2016 Fiscal Year Annual Research Report
急性心不全に対する補助循環治療成績を改善する新規グレリン皮下投与法の開発研究
| Project/Area Number |
16F16118
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| Research Institution | National Cardiovascular Center Research Institute |
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Principal Investigator |
巽 英介 国立研究開発法人国立循環器病研究センター, 研究所, 部長 (00216996)
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| Co-Investigator(Kenkyū-buntansha) |
SUKUMARAN VIJAYAKUMAR 国立研究開発法人国立循環器病研究センター, 研究所, 外国人特別研究員
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| Project Period (FY) |
2016-04-22 – 2018-03-31
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| Keywords | ghrelin / inflammation / organ damage / oxidative stress / cardiopulmonary support |
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| Outline of Annual Research Achievements |
Percutaneous cardiopulmonary support (PCPS) induced inflammation significantly contributes to the development of postoperative complications, including respiratory failure, myocardial, renal and neurological dysfunction and ultimately leads to multiple organ failure. Ghrelin is a small endogenous peptide with wide ranging physiological effects on metabolism and cardiovascular regulation. We investigated the protective effects of ghrelin against the PCPS-induced inflammatory reactions, oxidative stress and acute organ damage. Adult male rats were subjected to PCPS for 4 hrs and randomly received vehicle (n=6) or a bolus of ghrelin (150 microgram/kg, sc, n=6). Rats were euthanized and heart, lung, liver, kidney and brain samples were harvested for histopathology. Blood samples were taken before PCPS, after 2 hrs and 4 hrs of PCPS. We measured the plasma levels of cytokines, catecholamines and organ damage markers. PCPS-induced leucocytosis with increased plasma levels of TNF-α, IL-6 indicating an inflammatory response. Ghrelin treatment attenuated organ damage and protein levels of 3-nitrotyrosine, but not the inflammatory response or catecholamine increase. Administration of ghrelin might provide an effective co-treatment for reducing widespread PCPS-induced organ injury.
Conference: Presented as a poster during the Experimental Biology Meeting (2017) in Chicago, USA.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
Last year we modified our in-house PCPS protocol to achieve circulation for an extended period of 4 hours. As a result I was not yet able to optimise the protocol for performing PCPS after acute myocardial infarction. Currently I am working on this protocol to carry out the experiments successfully this year while a manuscript from the first study is being polished for submission very soon.
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| Strategy for Future Research Activity |
We investigated whether early pretreatment with one bolus of ghrelin administration prior to 4 hours of PCPS significantly improved PCPS-induced inflammation, oxidative stress and end organ damage in adult rats. Based on this first study we believe that in a small animal model prolonged contact between blood and the PCPS unit resulted in the destruction of blood cells and the activation of an inflammatory response and a progressive increase in catecholamines. Since ghrelin did reduce macrophage infiltration, oxidative stress and organ damage, based on this experience we will only use PCPS for a period of 2h in future experiments.
Acute myocardial infarction (AMI) morbidity has been strongly associated with an adverse and sustained increase in cardiac SNA, causes exacerbation of ischemic damage to cardiac tissue, and thus critically impairs the functional capacity of the heart leading to cardiogenic shock. Therefore, we will now investigate whether early pretreatment with ghrelin prior to PCPS can significantly improve cardiac function and remodeling events up to 2 weeks following AMI and whether these underlying mechanisms are associated with the suppression of sympathetic activation and inflammation. Sprague Dawley rats will be subjected to PCPS for 2 hrs only following AMI with pretreatment with either vehicle (n=10) or a bolus of ghrelin (150 microgram/kg, sc, n=10) prior to initiating PCPS. Using the same approaches as our first study we will determine if ghrelin suppresses sympathetic overactivation, inflammation and deterioration of cardiac function.
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