MAINTENANCE OF ORGAN FUNCTION FOLLOWING INJURY

我们最近的研究表明，雄激素(睾酮和 在出血前两周服用双氢睾丸素可预防 创伤-出血后心功能抑制和 复苏。或者，服用雄激素氟他胺 非去势大鼠失血复苏后给予拮抗剂(AA) 改善受抑的心功能和肝细胞功能。 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 导致心力衰竭和心力衰竭 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/再生障碍性贫血的机制 改善心脏功能和其他器官的功能 出血-复苏。以确定雄激素和/或 AA是由受体介导的，分离的心肌细胞将被分析雄激素 受体表达、性激素结合能力、受体激活 (热休克蛋白90的释放和磷酸化)，表达 转录因子(核因子-kappaB和AP-1)和α-和β-肌球蛋白- 重链基因与雄激素、雌二醇和性激素的结合 循环中的球蛋白水平。由于性类固醇可以影响 心肌细胞内Ca/2+、[Ca/2+]i与PKCepsilon的关系 并测定βII表达、cAMP和IP/3水平。基因 促炎和抗炎细胞因子(肿瘤坏死因子、白介素6、 IL-4和IL-10)，以及儿茶酚胺、ACTH和皮质酮的释放 将被测量以确定它们是否被雄激素改变 耗尽/AA。将使用分离的心脏和血管来确定 雄激素/AA是否对这些器官有直接影响。其他内容 研究将检查雄激素耗竭/AA是否会影响肾上腺和 改善儿茶酚胺对心脏、肝脏和 血管光滑的肌肉。将使用分离的心肌细胞和肝细胞 检测β或α肾上腺素能受体结合能力/亲和力 是由雄激素耗竭/AA引起的。我们还将确定AA是否 改善失血复苏后的肠道、肺和肾功能 以及它是否降低了对随后的脓毒症的易感性。如果是AA 治疗(单剂或3剂)改善了心血管疾病，但不能维持心血管 反应，我们将使用促黄体激素释放激素 激动剂、β-雌二醇、催乳素或甲氧氯普胺 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，左心功能，血管反应性，肝脏， 肠道、肾上腺和肺功能。心功能与心功能的整合 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 识别新治疗靶点的分子生物学技术 使用AA或激素的方式应该为 改善创伤大量失血的受害者的治疗和 降低继发性脓毒症的易感性。

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.