MAINTENANCE OF ORGAN FUNCTION FOLLOWING INJURY

损伤后器官功能的维持

• 批准号: 6628809
• 负责人: IRSHAD H CHAUDRY
• 金额: $ 32.24万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-02-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6628809
• 关键词: androgens; blood pressure; blood volume; calcium flux; cytokine; estradiol; gastrointestinal function; heart function; hemodynamics; hemorrhagic shock; hormone inhibitor; hormone receptor; hormone regulation /control mechanism; laboratory rat; liver function; male; male castration; protein kinase C; receptor expression; resuscitation; transcription factor; trauma

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.

我们最近的研究表明，雄激素（睾酮和睾酮）的消耗 出血前两周服用二氢睾酮可预防 外伤出血后心脏功能下降 复苏。或者，服用氟他胺（一种雄激素） 拮抗剂（AA），在非去势大鼠失血复苏后 改善低迷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 高比例的雄激素：雌二醇直接或间接 负责产生心脏功能的抑制和 男性创伤出血后其他器官的功能。研究是 提议确定雄激素耗竭/AA 的机制 改善心脏功能和其他器官的功能 失血复苏。确定雄激素和/或 AA 是受体介导的，分离的肌细胞将用于雄激素分析 受体表达、性类固醇结合能力、受体激活 （热休克蛋白90的释放和磷酸化），表达 转录因子（NF-kappaB 和 AP-1）以及 α- 和 β- 肌球蛋白- 重链基因与雄激素、雌二醇和性激素结合 循环中的球蛋白水平。由于性类固醇会影响 分离的肌细胞中的细胞内 Ca/2+、[Ca/2+]i 以及 PKCepsilon 将测量 betaII 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)，以及儿茶酚胺、ACTH 和皮质酮的释放 将进行测量以确定它们是否被雄激素改变 耗尽/AA。分离的心脏和血管将用于确定 如果雄激素/AA 对这些器官有直接影响。额外的 研究将检查雄激素消耗/AA是否影响肾上腺和 改变儿茶酚胺对心脏、肝脏和 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/亲和力是否 雄激素耗竭/AA 会改变。我们还将确定 AA 是否 改善失血复苏后的肠道、肺和肾功能 以及它是否会降低对随后败血症的易感性。如果AA 治疗（单次或 3 次剂量）可改善但不能维持心血管功能 反应，我们将施用黄体生成素释放激素 激动剂、β-雌二醇、催乳素或甲氧氯普胺以确定它们是否 产生协同有益效应。血流动力学参数和器官 测量的功能包括血流量、循环血容量、 心输出量、左心室性能、血管反应性、肝脏、 肠道、肾上腺和肺功能。心脏功能的整合 其他器官的功能和详细的机制研究 利用生理学、药理学和 分子生物学技术来确定新治疗的靶点 使用 AA 或激素的方式应该为 改善对严重失血的创伤受害者的治疗 降低对随后败血症的易感性。