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Mechanisms of cardiac dysfunction induced by hemorrhagic shock

失血性休克致心功能障碍的机制

基本信息

批准号：
17590589
负责人：
TANAKA Noriyuki
金额：
$ 1.86万
依托单位：
University of Occupational and Environmental Health, Japan
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
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

项目摘要

Cardiac dysfunction is a well-known complication of hemorrhagic shock as a consequence of local inflammatory response. Several studies have indicated that p38 mitogen-activated protein kinase (MAPK) is a key mediator in organ dysfunction which is associated with the inflammatory state through the activation of proinflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β. Whether the same applies to cardiac dysfunction after hemorrhagic shock has not been clearly determined. Therefore, in this study, the role of p38 MAPK on cardiac dysfunction after hemorrhagic shock was studied up to 5 hours after a hemorrhage using FR167653, a specific inhibitor of p38 MAPK phosphorylation. The p38 MAPK phosphorylation, the cardiac mRNA expressions of TNF-α and IL-1β, and intracardiac serum concentrations of each cytokine and CPK-MB increased after a hemorrhage. Activated neutrophil accumulation in the heart, histological inflammation-related injuries and frequent ventricular arrhythmia were observed in the late phase following hemorrhagic shock. FR167653 inhibited these hemorrhagic changes except the induction of the primary hypotensive state. These results demonstrate that p38 MAPK phosphorylation in hemorrhagic shock plays an important role in the cardiac expression of the proinflammatory cytokines, and in the development of cardiac dysfunction relative to the inflammatory responses.

心功能不全是失血性休克的一种众所周知的并发症，是局部炎症反应的结果。一些研究表明，p38丝裂原活化蛋白激酶是器官功能障碍的关键介质，它通过激活促炎症细胞因子如肿瘤坏死因子-α和白介素1-β与炎症状态相关。这是否同样适用于失血性休克后的心功能障碍还没有明确的确定。因此，在这项研究中，使用p38 MAPK磷酸化的特异性抑制剂FR167653，研究了p38 MAPK在失血性休克后5小时内的心功能障碍中的作用。出血后p38MAPK磷酸化、心肌细胞肿瘤坏死因子-α和IL-1β的表达及心内血清各细胞因子和肌酸磷酸肌酸激酶-MB的浓度均升高。失血性休克后期心脏中性粒细胞积聚活跃，组织学炎症相关损伤和频发室性心律失常。FR167653除诱导原发性低血压状态外，可抑制上述出血性改变。这些结果表明，失血性休克时p38MAPK的磷酸化在心脏促炎症细胞因子的表达以及与炎症反应相关的心功能不全的发生中起重要作用。