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首页> 外文期刊>BMC Pulmonary Medicine >Pirfenidone attenuates bleomycin-induced pulmonary fibrosis in mice by regulating Nrf2/Bach1 equilibrium
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Pirfenidone attenuates bleomycin-induced pulmonary fibrosis in mice by regulating Nrf2/Bach1 equilibrium

机译：通过调节NRF2 / BACH1平衡，Pirfenidone衰减博尔霉素诱导的肺纤维化

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Background Oxidative stress is one of the important factors involved in the pathogenesis of idiopathic pulmonary fibrosis (IPF). The equilibrium of Nuclear factor-erythroid-related factor 2 (Nrf2)/[BTB (broad-complex, tramtrack and bric-a-brac) and CNC (cap‘n’collar protein) homology 1, Bach1] determines the expression level of antioxidant factors, further regulating the function of oxidation/antioxidation capacity. Pirfenidone (PFD) is one of two currently for IPF therapy approved drugs. PFD regulates intracellular antioxidants, inhibits secretion of inflammatory cytokines and collagen synthesis. However the mechanisms of its antioxidant effects remain elusive. Methods Effects of PFD treatment were studied in mouse lung fibroblasts (MLF) following induction by transforming-growth factor beta 1 (TGF-β1) and in mice following bleomycin-induced lung fibrosis. The mRNA and protein levels of oxidative stress-related factors Nrf2/Bach1 and their downstream antioxidant factors heme oxygenase-1 (Ho-1) and glutathione peroxidase 1 (Gpx1) were determined by RT-PCR and Western blot. Fibrosis-related cytokines interleukin-6 (IL-6) and myofibroblast markers type 1 collagen α1 (COL1A1) levels in supernate of MLF, serum, and bronchoalveolar lavage fluid (BALF) as well as malondialdehyde (MDA) in serum and BALF were detected by ELISA, reactive oxygen species (ROS) generation was measured by 2′,7′- dichlorofluorescin diacetate (DCFH-DA) assay and lung pathological/morphological alterations in mice were observed by HE and Masson to assess the antioxidant mechanism and therapeutic effects on pulmonary fibrosis induced by bleomycin. Results PFD inhibited Bach1 mRNA and protein expressions in mouse lung fibroblasts induced by TGF-β1 and lung tissues with pulmonary fibrosis induced by bleomycin. Furthermore, it improved Nrf2, Ho-1 and Gpx1 mRNA and protein expressions. After PFD treatment, COL1A1and IL-6 levels in supernate of MLF, serum, and BALF as well as ROS in lung tissues and MDA in serum and BALF from a mouse with pulmonary fibrosis were significantly decreased, and the infiltration of lung inflammatory cells and fibrosis degree were alleviated. Conclusions Theraputic effects of PFD for IPF were involved in Nrf2/Bach1 equilibrium which regulated the capacity of oxidative stress. The study provided new insights into the antioxidant mechanism of PFD.
机译：背景技术氧化应激是具有特发性肺纤维化（IPF）发病机制的重要因素之一。核因子 - 红细胞相关因子2（NRF2）/ [BTB（广泛复合，轨道和BRIC-A-BRAC）和CNC（CAP'N'collar蛋白）同源1，BACH1]的核因子均衡确定了表达水平抗氧化因子，进一步调节氧化/抗氧化能力的功能。 Pirfenidone（PFD）是目前IPF治疗批准的药物的两个人之一。 PFD调节细胞内抗氧化剂，抑制炎症细胞因子和胶原合成的分泌。然而，其抗氧化效应的机制仍然难以捉摸。方法通过转化生长因子β1（TGF-β1）和在岩土霉素诱导的肺纤维化之后，在诱导中，在小鼠肺成纤维细胞（MLF）之后在小鼠肺成纤维细胞（MLF）中研究了PFD处理的效果。通过RT-PCR和Western印迹测定氧化应激相关因子NRF2 / BACH1及其下游抗氧化因子血红素氧酶-1（HO-1）和谷胱甘肽过氧化物酶1（GPX1）的mRF2 / bach1及其下游抗氧化因子。检测纤维化相关的细胞因子白细胞介素-6（IL-6）和MLF，血清和支气管肺泡灌洗液（BALF）和血清中的丙醛（MDA）的胶原蛋白α1（COL1A1）水平α1（COL1A1）水平，以及血清和BALF的丙二醛（MDA）通过ELISA，通过2'测量反应性氧物质（ROS）产生，7'-二氯荧光蛋白（DCFH-DA）测定和小鼠的肺病理/形态学/形态学改变，以评估抗氧化机制和治疗效果Bleomycin诱导的肺纤维化。结果PFD抑制了TGF-β1诱导的小鼠肺成纤维细胞和肺组织与肺纤维蛋白诱导的小鼠肺成纤维细胞抑制BACH1 mRNA和蛋白质表达。此外，它改善了NRF2，HO-1和GPX1 mRNA和蛋白质表达。 PFD治疗后，MLF，血清和BALF的血清中的血清中的COL1A1和IL-6水平以及血清中的肺组织和MDA中的rOS，与肺纤维化的小鼠的血清和BALF均显着降低，肺炎细胞和纤维化的渗透减轻了程度。结论PFD对IPF的治疗效应参与NRF2 / BACH1平衡，该平衡调节氧化应激能力。该研究为PFD的抗氧化机制提供了新的见解。

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