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

例如，最近改善心血管手术的方法，脑灌注碳一氧化碳（CO）的方法可以阻止细胞呼吸，但自相矛盾的是，它是由血红素氧酶1型（HO-1）响应缺血性压力而内源性的。 HO-1缺乏（HMOX1^<-/ - >）小鼠暴露了致命性缺血性肺损伤，但通过吸入CO驱动了缺血性保护酶，从而导致了缺血性保护酶，从而抑制了质体抑制剂抑制剂-1（PAI-1）在Modincielcience pai phag phag phag phag phag phag co co驱动了缺血性保护。纤维蛋白。在野生型小鼠中观察到的共同介导的缺血保护在无效的小鼠中丢失了编码PAI-1的基因（Serpine1）。这些数据基于CO消除纤溶轴的能力在CO与预防缺血性损伤之间建立了基本联系。这些数据还指出了遗传性二氧化碳的潜在疗法：心肌缺血 - reperfu…更多的sion损伤是表现后心脏功能障碍的主要原因，以及一系列促炎细胞因子，例如肿瘤坏死因子alpha，inthpha，interleukin beta 1 beta，interleukin beta，interleukin beta，interleukin beta，interleleukin 6＆interleleal prowes prowes a prowes a prowes a prowes a prowes a prowes a prowes a prowes a prowes a in interlay a prowes a最近，据报道JTE-607是内毒素休克小鼠模型中多种炎症细胞因子的潜在抑制剂。在这项研究中，我们证明了JTE-607可以减弱大鼠模型中的心肌缺血 - 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）中的孤立大鼠心脏持续30分钟30分钟，然后与Langendorff灌注系统进行60分钟的再灌注。结果：与C组相比，J组的左心室发展压力和最大DP/DT显着改善（p <.01）。 J组的肌酸磷酸激酶泄漏显着降低（p <.05）。此外，在J组中，心肌中的组织细胞因子水平，例如肿瘤坏死因子α，白介素6和白介素8，高于C组（p <.05）。结论：这些结果表明，JTE-607的药理预处理抑制心肌中的内源性细胞因子爆发，导致缺血再灌注损伤后心脏功能改善。该JTE-607可能是一种在心脏手术中保护术后心脏功能障碍的新型治疗策略。较少的

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