ADAPTIVE /MALADAPTIVE POST INJURY CARDIAC PRIMING

我们承认短暂性心肌缺血是急性心肌梗死的必备症状 严重创伤。创伤后心脏功能障碍损害早期宿主 修复并加重晚期多器官衰竭。缺血后 再灌流与肝细胞中的氧化剂爆发有关， 库普弗细胞和血单核细胞促进肿瘤坏死因子的产生。我们建议 心肌(包括心肌细胞和驻留巨噬细胞)可以产生肿瘤坏死因子。 我们假设：创伤后心肌缺血/再灌注(I/R) 诱导内源性心脏肿瘤坏死因子的产生及其功能 抑郁症。尽管多种炎性刺激和几个细胞 信号通路可诱导巨噬细胞释放肿瘤坏死因子，我们注意到I/R 诱导氧化剂同时激活P38 MAPK和核 KappaB因子(NRkappaB)。我们进一步假设：创伤后I/R 产生氧化剂，激活人类P38 MAPK和NFkappaB 心肌。针对损伤后P38 MAPK和NFkappaB的策略应该 减少内源性心肌肿瘤坏死因子的产生，改善创伤后 心脏功能。 为配合项目三和八，我们计划审查该员额 缺血/损伤信号导致内源性心肌肿瘤坏死因子的产生。 然后我们建议测定缺血后心肌肿瘤坏死因子蛋白的含量， 肿瘤坏死因子生物活性、肿瘤坏死因子亚细胞定位、P38 MAPK活化、 NFkappaB亚细胞定位与心功能 药理和热休克蛋白-72脂质体转移(联合 项目V)抑制肿瘤坏死因子产生的策略。我们接受 短暂性心肌缺血是严重创伤的必然后遗症。 创伤后心脏功能障碍损害早期宿主器官修复和 加重晚期多器官衰竭。缺血后再灌流 与氧化剂爆发有关，在肝细胞、库普弗细胞和 血单核细胞通过P38激活信号促进肿瘤坏死因子的产生 MAP激酶和核因子kappaB。我们假设： 全球假说：创伤后缺血/再灌流诱导内源性 心脏肿瘤坏死因子的产生和由此产生的机械性心脏抑制。我们 还假设损伤后的I/R产生氧化剂，激活两者 P38MAPK和NFkappaB在人心肌中的表达。

We acknowledge transient myocardial ischemia as an obligate companion of major trauma. Post-traumatic cardiac dysfunction compromises early host repair and exacerbates late multiple organ failure. Post-ischemic reperfusion is associated with an oxidant burst which in hepatocytes, Kupffer cells and blood monocytes promotes TNF production. We propose that myocardium (both cardiomyocytes and resident macrophage) can generate TNF. We postulate that: post-traumatic myocardial ischemia/reperfusion (I/R) induces endogenous cardiac TNF production with resultant functional depression. Although multiple inflammatory stimuli and several cell signalling routes can induce macrophage TNF release, we note that I/R induced oxidants activate both P38 MAP kinase (P38 MAPK) and nuclear factor kappaB (NRkappaB). We further hypothesize that: Post-traumatic I/R generates oxidants which activate both P38 MAPK and NFkappaB in human myocardium. Strategies targeting post-injury P38 MAPK and NFkappaB should reduce endogenous myocardial TNF production and improve post-traumatic cardiac function. In concert with Projects III and VIII we plan to examine the post ischemia/injury signals that lead to endogenous myocardial TNF production. We then propose to determine post-ischemic myocardial TNF protein content, TNF bioactivity, TNF subcellular localization, P38 MAPK activation, NFkappaB subcellular localization and cardiac function following both pharmacologic and heat shock protein-72 liposomal transfer (in conjunction with Project V) strategies of inhibiting TNF production. We accept transient myocardial ischemia as an obligate sequela of major trauma. Post-traumatic cardiac dysfunction compromises early host organ repair and exacerbates late multiple organ failure. Post-ischemic reperfusion is associated with an oxidant burst which in hepatocytes, Kupffer cells and blood monocytes promotes TNF production by activating signals through P38 map kinase and nuclear factor kappaB. We hypothesize: Global hypothesis: Post-traumatic ischemia/reperfusion induces endogenous cardiac TNF production with resultant mechanical cardiac depression. We also postulate that post-injury I/R generates oxidants which activate both P38 MAPK and NFkappaB in human myocardium.