Inflammation and oxidative stress are critical pathologies that contribute to sepsis-induced acute lung injury (ALI). This study investigated the regulatory role of estrogen-related receptor alpha (ERRα) in an experimental model of sepsis-induced ALI. In vivo, a cecal ligation and puncture- (CLP-) induced ALI model was established in anesthetized rats. Animals were then randomly assigned to receive an intraperitoneal injection of vehicle or ERRα inverse agonist (XCT-790, 2.5 mg/kg). Administration of XCT-790 significantly aggravated a sepsis-induced increase in pathological damage of lung tissues, lung endothelial permeability, myeloperoxidase (MPO) activity in lung tissues, production of serum inflammatory factors, and inflammatory cell accumulation in bronchoalveolar lavage fluid. In addition, XCT-790 treatment exacerbated a CLP-induced decrease in lung superoxide dismutase and an increase in lung malondialdehyde levels. In vitro, the exposure of rat pulmonary microvascular endothelial cells (PMVECs) to lipopolysaccharide (LPS) resulted in increased endothelial permeability and reduced expression of tight junction protein ZO-1, Occludin, JAM-A, and adherens junction protein VE-cadherin, which were further deteriorated by knockdown of ERRα. In addition, LPS-triggered inflammatory factor production and increase in the expression of phosphorylated IκBα and NF-κB p65 were also exacerbated by silencing ERRα gene. Meanwhile, knockdown of ERRα dramatically promoted LPS-activated mitochondrial reactive oxygen species production and LPS-induced downregulation of Sirt3 protein levels in rat PMVECs. Taken together, our present study provides evidences that ERRα functions as a novel negative modulator of sepsis-induced ALI in rats. The underlying mechanisms responsible for ERRα-elicited effects are largely dependent on the regulation of inflammatory response and oxidative stress.

中文翻译：

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ERRα的抑制会加剧炎症和氧化应激，从而加剧败血症诱导的大鼠急性肺损伤。

炎症和氧化应激是导致败血症诱发的急性肺损伤（ALI）的关键病理。这项研究调查了雌激素相关受体α（ERR的调节作用α在脓毒症急性肺损伤的实验模型）。在体内，在麻醉的大鼠中建立盲肠结扎和穿刺（CLP-）诱导的ALI模型。然后将动物随机分配接受媒介物或ERR腹膜内注射α反向激动剂（XCT-790，2.5mg / kg）。XCT-790的使用显着加重了脓毒症引起的肺组织病理损伤，肺内皮通透性，肺组织中的髓过氧化物酶（MPO）活性，血清炎性因子的产生以及支气管肺泡灌洗液中炎性细胞的积累。此外，XCT-790治疗加剧了CLP诱导的肺超氧化物歧化酶减少和肺丙二醛水平增加。在体外，大鼠肺微血管内皮细胞（PMVEC）暴露于脂多糖（LPS）导致内皮通透性增加，紧密连接蛋白ZO-1，Occludin，JAM-A和粘附连接蛋白VE-钙粘着蛋白的表达降低。 ERR的敲低进一步恶化α。此外，LPS触发炎症因子生产和磷酸化I的表达增加κ乙α和NF- κ乙P65也通过沉默ERR加剧α基因。同时，ERR的敲低α显着促进LPS活化线粒体活性氧的产生和在大鼠PMVECs SIRT3蛋白水平的LPS诱导的下调。两者合计，我们目前的研究提供的证据表明ERR α用作大鼠败血症诱导ALI的新颖负调节剂。负责ERR的基本机制α -elicited效果在很大程度上依赖于炎症反应和氧化应激的调节。