2004 Fiscal Year Final Research Report Summary
Protective effect on inhalated carbon monoxide for multiple organ dysfunction at cardiovascular surgery
| Project/Area Number |
15390413
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Thoracic surgery
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| Research Institution | Osaka University |
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Principal Investigator |
TAKANO Hiroshi Osaka Univ, Graduate School of Medicine, Assistant Professor, 医学系研究科, 講師 (70346196)
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| Co-Investigator(Kenkyū-buntansha) |
MATSUDA Hikaru Osaka University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (00028614)
SAWA Yoshiki Osaka University, Hospital, Associate Professor, 医学部附属病院, 助教授 (00243220)
FUKUSHIMA Norihide Osaka University, Graduate School of Medicine, Lecturer, 医学系研究科, 講師 (30263247)
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| Project Period (FY) |
2003 – 2004
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| Keywords | inhalted carbon monoxide / ischemia-reperfusion injury / lung transplantation / cytokine / stress protein |
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| Research Abstract |
Recently improvement of cardiovascular surgery, for instance, the method of cerebral perfusion
Carbon 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
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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
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