Fibrin deposition following bile duct injury limits fibrosis through an αMβ2-dependent mechanism
Fibrin deposition following bile duct injury limits fibrosis through an αMβ2-dependent mechanism
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DOI：
10.1182/blood-2015-09-670703
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发表时间：
2016-06-02
期刊：
影响因子：
20.3
通讯作者：
Luyendyk, James P.
中科院分区：
文献类型：
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作者：
Joshi, Nikita;Kopec, Anna K.;Luyendyk, James P.
凝血级联激活和纤维蛋白沉积与多种形式的肝损伤有关。鉴于纤维蛋白通过整合素受体α (M) β(2)放大多种疾病的病理性炎症(2)，我们在Fib γ (390-396A)小鼠中验证了纤维蛋白（原）- α (M) β(2)相互作用的破坏将减少化学性肝损伤实验环境中的肝脏炎症和纤维化的假设。与我们的假设相反，a-萘基异硫氰酸酯（ANIT）诱导的Fib γ (390-396A)小鼠肝纤维化增加，而炎症细胞因子表达和肝坏死与ANIT攻击野生型（WT）小鼠相似。Fib γ (390-396A)小鼠的纤维化增加似乎与凝血因子13 （FXIII）转谷氨酰胺酶无关，因为FXIII缺陷小鼠的ANIT攻击导致以肝坏死增加为特征的独特病理表型。相反，胆管增生是暴露于anti的Fib γ (390-396A)小鼠纤维化增加的基础。纤维蛋白介导的纤维化机制与干扰素(IFN) γ诱导诱导型一氧化氮合酶（iNOS）有关，iNOS是一种与胆管增生和肝纤维化有关的基因。anit暴露的Fib γ (390-396A)小鼠肝脏中iNOS信使RNA的表达显著增加。在体外实验中，纤维蛋白（原）- α (M) β(2)相互作用抑制IFN γ刺激巨噬细胞中iNOS的诱导，而IFN γ缺乏的小鼠则减少了iNOS的诱导、胆管增生和肝纤维化。此外，在给予白细胞粘附素-1(一种小分子，可变地增强α （M) β(2)依赖性细胞对纤维蛋白的粘附）的WT小鼠中，anti诱导的iNOS表达、肝纤维化和胆管增生显著减少。这些研究描述了一种新的机制，其中纤维蛋白（原）-整合素(M) β(2)相互作用减少了胆道纤维化，并为这种难以治疗的纤维化疾病提供了一种新的假定治疗靶点。
Coagulation cascade activation and fibrin deposits have been implicated or observed in diverse forms of liver damage. Given that fibrin amplifies pathological inflammation in several diseases through the integrin receptor alpha(M)beta(2), we tested the hypothesis that disruption of the fibrin(ogen)-alpha(M)beta(2) interaction in Fib gamma(390-396A) mice would reduce hepatic inflammation and fibrosis in an experimental setting of chemical liver injury. Contrary to our hypothesis, a-naphthylisothiocyanate (ANIT)-induced liver fibrosis increased in Fib gamma(390-396A) mice, whereas inflammatory cytokine expression and hepatic necrosis were similar to ANIT-challenged wild-type (WT) mice. Increased fibrosis in Fib gamma(390-396A) mice appeared to be independent of coagulation factor 13 (FXIII) transglutaminase, as ANIT challenge in FXIII-deficient mice resulted in a distinct pathological phenotype characterized by increased hepatic necrosis. Rather, bile duct proliferation underpinned the increased fibrosis in ANIT-exposed Fib gamma(390-396A) mice. The mechanism of fibrin-mediated fibrosis was linked to interferon (IFN)gamma induction of inducible nitric oxide synthase (iNOS), a gene linked to bile duct hyperplasia and liver fibrosis. Expression of iNOS messenger RNA was significantly increased in livers of ANIT-exposed Fib gamma(390-396A) mice. Fibrin(ogen)-alpha(M)beta(2) interaction inhibited iNOS induction in macrophages stimulated with IFN gamma in vitro and ANIT-challenged IFN gamma-deficient mice had reduced iNOS induction, bile duct hyperplasia, and liver fibrosis. Further, ANIT-induced iNOS expression, liver fibrosis, and bile duct hyperplasia were significantly reduced in WT mice administered leukadherin-1, a small molecule that allosterically enhances alpha(M)beta(2)-dependent cell adhesion to fibrin. These studies characterize a novel mechanism where by the fibrin(ogen)-integrin-alpha(M)beta(2) interaction reduces biliary fibrosis and suggests a novel putative therapeutic target for this difficult-to-treat fibrotic disease.