Abstract：
Pulmonary fibrosis (PF) results from excessive extracellular matrix (ECM) deposition and tissue remodeling after activation of fibroblasts into myofibroblasts. Abnormally deposited fibrotic ECM, in turn, promotes fibroblast activation and accelerates loss of lung structure and function. However, the molecular mediators and exact mechanisms by which fibrotic ECM promotes fibroblast activation are unclear. In a bleomycin-induced PF mouse model, we found Galectin-1 (Gal-1) expression was significantly increased in lung tissue, and overexpression of Gal-1 plasmid-transfected fibroblasts were activated into myofibroblasts. Using the decellularization technique to prepare decellularized fibrotic ECM and constructing a 3D in vitro co-culture system with fibroblasts, we found that decellularized fibrotic ECM induced a high expression of Gal-1 and promoted the activation of fibroblasts into myofibroblasts. Therefore, Gal-1 has been identified as a pivotal mediator in PF. Further, we found that decellularized fibrotic ECM delivered mechanical signals to cells through the Gal-1-mediated FAK-Src-P130Cas mechanical signalling pathway, while the CYP450 enzymes (mainly involved in CYP1A1, CYP24A1, CYP3A4, and CYP2D6 isoforms) acted as a chemical signalling pathway to receive mechanical signals transmitted from upstream Gal-1, thereby promoting fibroblast activation. The Gal-1 inhibitor OTX008 or the CYP1A1 inhibitor 7-Hydroxyflavone prevented PF in mice and inhibited the role of fibrotic ECM in promoting fibroblast activation into myofibroblasts, preventing PF. These results reveal novel molecular mechanisms of lung fibrosis formation and identify Gal-1 and its downstream CYP1A1 as potential therapeutic targets for PF disease treatmnts.
摘要：
肺纤维化（PF）是由成纤维细胞活化为肌成纤维细胞后的过度细胞外基质（ECM）沉积和组织重塑引起的。异常沉积的纤维化ECM，反过来,促进成纤维细胞活化并加速肺结构和功能的丧失。然而,纤维化ECM促进成纤维细胞活化的分子介质和确切机制尚不清楚.在博来霉素诱导的PF小鼠模型中，我们发现Galectin-1(Gal-1)在肺组织中的表达显著增加,和Gal-1质粒转染的成纤维细胞的过表达被激活为肌成纤维细胞。利用脱细胞技术制备脱细胞纤维化ECM，并与成纤维细胞构建3D体外共培养体系，我们发现去细胞纤维化ECM诱导Gal-1的高表达并促进成纤维细胞活化为肌成纤维细胞。因此,Gal-1已被确定为PF中的关键介体。Further,我们发现去细胞纤维化ECM通过Gal-1介导的FAK-Src-P130Cas机械信号通路向细胞传递机械信号,而CYP450酶（主要涉及CYP1A1，CYP24A1，CYP3A4和CYP2D6亚型）充当化学信号通路，以接收从上游Gal-1传递的机械信号，从而促进成纤维细胞活化。Gal-1抑制剂OTX008或CYP1A1抑制剂7-羟基黄酮在小鼠中预防PF并抑制纤维化ECM在促进成纤维细胞活化为肌成纤维细胞中的作用，防止PF。这些结果揭示了肺纤维化形成的新分子机制，并鉴定了Gal-1及其下游CYP1A1作为PF疾病治疗的潜在治疗靶标。
