Research for artificial modulation of the stress response and active interference into the biological protective mechanism

本研究旨在通过药物调节来提高应激反应的疗效。为了阐明药物的有效作用点，本研究探讨了热休克预处理在缺血耐受获得中的作用机制。结果，证明了在缺血期间的线粒体保护和在氧化应激时对蛋白质变性的保护。此外，热休克预处理是有效的，即使在脂肪变性或纤维化的肝脏。热休克预处理也能改善脑死亡状态下恶化的肝脏微循环，阿霉素和香叶基香叶基丙酮（GGA）能改善应激反应。虽然我们也尝试了Herbimycin A、Futhan、DCIC和Sulindac，但这些药物对肝脏的预处理没有明显影响。多柔比星静脉给药48 h后可诱导肝脏产生HSP 72和HSP 73，并产生与热休克预处理同样强的缺血耐受。虽然口服GGA本身不能诱导肝脏中的HSPs，但它可以缩短诱导HSPs所必需的热休克应激的持续时间，重复热休克预处理也是提高热休克预处理效应的有效方法。另外，肝组织腺苷含量的增加是缺血预处理后肝组织缺血耐受的一个机制。腺苷A2受体激动剂可替代缺血预处理的作用。

This study aimed to increase the efficacy of stress response by modulating with drugs. In order to clarify the effective action points of drugs, mechanism of heat shock preconditioning in the acquisition of ischemic tolerance was investigated. As a result, mitochondrial protection during ischemia and protection from protein denaturation upon oxidative stress were proved. In addition, heat shock preconditioning was effective even in the livers with steatosis or fibrosis. Deteriorated hepatic microcirculation in the state of brain death was also improved by heat shock preconditioning.Two drugs, --Doxorubicin and Geranylgeranylacetone (GGA) -- could modify the stress response. Although we tried also Herbimycin A, Futhan, DCIC, and Sulindac, these drugs had no apparent effects on the preconditioning of the liver. With regard to Doxorubicin, it could induce HSP72 and HSP73 in the liver 48 hours after intravenous systemic administration and produced ischemic tolerance as strong as heat shock preconditioning. Although oral administration of GGA per se did not induce HSPs in the liver, it could decrease the duration of heat shock stress that is necessary to induce HSPs.As other strategies to increase the heat shock preconditioning effect, repetition of heat shock preconditioning was also effective. In addition, increase of adenosine in the liver tissue was a mechanism of ischemic tolerance after ischemic preconditioning. Adenosine A2 receptor stimulator supplanted the effects of ischemic preconditioning.