Chronological expression of PAR isoforms in acute liver injury and its amelioration by PAR2 blockade in a rat model of sepsis
Chronological expression of PAR isoforms in acute liver injury and its amelioration by PAR2 blockade in a rat model of sepsis
复制标题
DOI：
10.1160/th06-07-0379
复制
发表时间：
2006-12-01
影响因子：
6.7
通讯作者：
Sakuraya, Fumika
中科院分区：
文献类型：
--
作者：
Jesmin, Subrina;Gando, Satoshi;Sakuraya, Fumika
脓毒症中凝血和炎症过程的激活可能会损伤肝脏并改变其功能。本研究的目的是研究脂多糖（LPS）诱导的急性肝损伤模型中蛋白酶激活受体（PARS）随时间的变化模式。以及PARS是否在此过程中发挥作用并通过炎症和凝血发挥作用。给予 LPS 1 小时后，肿瘤坏死因子-α (TNF-α) 水平显着表达，随后： i) 组织因子、因子 VIIa、凝血酶和纤溶酶原激活物抑制剂-1 水平增加； ii) 组织因子途径抑制剂的水平不变或稳定； iii) 随后纤维蛋白在肝组织中沉积，导致天冬氨酸转氨酶 (AST) 和丙氨酸转氨酶 (ALT) 升高，这与肝损伤有关。所有 PAR 异构体 (1-4) 的表达均升高，并且每种异构体具有独特的细胞定位（肝细胞、库普弗细胞、门静脉三联区和中央静脉）和时间依赖性表达模式。 Kupffer 细胞中 PAR2 和 4 的免疫反应性很强。有趣的是，PAR2 阻断肽可改善肝损伤的愈合，这种作用与抑制 TNF-α 升高以及凝血和纤维蛋白溶解正常化有关。这最终导致受损肝脏中纤维蛋白的形成减少。本研究揭示了 PAIRS 在 LPS 介导的肝损伤中的独特时间表达和细胞定位，并表明阻断 PAR2 可能通过炎症、凝血和纤溶途径的正常化在治疗肝损伤中发挥关键作用。
The liver can be injured and its functions altered by activation of the coagulation and inflammatory processes in sepsis. The objective of the present study was to investigate the pattern of protease-activated receptors (PARS) over time in a model of acute liver injury induced by lipopolysaccharide (LPS); and whether PARS play a role in this process and exert their effects through inflammation and coagulation. Levels of tumor necrosis factor-alpha (TNF-alpha) were significantly expressed 1 h after LPS administration followed by: i) an increase in levels of tissue factor, factor VIIa, thrombin and plasminogen activator inhibitor-1; ii) unchanged or steady levels of tissue factor pathway inhibitor; and iii) subsequent deposition of fibrin in the liver tissue, that led to the elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), which are associated with liver injury. The expression of all PAR isoforms (1-4) was elevated,and each isoform had a distinct cellular localization (hepatocytes, Kupffer cells, the portal triad area, and central veins) and a time-dependent pattern of expression. The immuno-reactivity of PAR2 and 4 in Kupffer cells was intense. Interestingly, PAR2 blocking peptide improved the healing of liver injuries, an effect that was associated with suppression of TNF-alpha elevation, and normalization of coagulation and fibrinolysis. This ultimately led to decreased fibrin formation in the injured liver. The present study reveals a distinct chronological expression and cellular localization of PAIRS in LPS-mediated liver injury and shows that blockade of PAR2 may play a crucial role in treating liver injury, via normalization of inflammation, coagulation and fibrinolytic pathways.