Department of Pharmacology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Fundam Clin Pharmacol. 2022 Oct;36(5):827-836. doi: 10.1111/fcp.12774. Epub 2022 Mar 13.
Nonalcoholic steatohepatitis is a clinically important liver disease. Its symptoms are exacerbated by macrophage foaming, which is promoted by plasminogen in vitro. However, the influence of plasminogen on nonalcoholic steatohepatitis has not been reported. In this study, we evaluated the influence of plasminogen in a mouse model of nonalcoholic steatohepatitis with macrophage foaming. L /A mice, characterized by hypercholesterolemia, were injected with streptozotocin and fed a high-fat diet to develop nonalcoholic steatohepatitis with macrophage foaming. To confirm the influence of plasminogen, we used the well-known plasminogen inhibitor tranexamic acid and L /A /Plg mice, which are deficient in plasminogen and investigated the influence on nonalcoholic steatohepatitis. The influence of plasminogen on the expression levels of proinflammatory cytokines involved in foaming in macrophages was also assessed. The formation of nonalcoholic steatohepatitis lesions with macrophage foaming was confirmed in the L /A mouse model. Tranexamic acid attenuated foaming and fibrosis in the L /A mice. Similarly, foaming and liver fibrosis were also attenuated in the L /A /Plg mice. The mRNA expression levels of TGF-β1 and IL-1β in liver and peritoneal macrophages were reduced upon plasminogen inhibition. We show that inhibition of plasminogen suppressed macrophage foaming, cytokine expression, and consequently fibrosis in nonalcoholic steatohepatitis. Our results provide a clue toward various processes leading to fibrosis and may contribute to new therapeutic strategies for nonalcoholic steatohepatitis.
非酒精性脂肪性肝炎是一种重要的临床肝脏疾病。其症状因巨噬细胞泡沫化而加重，而纤溶酶原在体外可促进巨噬细胞泡沫化。然而，纤溶酶原对非酒精性脂肪性肝炎的影响尚未有报道。在本研究中，我们评估了纤溶酶原在伴有巨噬细胞泡沫化的非酒精性脂肪性肝炎小鼠模型中的影响。L / A 小鼠以高胆固醇血症为特征，用链脲佐菌素注射并给予高脂肪饮食，以发展伴有巨噬细胞泡沫化的非酒精性脂肪性肝炎。为了证实纤溶酶原的影响，我们使用了众所周知的纤溶酶原抑制剂氨甲环酸和缺乏纤溶酶原的 L / A / Plg 小鼠，并研究了其对非酒精性脂肪性肝炎的影响。还评估了纤溶酶原对参与巨噬细胞泡沫化的促炎细胞因子表达水平的影响。在 L / A 小鼠模型中证实了伴有巨噬细胞泡沫化的非酒精性脂肪性肝炎病变的形成。氨甲环酸减弱了 L / A 小鼠的泡沫化和纤维化。同样，L / A / Plg 小鼠的泡沫化和肝纤维化也减弱。肝和腹腔巨噬细胞中 TGF-β1 和 IL-1β 的 mRNA 表达水平在纤溶酶原抑制后降低。我们表明，纤溶酶原抑制抑制了巨噬细胞泡沫化、细胞因子表达，进而抑制了非酒精性脂肪性肝炎的纤维化。我们的研究结果为纤维化的各种过程提供了线索，并可能为非酒精性脂肪性肝炎的新治疗策略做出贡献。
