ADAPTIVE /MALADAPTIVE POST INJURY CARDIAC PRIMING

我们认为短暂性心肌缺血是心肌缺血的一种伴随疾病， 严重创伤创伤后心功能不全损害早期宿主 修复并加重晚期多器官衰竭。缺血后 再灌注与肝细胞中的氧化剂爆发有关， 枯否细胞和血液单核细胞促进TNF产生。我们建议 心肌（心肌细胞和驻留的巨噬细胞）可以产生TNF。 我们假设：创伤后心肌缺血/再灌注（I/R） 诱导内源性心脏TNF产生， 萧条虽然多种炎症刺激和几种细胞 信号通路可以诱导巨噬细胞TNF的释放，我们注意到I/R 诱导的氧化剂激活P38 MAP激酶（P38 MAPK）和核 因子κ B（NRkappaB）。我们进一步假设：创伤后I/R 产生氧化剂，激活人P38 MAPK和NF κ B 心肌针对损伤后P38 MAPK和NF κ B的策略应该 减少内源性心肌TNF的产生，改善创伤后 心脏功能 为配合工程计划III和VIII，我们计划研究这个职位 缺血/损伤信号导致内源性心肌TNF产生。 然后，我们建议测定缺血后心肌TNF蛋白含量， TNF生物活性，TNF亚细胞定位，P38 MAPK激活， NF κ B亚细胞定位和心脏功能 药理学和热休克蛋白-72脂质体转移（联合 与项目V）抑制TNF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。 创伤后心功能不全损害早期宿主器官修复， 加重了晚期多器官衰竭缺血再灌注后 与氧化剂爆发有关，在肝细胞、枯否细胞和 血单核细胞通过激活P38信号促进TNF产生 map激酶和核因子κ B。我们假设： 总体假设：创伤后缺血/再灌注诱导内源性 导致机械性心脏抑制的心脏TNF产生。我们 我还假设损伤后I/R产生氧化剂， P38 MAPK和NF κ B在人心肌中的作用

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.