MAINTENANCE OF ORGAN FUNCTION FOLLOWING INJURY

我们最近的研究表明，雄激素（睾酮和 二氢睾酮）在出血发作前两周可防止 创伤出血后心功能下降， 复苏术或者，给予氟替卡松，一种雄激素， 拮抗剂（AA），在非去势大鼠中， 改善降低的心脏性能和肝细胞功能。 因此，我们的假设是，雄激素和/或低雌二醇或 高比例雄激素：雌二醇直接和间接地 导致心脏功能下降， 男性创伤出血后其他器官的功能。研究是 建议确定雄激素耗竭/AA 改善心脏性能和其他器官的功能， 抢救复苏为了确定雄激素和/或 AA是受体介导的，将分析分离的肌细胞的雄激素 受体表达，性类固醇结合力，受体激活 （热休克蛋白90的释放和磷酸化）， 转录因子（NF-κ B和AP-1）和α-和β-肌球蛋白- 重链基因沿着与雄激素、雌二醇和性激素结合 循环中的球蛋白水平。因为性类固醇会影响 离体心肌细胞内Ca/2+、[Ca/2+]i与PKC β沿着 并测量β II表达、cAMP和IP/3水平。基因 促炎和抗炎细胞因子（TNF，IL-6， IL-4和IL-10），以及释放儿茶酚胺、ACTH和皮质酮 将进行测量，以确定它们是否被雄激素改变 耗竭/AA。将使用离体心脏和血管来确定 雄激素/AA是否对这些器官有直接影响。额外 研究将检查雄激素耗竭/AA是否影响肾上腺， 改变了心脏、肝脏和肝脏上的儿茶酚胺的反应， 血管平滑肌将使用分离的肌细胞和肝细胞 检查β-或α-肾上腺素能受体结合能力/亲和力 被雄激素耗竭/AA改变。我们还将确定AA是否 改善心肺复苏后肠、肺、肾功能 以及它是否降低了对随后败血症的易感性。如果AA 治疗（单次或3次给药）可改善但不维持心血管疾病 反应，我们将管理促黄体生成激素释放激素 激动剂，β-雌二醇，催乳素或甲氧氯普胺，以确定它们是否 产生协同有益的效果。血流动力学参数和器官 要测量的功能包括血流量，循环血量， 心输出量，左心室功能，血管反应性，肝脏， 肠道肾上腺和肺功能心脏功能与 其他器官的功能和详细的机制研究， 细胞和亚细胞水平，使用生理学，药理学和 分子生物学技术，以确定新的治疗目标 使用AA或激素的方式应提供新的信息， 改善对大量失血的创伤受害者的治疗， 降低对随后败血症的易感性。

Our recent studies indicate that depletion of androgens (testosterone and dihydrotestosterone) two weeks prior to onset of hemorrhage prevents the depression of cardiac function following trauma-hemorrhage and resuscitation. Alternatively, administration of flutamide, an androgen antagonist (AA), after hemorrhage-resuscitation in non-castrated rats improves the depressed cardiac performance and hepatocellular function. Our hypothesis, therefore, is that androgens and/or low estradiol or the high ration of androgens:estradiol are directly as well as indirectly responsible for producing the depression in cardiac performance and the function of other organs after trauma-hemorrhage in males. Studies are proposed to determine the mechanism by which androgen depletion/AA improves cardiac performance and the function of other organs after hemorrhage-resuscitation. To determine if the effects of androgens and/or AA are receptor-mediated, isolated myocytes will be analyzed for androgen receptor expression, sex steroid binding capacity, receptor activation (release of heat shock protein 90 and phosphorylation), expression of transcription factors (NF-kappaB and AP-1) and alpha- and beta-myosin- heavy chain genes along with androgens, estradiol and sex hormone binding globulin levels in circulation. Since sex steroids can affect intracellular Ca/2+, [Ca/2+]i in isolated myocytes along with PKCepsilon and betaII expressions, cAMP and IP/3 levels will be measured. The gene expression and release of pro-and anti-inflammatory cytokines (TNF, IL-6, IL-4 & IL-10), and the release of catecholamines, ACTH and corticosterone will be measured to determine if they are altered by androgen depletion/AA. Isolated hearts and blood vessels will be used to determine if there are direct effects of androgen/AA on these organs. Additional studies will examine if androgen depletion/AA affects the adrenals and modifies the response of catecholamines on the heart, liver and vascularity smooth muscle. Isolated myocytes and hepatocytes will be used to examine if beta- or alpha-adrenergic receptor binding capacity/affinity are altered by androgen depletion/AA. We will also determine if AA improves the gut, lung and renal functions after hemorrhage-resuscitation and whether it decreases susceptibility to subsequent sepsis. If AA treatment (single or 3 doses) improves but does not sustain cardiovascular responses, we will administer luteinizing hormone-releasing hormone agonist, beta-estradiol, prolactin or metoclopramide to determine if they produce synergistic salutary effects. The hemodynamic parameters and organ functions to be measured include blood flow, circulating blood volume, cardiac output, left ventricular performance, vascular reactivity, liver, gut, adrenal and lung functions. The integration of cardiac function with the function of other organs and detailed mechanistic studies at the cellular and subcellular levels using physiologic, pharmacological and molecular biology techniques to identify targets for novel treatment modalities using AA or hormones should provide new information for the improved treatment of trauma victims with major blood loss and for decreasing susceptibility to subsequent sepsis.