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Pro- and Anti-fibrogenic Functions of Gram-Negative Bacterial Lipopolysaccharide in the Liver

机译:肝脏革兰阴性细菌脂多糖的抗纤纤功能

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Extensive research performed over several decades has identified cells participating in the initiation and progression of fibrosis, and the numerous underlying inter- and intra-cellular signaling pathways. However, liver fibrosis continues to be a major clinical challenge as the precise targets of treatment are still elusive. Activation of physiologically quiescent perisinusoidal hepatic stellate cells (HSCs) to a myofibroblastic proliferating, contractile and fibrogenic phenotype is a critical event in the pathogenesis of chronic liver disease. Thus elucidation of the mechanisms of the reversal to quiescence or inhibition of activated HSCs, and/or their elimination via apoptosis has been the focus of intense investigation. Lipopolysaccharide (LPS), a gut-resident Gram-negative bacterial endotoxin, is a powerful pro-inflammatory molecule implicated in hepatic injury, inflammation and fibrosis. In both acute and chronic liver injury, portal venous levels of LPS are elevated due to increased intestinal permeability. LPS, via CD14 and Toll-like receptor 4 (TLR4) and its adapter molecules, stimulates macrophages, neutrophils and several other cell types to produce inflammatory mediators as well as factors that can activate HSCs and stimulate their fibrogenic activity. LPS also stimulates synthesis of pro- and anti-inflammatory cytokines/chemokines, growth mediators and molecules of immune regulation by HSCs. However, LPS was found to arrest proliferation of activated HSCs and to convert them into non-fibrogenic phenotype. Interestingly, LPS can elicit responses in HSCs independent of CD14 and TLR4. Identifying and/or developing non-inflammatory but anti-fibrogenic mimetics of LPS could be relevant for treating liver fibrosis.
机译:在几十年内进行的广泛研究已经确定了参与纤维化的开始和进展的细胞,以及众多潜在的细胞内信号传导途径。然而,随着精确的治疗目标仍然​​难以实现,肝纤维化仍然是一个重大的临床挑战。将生理学静态嗜酸性肝星状细胞(HSC)的激活活化至肌纤维纤维增殖,收缩和纤维型表型是慢性肝病发病机制中的关键事件。因此,阐明了逆转的静态或抑制活性HSC的机制,和/或通过细胞凋亡的消除是激烈调查的重点。脂多糖(LPS),肠道植物革兰氏阴性细菌内毒素,是一种含有肝损伤,炎症和纤维化的强大的促炎分子。在急性和慢性肝损伤中,由于肠道渗透性增加,LPS的LPS的门静脉水平升高。 LPS,通过CD14和Toll样受体4(TLR4)及其衔接子分子,刺激巨噬细胞,中性粒细胞和其他几种细胞类型,以产生炎症介质以及可以激活HSC的因素并刺激其纤维纤维生成活性。 LPS还通过HSC刺激合成促炎细胞因子/趋化因子,生长介质和免疫调节分子。然而,发现LPS会阻止活化HSC的增殖,并将它们转化为非纤维型表型。有趣的是,LPS可以独立于CD14和TLR4引起HSC的回应。鉴定和/或发育LPS的非炎症但抗纤维原料可与治疗肝纤维化有关。

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