Estrogen Modulates Injury-Induced Inflammation

描述(申请人提供)：炎症在许多形式的血管疾病的发病机制中起着重要作用，更年期激素治疗已被证明可以调节女性炎症生物标记物的表达。这项建议将利用一个具有良好特征的啮齿动物模型来阐明卵巢激素，特别是雌激素(E2)调节急性腔内血管损伤的炎症反应的基本细胞/分子机制。我们的初步研究表明，在球囊损伤后的数小时内，去卵巢大鼠颈动脉内广泛的炎细胞浸润和多种致炎介质的表达增加。我们进行了新颖的、具有挑衅性的初步观察，即雌二醇抑制受损动脉中粒细胞和单核/巨噬细胞的浸润，以及促炎介质的表达。合成的孕激素甲羟孕酮醋酸酯(MPA)可以阻断这种抗炎作用。我们还观察到，在体外，E2抑制了已知的趋化因子在血管平滑肌细胞(VSMCs)中对白细胞的趋化作用。这项拟议的研究基于这些令人兴奋和具有挑衅性的初步观察，以及我们在研究卵巢激素诱导的血管损伤反应调节方面的丰富经验，将确定卵巢激素可以调节其激活/迁移的炎性细胞类型，并将确定这些细胞在存在和不存在卵巢激素的情况下引导对腔内动脉损伤的反应的信号级联。新的高选择性(亚型特异性)和有效的雌激素受体激动剂和拮抗剂(ERα和ERβ)、RNA干扰技术和微阵列分析将用于在该模型中严格评估抗炎机制在介导E2血管保护作用中的功能作用。在这项拟议的研究成功完成后，E2对受损动脉的抗炎作用以及MPA对其抑制的细胞/分子机制将被阐明，并与损伤反应的程度(即新生内膜形成)有关。这些基础机制研究将加深我们对血管疾病的病理生物学的了解，特别是当它发生在老年妇女中时，并将为开发新的治疗策略提供基础。

DESCRIPTION (provided by applicant): Inflammation plays an important role in the pathogenesis of many forms of vascular disease, and menopausal hormone therapy has been shown to modulate the expression of inflammatory biomarkers in women. This proposal will utilize a well-characterized rodent model to elucidate the fundamental cellular/molecular mechanisms by which ovarian hormones, particularly estrogen (E2), modulate the inflammatory response to acute endoluminal vascular injury. Our preliminary studies have demonstrated extensive inflammatory cell infiltration and increased expression of a variety of proinflammatory mediators in carotid arteries of ovariectomized rats within hours after balloon injury. We have made the novel and provocative preliminary observation that E2 inhibits granulocyte and monocyte/macrophage infiltration, as well as proinflammatory mediator expression in injured arteries. The synthetic progestin medroxyprogesterone acetate (MPA) blocks this anti-inflammatory effect. We have also observed that E2 inhibits expression of chemokines known to be chemoattractant for leukocytes in vascular smooth muscle cells (VSMCs) in vitro. The proposed research, based on these exciting and provocative preliminary observations, as well as our extensive experience in studying ovarian hormone-induced modulation of the vascular injury response, will identify the inflammatory cell types whose activation/migration can be modulated by ovarian hormones and will define the signaling cascade by which these cells direct the response to endoluminal arterial injury in the presence and absence of ovarian hormones. Novel highly selective (subtype specific) and potent agonists and antagonists of estrogen receptors (ERalpha and ERbeta), RNA interference technology and microarray analyses will be used to provide a rigorous assessment of the functional role of anti-inflammatory mechanisms in mediating the vasoprotective effects of E2 in this model. Upon successful completion of the proposed research, the cellular/molecular mechanisms responsible for the anti-inflammatory effects of E2 on injured arteries and their inhibition by MPA will be elucidated and related to the extent of the injury response (i.e. neointima formation). These fundamental mechanistic studies will enhance our understanding of the pathobiology of vascular disease, particularly as it occurs in aging women, and will provide the basis for development of novel therapeutic strategies.