NITRIC OXIDE RESPONSES OF MAST CELLS AND EOSINOPHILS

哺乳动物组织中L精氨酸产生一氧化氮(NO)的研究 成为密集调查的一个领域。不同的生理角色有 因此被证明或假设表明NO是一个重要的 血管反应中的效应分子，血小板活性， 神经传递和炎症。最明确确立的角色是 来自炎症/免疫活性细胞的NO是细胞毒性的 激活的巨噬细胞的作用。本建议的核心是 肥大细胞和嗜酸性粒细胞产生NO几乎是未被研究的，两者都是 炎症细胞与变态反应性疾病、关节炎、神经性疾病有关 炎症和哮喘的潜在肺部炎症。在……里面 与NO的动态平衡作用不同，它的夸大释放 活化的炎性细胞可能参与大动脉的病理生理 某些炎症/过敏性疾病的症状。使用在中建立 肥大细胞和嗜酸性粒细胞体外培养模型--L-精氨酸/一氧化氮 将在激活的细胞中探索这一途径。建议的具体目标和重点 旨在研究NO后续细胞生成的实验 通过各种信号转导途径进行刺激。肥大细胞将是 单独用IgE-抗二硝基苯酚BSA、佛波酯刺激 与离子载体A23187、P物质、γ-干扰素、肿瘤坏死 因子-α和脂多糖。嗜酸性粒细胞将被刺激 干扰素、肿瘤坏死因子-α、脂多糖、 细菌细胞壁肽fMLP、血小板活化因子、佛波醇 肉豆蔻酸盐和P物质。因此，细胞将通过 免疫通路、多肽受体刺激与蛋白激酶C 激活。超氧化物歧化酶和超氧化物歧化酶对NO的调节作用 将探索发布。NO的异构体选择性药理抑制剂 合酶将被用来描述一氧化氮合酶同工酶的类型(S 存在于肥大细胞和嗜酸性粒细胞中。成功完成这些任务 调查可能会产生对未来新的发展有用的结果 炎症性疾病的治疗方法 危害内环境平衡的血管 NO的升压机制。

Generation of nitric oxide (NO) from L-arginine in mammalian tissues is becoming an area of intense investigation. Diverse physiologic roles are thus being demonstrated or postulated suggesting that NO is an important effector molecule in vascular responses, platelet activity, neurotransmission and inflammation. The most clearly established role for NO from inflammatory/immunologically competent cells is the cytotoxic effect of activated macrophages. Central to the present proposal is the virtually unstudied generation of NO from mast cells and eosinophils, both inflammatory cells implicated in allergic disorders, arthritis, neurogenic inflammation and the underlying pulmonary inflammation of asthma. In contrast to the homeostatic roles of NO, its exaggerated release by these activated inflammatory cells may contribute to tahe pathophysiologic symptoms of certain inflammatory/allergic diseases. Using established in vitro mast cell and eosinophil cell culture models, the l-arginine/NO pathway will be explored in activated cells. Proposed specific aims focus on experiments designed to investigate generation of NO following cell stimulation via various signal transduction pathways. Mast cells will be stimulated with IgE-anti-dinitrophenol BSA, phorbol myristate acetate alone and with ionophore A23187, Substance P, gamma-interferon, tumor necrosis factor-alpha and lipopolysaccharide. Eosinophils will be stimulated with gamma-interferon, tumor necrosis factor-alpha, lipopolysaccharide, the bacterial cell wall peptide fMLP, platelet activating factor, phorbol myristate acetate and Substance P. Thus, cells will be stimulated via immunologic pathways, peptide receptor stimulation and protein kinase C activation. Modulatory roles of superoxide and superoxide dismutase on No release will be explored. Isoform-selective pharmacologic inhibitors of NO synthase will be used to describe the type(s) of NO synthase isoforms present in mast cells and eosinophils. Successful completion of these investigations may yield results useful in the future development of new therapeutic approaches to the treatment of inflammatory diseases without compromising homeostatic vascular pressor mechanisms of NO.