NITRIC OXIDE TRANSDUCTION MECHANISMS IN UTIS AND IC

描述(改编自申请者摘要)：尿路 感染(UTIs)和间质性膀胱炎(IC)是两种病理 主要影响女性的泌尿系统状况 有医学、心理学、社会学和经济学方面的影响。这个 这一提议的统一假设是，一氧化氮(NO)，一个小的 亲脂性气体分子，从非肾上腺素能释放出来， 非胆碱能神经元，在多种哺乳动物中合成 包括巨噬细胞和中性粒细胞在内的组织在尿路感染中起中介作用。 和IC。申请人已经：1)证明了一氧化氮合酶(NOS) 慢性支气管炎患者尿液中活性和cGMP水平升高 尿路感染和IC患者尿液中的减少；2)提供第一 生物活性物质存在的确凿的分子证据 中性粒细胞感染过程中诱导型一氧化氮合酶(INOS)的表达 3)血管内皮细胞瘤患者应用L精氨酸后，一氧化氮合酶水平升高 活动和尿环GMP和NOx(硝酸盐加亚硝酸盐)水平，以及 导致IC相关症状的减少。为了检验他们的假设，他们 计划：1)确定因素，包括细胞因子和细菌产物， 在分离的人类中性粒细胞中调节一氧化氮的产生， 为了确定中性粒细胞是否以及如何产生NO参与了 吞噬和杀菌；2)鉴定炎症因子， 即细菌产物和细胞因子、酶反应和细胞类型， 参与诱导型一氧化氮合酶的表达 对尿路炎症/感染过程的修复性反应 3)表征亚细胞定位和定位。 调节人诱导型一氧化氮合酶(HiNOS)表达的翻译修饰 使用体外异源系统；以及4)确定关系 炎症细胞特性、一氧化氮、前列腺素和细胞因子之间的关系 生产，以及IC相关症状。数据的解释 所获得的不仅与He的感染/炎症过程有关 尿路，但也将有助于了解过程在 不太容易接受调查的人类。

DESCRIPTION (Adapted from the Applicant's Abstract): Urinary tract infections (UTIs) and interstitial cystitis (IC) are two pathologic conditions of the urinary system which predominately affect women and which have medical, psychological, sociological and economic implications. The unifying hypothesis of this proposal is that nitric oxide (NO), a small lipophilic gaseous molecule, which is released from non-adrenergic, non-cholinergic neurons and which is synthesized in a variety of mammalian tissues including macrophages and neutrophils, acts as a mediator in UTIs and IC. The applicants have: 1) shown that nitric oxide synthase (NOS) activity and cyclic GMP levels are elevated in the urine of patients with a UTI and decreased in the urine of patients with IC; 2) providing the first definitive molecular evidence for the presence of a biologically active inducible NOS (iNOS) in human neutrophils during an infectious process; and 3) shown that L-arginine administration to IC patients increases NOS activity and urinary cyclic GMP and Nox (nitrate plus nitrite) levels, and results in a decrease in IC related symptoms. To test their hypothesis they plan to: 1) determine factors, including cytokines and bacterial products, that mediate the production of nitric oxide in isolated human neutrophils, and to determine if and how neutrophil produced NO is involved in phagocytosis and bacterial killing; 2) identify the inflammatory agents, i.e., bacterial products and cytokines, enzymatic reactions, and cell types, that are involved in the induction of NOS during the initiation of and reparative response to inflammatory/infectious processes in the urinary tract; 3) characterize the subcellular localization and the post translational modifications that regulate human iNOS (hiNOS) expression using an in vitro heterologous system; and 4) determine the relationship between inflammatory cell identity, nitric oxide, prostaglandin and cytokine production, and IC related symptoms. The interpretation of the data obtained will not only pertain to infectious/inflammatory processes of he urinary tract, but also will facilitate the understanding of processes in humans which are less amenable to investigation.