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首页> 外文期刊>American Journal of Physiology >PAI-1 plays a protective role in CCl4-induced hepatic fibrosis in mice: Role of hepatocyte division
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PAI-1 plays a protective role in CCl4-induced hepatic fibrosis in mice: Role of hepatocyte division

机译：PAI-1在CCl4诱导的小鼠肝纤维化中起保护作用：肝细胞分裂的作用

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摘要

Plasminogen activator inhibitor-1 (PAI-1) is an acute phase protein that has been shown to play a role in experimental fibrosis caused by bile duct ligation (BDL) in mice. However, its role in more severe models of hepatic fibrosis (e.g., carbon tetrachloride; CCl4) has not been determined and is important for extrapolation to human disease. Wild-type or PAI-1 knockout mice were administered CCl4 (1 ml/kg body wt ip) 2x/wk for 4 wk. Plasma (e.g., transaminase activity) and histological (e.g., Sirius red staining) indexes of liver damage and fibrosis were evaluated. Proliferation and apoptosis were assessed by PCNA and TdT-mediated dUTP nick-end labeling (TUNEL) staining, respectively, as well as by indexes of cell cycle (e.g., p53, cyclin D1). In contrast to previous studies with BDL, hepatic fibrosis was enhanced in PAI-1-/- mice after chronic CCl4 administration. Indeed, all indexes of liver damage were elevated in PAI-1-/- mice compared with wild-type mice. This enhanced liver damage correlated with impaired hepatocyte proliferation. A similar effect on proliferation was observed after one bolus dose of CCl4, without concomitant increases in liver damage. Under these conditions, a decrease in phospho-p38, coupled with elevated p53 protein, was observed; these results suggest impaired proliferation and a potential G1/S cell cycle arrest in PAI-1-/- mice. These data suggest that PAI-1 may play multiple roles in chronic liver diseases, both protective and damaging, the latter mediated by its influence on inflammation and fibrosis and the former via helping maintain hepatocyte division after an injury.
机译：纤溶酶原激活物抑制剂1（PAI-1）是一种急性期蛋白，已显示在小鼠胆管结扎（BDL）引起的实验性纤维化中起作用。然而，它在更严重的肝纤维化模型（例如四氯化碳; CCl4）中的作用尚未确定，对于推断人类疾病很重要。给野生型或PAI-1敲除小鼠2x / wk的CCl4（1 ml / kg体重腹膜内）2周/周。评价了肝损伤和纤维化的血浆（例如转氨酶活性）和组织学（例如天狼星红染色）指数。分别通过PCNA和TdT介导的dUTP缺口末端标记（TUNEL）染色以及细胞周期指数（例如p53，cyclin D1）评估增殖和凋亡。与以前的BDL研究相反，长期施用CCl4后，PAI-1-/-小鼠肝纤维化增强。实际上，与野生型小鼠相比，PAI-1-/-小鼠的所有肝损伤指标均升高。这种增强的肝损伤与肝细胞增殖受损有关。推注一剂CCl4后，观察到对增殖的类似作用，但未伴随肝损害的增加。在这些条件下，观察到磷酸化-p38减少，同时p53蛋白升高。这些结果表明，PAI-1-/-小鼠的增殖受到损害，并且潜在的G1 / S细胞周期停滞。这些数据表明，PAI-1在慢性肝病中可能起多种作用，包括保护性和损伤性，后者通过其对炎症和纤维化的影响而介导，而前者则通过帮助维持损伤后的肝细胞分裂来发挥作用。

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