Mechanisms of cardiac dysfunction induced by hemorrhagic shock

心功能不全是失血性休克的常见并发症，是局部炎症反应的结果。许多研究表明p38丝裂原活化蛋白激酶（MAPK）是器官功能障碍的关键介质，其通过激活促炎细胞因子如肿瘤坏死因子（TNF）-α和白细胞介素（IL）-1β与炎症状态相关。失血性休克后的心功能不全是否也是如此还没有明确的定论。因此，在本研究中，使用FR 167653（一种p38 MAPK磷酸化的特异性抑制剂）研究了出血性休克后5小时内p38 MAPK对心功能障碍的作用。出血后p38 MAPK磷酸化、心肌TNF-α和IL-1β mRNA表达以及心内血清中各细胞因子和CPK-MB浓度均升高。失血性休克后期，心脏内中性粒细胞大量聚集，组织学炎症相关损伤，室性心律失常频繁发生。FR 167653抑制这些出血性变化，但不诱导原发性肿胀状态。这些结果表明，p38 MAPK磷酸化在失血性休克的心脏表达的促炎细胞因子，并在心脏功能不全的发展相对于炎症反应中起着重要作用。

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.