Protective effect on inhalated carbon monoxide for multiple organ dysfunction at cardiovascular surgery

最近心血管外科的改进，例如脑灌注法一氧化碳（CO）可以阻止细胞呼吸，但矛盾的是，它是由血红素加氧酶1型（Ho-1）内源性合成的，以应对缺血应激。ho -1缺陷（Hmox1^<-/->）小鼠表现出致死性缺血性肺损伤，但吸入CO可使其免于死亡。CO通过激活可溶性鸟苷酸环化酶来促进缺血保护，从而抑制单核吞噬细胞中编码纤溶酶原激活物抑制剂-1（PAI-1）基因的缺氧诱导，从而减少微血管纤维蛋白的积累。在野生型小鼠中观察到的co介导的缺血保护在编码PAI-1 （Serpine1）基因缺失的小鼠中消失。这些数据建立了CO与预防缺血性损伤之间的基本联系，该联系基于CO抑制纤溶轴的能力。背景：心肌缺血再灌注损伤是术后心功能障碍的主要原因，促炎细胞因子的爆发，如肿瘤坏死因子α、白细胞介素1 β、白细胞介素6和白细胞介素8，起着关键作用。最近，JTE-607被报道为内毒素休克小鼠模型中多种炎症细胞因子的有效抑制剂。在本研究中，我们证实了JTE-607可能减轻大鼠心肌缺血再灌注损伤的假设。方法：JTE-607预处理组（J组，n=8）和对照组（C组，n=8）取离体大鼠心脏进行热缺血（37℃）30min后，再灌注Langendorff灌注系统60 min。结果：J组再灌注后左室发育压和最大dp/dt显著高于C组（P< 0.01）。J组肌酸磷酸激酶漏量明显降低（P< 0.05）。心肌组织细胞因子如肿瘤坏死因子α、白细胞介素6、白细胞介素8水平J组明显低于C组（P< 0.05）。结论：JTE-607的药理预处理可抑制心肌内源性细胞因子的爆发，从而改善缺血再灌注损伤后的心功能。因此，JTE-607可能成为心脏外科术后保护心功能障碍的一种新的治疗策略。少

Recently improvement of cardiovascular surgery, for instance, the method of cerebral perfusionCarbon monoxide (CO) can arrest cellular respiration, but paradoxically, it is synthesized endogenously by heme oxygenase type 1(Ho-1) in response to ischemic stress. Ho-1-deficient (Hmox1^<-/->) mice exhibited lethal ischemic lung injury, but were rescued from death by inhaled CO. CO drove ischemic protection by activating soluble guanylate cyclase and thereby suppressed hypoxic induction of the gene encoding plasminogen activator inhibitor-1(PAI-1) in mononuclear phagocytes, which reduced accrual of microvascular fibrin. CO-mediated ischemic protection observed in wild-type mice was lost in mice null for the gene encoding PAI-1 (Serpine1). These data establish a fundamental link between CO and prevention of ischemic injury based on the ability of CO to derepress the fibrinolytic axis. These data also point to a potential therapeutic use for inhaled CO.BACKGROUND : Myocardial ischemia-reperfu … More sion injury is a main cause of postoperative cardiac dysfunction, and a burst of proinflammatory cytokines, such as tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, and interleukin 8, plays a pivotal role. Recently, JTE-607 has been reported as a potent inhibitor of the multiple inflammatory cytokines in the endotoxin shock mouse model. In this study we proved the hypothesis that JTE-607 might attenuate myocardial ischemia-reperfusion injury in a rat model. METHODS : The isolated rat hearts in the JTE-607 preconditioning group (J group, n=8) or control group (C group, n=8) were subjected to warm ischemia (37 degrees C) for 30 minutes, followed by 60 minutes of reperfusion with the Langendorff perfusion system. RESULTS : Left ventricular developed pressure and maximum dp/dt after reperfusion were significantly improved in the J group than in the C group (P<.01). Creatine phosphokinase leakage is significantly lower in the J group (P<.05). Moreover, the tissue cytokine levels, such as tumor necrosis factor alpha, interleukin 6, and interleukin 8, in the myocardium were significantly lower in the J group than in the C group (P<.05). CONCLUSION : These results suggested that the pharmacologic preconditioning of JTE-607 inhibits a burst of endogenous cytokines in the myocardium, resulting in the improvement of cardiac function after ischemia-reperfusion injury. Thus JTE-607 might be a novel therapeutic strategy for the protection of postoperative cardiac dysfunction in cardiac surgery. Less