肝X受体在博莱霉素诱导的小鼠肺纤维化中的作用及机制

Presently,no medical therapy has been domonstrated effectively for pulmonary fibrosis(PF), so there is an urgent need to deepen the understanding of its pathogenesis and find new targets for drugs.It has been confirmed that the activation of Wnt/ β-catenin signaling pathway, the renin-angiotensin-aldosterone system,endothelin or osteopontin played important roles in the pathogenesis of PF. Liver X receptors(LXRs), a member of the nuclear receptor superfamily, beside its role in the regulation of lipid metabolism, can also inhibit the activation of the above signaling pathways or molecules.Latest studies suggest that LXRs inhibition can lead to liver fibrosis and formation of prostatic fiber nodules which is similar to fibrosis, LXRs activation can alleviate lung inflammation and injury caused by varieties of factors, so we speculate that LXRs might play an important role in the pathogenesis of PF. Our preliminary studies initially confirmed that LXRs agonist can inhibit the expression of α-SMA and fibronectin in human lung fibroblast induced by TGFβ, thus inhibit the trans-differentiation of fibroblasts to myofibroblasts.In this study, with the expect of the finding of new targets for drug therapies, we will investigate changes in the expression of LXRs in the mouse model of PF induced by bleomycin, and explore the intervention role and possible mechanisms of LXRs in bleomycin-induced PF of mice in vivo.

目前尚无肺间质纤维化的有效治疗方法或药物，迫切需要加深对其发病机制的 认识，寻找新的药物治疗靶点。研究证实，Wnt/β-catenin 信号通路，肾素-血管紧张素- 醛固酮系统，内皮素，骨桥蛋白等的活化在纤维化的发生和发展中均发挥重要作用。核受体家族成员肝X 受体（LXRs）对上述信号通路或信号分子均有明显抑制作用，其抑制可导致动物肝纤维化及类似纤维化的前列腺结节，而其活化可以减轻各种原因引起的肺部炎症和损伤，我们推测LXRs在肺间质纤维化中也发挥重要作用，我们前期研究提示LXRs 激动剂可以抑制TGFβ刺激的人肺成纤维细胞α-SMA 及纤维连接蛋白的表达，抑制其转分化。在本研究中，我们将研究LXRs 在小鼠肺纤维化模型中表达的变化,LXRs激动剂、LXRs的外源性表达或表达抑制对博莱霉素诱导肺纤维化的干预作用及可能机制，以期寻找到肺间质纤维化治疗的新靶点。