Differential expression time course and the distribution of 4 PARs in rats with endotoxin-induced acute lung injury.

在脓毒症中，凝血和炎症过程的激活可损伤肺和肝，并改变其功能。本研究的目的是：1）研究蛋白酶激活受体（PAR）在脂多糖（LPS）诱导的急性肺和肝损伤模型中随时间推移的模式;以及PAR是否在此过程中发挥作用并通过炎症和凝血发挥其作用。TNF-α水平在LPS给药后1h显著表达，随后：1）组织因子、因子Vila、凝血酶和纤溶酶原激活物抑制剂-1水平增加; 2）组织因子途径抑制剂水平不变或稳定; 3）随后纤维蛋白在肺和肝组织中沉积，导致血气分析改善和AST和ALT升高，这与肺和肝损伤有关。所有PAR异构体（1-4）的表达均升高，并且每种异构体在肺和肝组织中具有不同的细胞定位和时间依赖性表达模式。有趣的是，PAR 2阻断肽（BP）改善了肝损伤的愈合，这是一种与抑制TNF-α升高以及凝血和纤维蛋白溶解正常化相关的作用。这最终导致受损肝脏中纤维蛋白形成减少。我们的研究揭示了PAR-2在LPS介导的肺和肝损伤中的不同时间表达和细胞定位，并表明PAR-2的阻断在治疗肝损伤中起着至关重要的作用，通过正常化炎症，凝血和纤溶途径。这些结果清楚地表明，炎症和凝血之间的相互作用在脓毒症诱导的器官功能障碍中起着关键作用。

The lung and liver can be injured and their functions altered by activation of the coagulation and inflammatory processes in sepsis. The objective of the study was to: 1) investigate the pattern of protease-activated receptors (PARs) over time in a model of acute lung and liver injuries induced by lipopolysaccharide (LPS); and whether PARs play a role in this process and exert their effects through inflammation and coagulation. Levels of TNF-a were significantly expressed 1 h after LPS administration followed by: 1) an increase in levels of tissue factor, factor Vila, thrombin and plasminogen activator inhibitor-1; 2) unchanged or steady levels of tissue factor pathway inhibitor; and 3) subsequent deposition of fibrin in the lung and liver tissues, that led to the amelioration of blood gas analysis and the elevation of AST and ALT, which are associated with lung and liver injuries. The expression of all PAR isoforms (1-4) was elevated, and each isoform had a distinct cellular localization in the tissues of lung and liver, and a time-dependent pattern of expression. Interestingly, PAR2 blocking peptide (BP) improved the healing of liver injuries, an effect that was associated with suppression of TNF-a elevation, and normalization of coagulation and fibrinolysis. This ultimately led to decreased fibrin formation in the injured liver. Our study reveals a distinct chronological expression and cellular localization of PARs-in LPS-mediated lung and liver injuries and shows that blockade of PAR2 play a crucial role in treating liver injury, via normalization of inflammation, coagulation and fibrinolytic pathways.These results clearly suggest that cross-talk between inflammation and coagulation has pivotal roles in sepsis-induced organ dysfunctions.