The role of gender on post-traumatic inflammation

描述(由申请人提供)：雌激素治疗在几种损伤模型中的疗效先前已有报道。我们最近的工作表明，与雄性或去卵巢的雌性大鼠相比，雌性大鼠在创伤性脑损伤(TBI)后的挫伤体积有所减少。虽然已经探索了这种神经保护的几种机制途径，但有一种途径在脑外伤后没有而且很重要，那就是炎症。脑损伤产生强烈的炎症反应，在持续时间上既有急性的，也有慢性的。一些使用其他模型的研究人员已经报告了雌激素抑制炎症级联反应的特定成分的能力。拟议的研究将评估脑外伤后男性和女性在创伤后炎症方面的差异。为解决这一问题，提出了四个具体目标。在特定的目标1中，我们将测量促炎症细胞因子的水平，并确定这些炎症启动者的细胞来源。这些研究将提供关于男性和女性之间差异的新数据，此外，通过使用切除卵巢的女性，生殖类固醇的影响。在第二个目标中，我们将研究iNOS表达的区域模式，并确定这种反应是否与性别和激素有关。由于诱导型一氧化氮合酶参与了脑外伤的发病机制，因此这种对创伤的炎症反应需要在目前的环境下进行研究。具体目标3将评估雌激素对创伤性脑损伤后炎症级联反应的影响是由于抗氧化特性还是受体介导的机制。由于雌激素已被报道影响炎症级联反应的各种成分，其在创伤诱导的炎症过程中的作用需要进一步研究。这项研究的结果将为神经激素在脑外伤治疗中的潜在应用提供新的数据。最终目的是在颅脑损伤后给予雌激素异构体或雌激素受体特异性拮抗剂/激动剂，以评估功能的恢复。综上所述，这些实验将提供有关神经激素对脑外伤后结构和功能结果的重要性的新数据。已建立的方法，包括脑外伤的啮齿动物模型、行为测试以及免疫细胞化学和分子方法，将在这项提议中使用。

DESCRIPTION (provided by applicant): The efficacy of estrogen treatment in several injury models has been previously reported. Our own recent work has demonstrated a reduction in contusion volumes following traumatic brain injury (TBI) in female rats versus males or ovariectomized females. Although several mechanistic pathways for this neuroprotection have been explored, one that has not and is important after TBI is inflammation. TBI produces a robust inflammatory response that is both acute and chronic in duration. Several investigators using other models have reported the ability of estrogen to inhibit specific components of the inflammatory cascade. The proposed studies will assess differences between males and females after TBI with regard to post-traumatic inflammation. Four specific aims are proposed to address this issue. In specific aim 1, we will measure levels of proinflammatory cytokines and determine the cellular source of these initiators of inflammation. These studies will provide novel data on differences between males and females and in addition, by using ovariectomized females, the influence of reproductive steroids. In the second aim, we will study regional patterns of iNOS expression and determine if this response is sex and hormone-dependent. Because iNOS has been implicated in the pathogenesis of TBI, this inflammatory response to trauma requires investigation in the present setting. Specific aim 3 will assess whether estrogen's effect on the inflammatory cascade after TBI is due to antioxidant properties or receptor-mediated mechanisms. Because estrogen has been reported to effect various components of the inflammatory cascade, its effect on trauma-induced inflammatory processes requires further investigation. Results from this study will provide novel data for the potential use of neurohormones in the treatment of TBI. In the final aim, estrogen isomers or specific estrogen receptor antagonist/agonist will be administered after TBI to assess recovery of function. Taken together, these experiments will provide new data on the importance of neurohormones on structural and functional outcome after TBI. Established methods including rodent models of TBI, behavioral tests, as well as immunocytochemical and molecular approaches will be used in this proposal.