Local administration of liposomal-based Srpx2 gene therapy reverses pulmonary fibrosis by blockading fibroblast-to-myofibroblast transition.
Local administration of liposomal-based Srpx2 gene therapy reverses pulmonary fibrosis by blockading fibroblast-to-myofibroblast transition.
复制标题
基于脂质体的 Srpx2 基因治疗的局部给药通过阻断成纤维细胞向肌成纤维细胞的转变逆转肺纤维化
作者：
Wang Q;Liu J;Hu Y;Pan T;Xu Y;Yu J;Xiong W;Zhou Q;Wang Y
特发性肺纤维化（IPF）是一种慢性、进行性、致死性间质性肺疾病，以成纤维细胞异常转化和增殖为特征。成纤维细胞（通常称为肌成纤维细胞）的不受控制的转变是肺实质中沉积的大量细胞外基质（ECM）的主要来源，导致患者的气体交换逐渐失败和死亡。然而，到目前为止，已开发出罕见的有效治疗策略来阻断IPF中的成纤维细胞向肌成纤维细胞转化（FMT）。方法：我们阐明了源自IPF患者和肺纤维化小鼠的肺的特征在于含sushi重复序列的蛋白X连锁2（SRPX 2）的过表达。进一步的功能研究确定了SRPX 2在FMT中的关键作用。SRPX 2参与TGF β R1/SMAD3/SRPX 2/AP 1/SMAD7正反馈循环。TGF-β 1以TGF β R1/SMAD3依赖的方式上调SRPX 2，然后SRPX 2抑制AP 1的表达，进而抑制SMAD7的表达，从而减少与TGF β R1形成抑制复合物，增强SMAD信号通路，促进FMT，加重肺纤维化。值得注意的是，动脉内施用负载siRNA的脂质体可以有效地抑制肺中BLM x2的表达，并显著保护小鼠免受BLM诱导的肺纤维化，同时显著降低FMT。结果如下：因此，这些数据表明，pMX2在肺纤维化的发病机制中起重要作用，并表明旨在沉默pMX2的策略可能是临床环境中针对肺纤维化的有希望的治疗方法。
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fatal interstitial lung disease characterized by abnormal transition and proliferation of fibroblasts. The uncontrolled transition of fibroblasts, commonly known as myofibroblasts, are the principal source of the enormous extracellular matrix (ECM) depositing in lung parenchyma, leading to gradual failure of gas exchange and mortality of the patients. However, up to now, rare effective therapeutic strategies have been developed to blockade fibroblast-to-myofibroblast transition (FMT) in IPF. Method: We illustrated that the lungs originated from IPF patients and mice with pulmonary fibrosis are characterized by the overexpression of sushi-repeat-containing protein, X-linked 2 (SRPX2). Further functionality studies identified the pivotal role of SRPX2 in FMT. Mechanistically, SRPX2 was involved in a TGFβR1/SMAD3/SRPX2/AP1/SMAD7 positive feedback loop. Specifically, SRPX2 was upregulated by TGF-β1 in a TGFβR1/SMAD3-dependent manner, after which SRPX2 in turn repressed the expression of AP1, subsequently minimized SMAD7 expression, through which it reduced the formation of inhibitory complex with TGFβR1 and enhanced SMAD signaling pathway to promote FMT and exacerbate pulmonary fibrosis. Notably, intratracheal administration of siRNA-loaded liposomes could effectively suppress the expression of Srpx2 in the lung and remarkably protect mice against BLM-induced pulmonary fibrosis, concomitant with a significant reduction of FMT. Results: Accordingly, these data indicate that Srpx2 plays an essential role in the pathogenesis of pulmonary fibrosis and suggests the strategy aiming at silencing Srpx2 could be a promising therapeutic approach against pulmonary fibrosis in clinical settings.