Differential expression time course and the distribution of 4 PARs in rats with endotoxin-induced acute lung injury.
内毒素诱导的急性肺损伤大鼠中4个PARs的差异表达时程和分布。
基本信息
- 批准号:17390479
- 负责人:
- 金额:$ 8.26万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Scientific Research (B)
- 财政年份:2005
- 资助国家:日本
- 起止时间:2005 至 2006
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
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.
脓毒症中凝血和炎症过程的激活可能会导致肺和肝受损,其功能也会发生改变。该研究的目的是:1)研究脂多糖(LPS)诱导的急性肺和肝损伤模型中蛋白酶激活受体(PAR)随时间变化的模式; 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后1小时,TNF-α水平显着表达,随后:1)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; 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,导致血气分析改善以及与肺和肝损伤相关的 AST 和 ALT 升高。所有 PAR 亚型 (1-4) 的表达均升高,并且每种亚型在肺和肝组织中具有独特的细胞定位,并且具有时间依赖性的表达模式。有趣的是,PAR2 阻断肽 (BP) 可以改善肝损伤的愈合,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。我们的研究揭示了 PARs 在 LPS 介导的肺和肝损伤中的独特的时间表达和细胞定位,并表明 PAR2 的阻断通过炎症、凝血和纤溶途径的正常化在治疗肝损伤中发挥着至关重要的作用。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引起的器官功能障碍中发挥着关键作用。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Chronological expression of PAR isoforms in acute liver injury and its amelioration by PAR2 blockade in a rat model of sepsis
- DOI:10.1160/th06-07-0379
- 发表时间:2006-12-01
- 期刊:
- 影响因子:6.7
- 作者:Jesmin, Subrina;Gando, Satoshi;Sakuraya, Fumika
- 通讯作者:Sakuraya, Fumika
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