibrogenic markers. The regulatory effects of miR-34a were altered by modifying the p53 expression. Precursor-miR-34a lung transduction reduced bleomycin-induced PF in wild-type mice. fLfs treated with caveolin-1 scaffolding domain peptide (CSP) or its fragment, CSP7, restored miR-34a, p53, and PAI-1. CSP/CSP7 reduced PDGFR-β and pro-fibrogenic markers, which was abolished in fLfs following blockade of miR-34a expression. These peptides failed to resolve PF in mice lacking miR-34a in fLfs, indicating miR-34a-p53-feedback induction required for anti-fibrotic effects.
特发性肺纤维化（IPF）是一种由对肺损伤的修复反应失调导致的危及生命的疾病。增殖的肌成纤维细胞和纤维化肺成纤维细胞（fLfs）过度沉积细胞外基质与包括IPF在内的PF发病机制有关。我们研究了IPF组织中fLfs的微小RNA-34a（miR-34a）表达。基础miR-34a水平随着p53与启动子DNA和3'UTR mRNA序列结合减少而降低。fLfs中miR-34a过表达增加了p53、PAI-1，并降低了促纤维化标志物。通过改变p53表达改变了miR-34a的调节作用。前体miR-34a肺转导减少了野生型小鼠博来霉素诱导的PF。用小窝蛋白-1支架结构域肽（CSP）或其片段CSP7处理的fLfs恢复了miR-34a、p53和PAI-1。CSP/CSP7降低了PDGFR-β和促纤维化标志物，在miR-34a表达被阻断后的fLfs中这种作用被消除。这些肽未能解决fLfs中缺乏miR-34a的小鼠的PF，表明抗纤维化作用需要miR-34a-p53反馈诱导。
