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

吸入一氧化碳对心血管手术中多器官功能障碍的保护作用

• 批准号: 15390413
• 负责人: TAKANO Hiroshi
• 金额: $ 8.9万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390413/
• 关键词: inhalted carbon monoxide; ischemia-reperfusion injury; lung transplantation; cytokine; stress protein; 再灌流虚血障害; 一酸化炭素; 臓器障害; 心臓血管外科; 臓器保護因子

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

近年来心血管外科手术的改进，如脑灌注技术的发展，一氧化碳（CO）可抑制细胞呼吸，但与之矛盾的是，它是由血红素氧合酶1（Ho-1）内源性合成的。Ho-1缺陷（Hmox ^-/->）小鼠表现出致命的缺血性肺损伤，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驱动缺血保护，从而抑制单核吞噬细胞中编码纤溶酶原激活物抑制剂-1（派-1）的基因的缺氧诱导，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派-1（Serpine 1）的基因缺失的小鼠中丧失。这些数据建立了一个基本的联系CO和预防缺血性损伤的基础上，CO的能力，去抑制纤维蛋白溶解轴。这些数据也指出了吸入CO的潜在治疗用途。 ...更多信息 锡永是术后心功能不全的主要原因，促炎细胞因子如肿瘤坏死因子α、白细胞介素1 β、白细胞介素6和白细胞介素8的爆发起着关键作用。最近，JTE-607已被报道为内毒素休克小鼠模型中多种炎性细胞因子的有效抑制剂。本研究证实了JTE-607可能减轻大鼠心肌缺血再灌注损伤的假设。方法：将JTE-607预处理组（J组，n=8）或对照组（C组，n=8）的离体大鼠心脏进行热缺血（37 ℃）30分钟，随后用Langendorff灌注系统再灌注60分钟。研究结果：J组再灌注后左室发展压和最大dp/dt明显高于C组（P<0.01）。肌酸磷酸激酶渗漏在J组中显著较低（P<0.05）。此外，J组心肌中的组织细胞因子水平，如肿瘤坏死因子α、白细胞介素6和白细胞介素8显著低于C组（P<0.05）。结论：这些结果表明，JTE-607的药物预处理抑制了心肌内源性细胞因子的爆发，从而改善了缺血再灌注损伤后的心功能。因此，JTE-607可能成为心脏手术后心功能不全的一种新的治疗策略。少

项目成果

Gene transfer of hepatocyte growth factor with prostacyclin synthase in severe pulmonary hypertension of rats.

• DOI: 10.1016/j.ejcts.2004.08.031
• 发表时间: 2004-12
• 期刊: European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery
• 作者: M. Ono;Y. Sawa;N. Fukushima;H. Suhara;Toshikazu Nakamura;C. Yokoyama;T. Tanabe;H. Matsuda

Pharmacologicac preconditioning of JTE-607, a novel cytokine inhibitor, attenuates ischemia-reperfusion injury in the myocardium

JTE-607（一种新型细胞因子抑制剂）的药理预处理可减轻心肌缺血再灌注损伤

• 发表时间: 2004
• 期刊: Journal of thoracic cardiovascular surgery 127
• 作者: Nagasaki;K;Orihashi K;Ryugo M
• 通讯作者: Ryugo M

BH4 peptide derivative from Bcl-xl attenuates ischemia/reperfusion injury through anti-apoptotic mechanism in rat hearts.

Bcl-xl 的 BH4 肽衍生物通过抗凋亡机制减轻大鼠心脏的缺血/再灌注损伤。

• 发表时间: 2005
• 期刊: European Journal of Cardio-Thoracic surgery 27
• 作者: Aramaki O;Inoue F;Takayama T;Shimazu M;Kitajima M;Ikeda Y;Okumura K;Yagita H;Shirasugi N;Niimi M.;Ono M
• 通讯作者: Ono M

150-kDa oxygen-regulated protein attenuates myocardial ischemia-reperfusion injury in rat heart

• DOI: 10.1016/j.yjmcc.2005.01.001
• 发表时间: 2005-03-01
• 期刊: JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
• 影响因子: 5
• 作者: Aleshin, AN;Sawa, Y;Matsuda, H
• 通讯作者: Matsuda, H

Pharmacologic preconditioning of JTE-607,1 novel cytokine inhibitor, attenuates ischemia-reperfusion injury in the myocardium.

JTE-607,1 新型细胞因子抑制剂的药理预处理可减轻心肌缺血再灌注损伤。

• 发表时间: 2004
• 期刊: The Journal of Thoracic and Cardiovascular Surgery 127(6)
• 作者: Kondo M;Nagano H;et al.;Sugawara Yuji;M.Ryugo
• 通讯作者: M.Ryugo