INTERLEUKIN 1 REGULATION OF BRADYKININ RECEPTORS

缓激肽（BK），在许多病理损伤后合成， 导致平滑肌收缩，血管通透性增加 和刺激神经元疼痛受体，作用一般 通过B2受体介导。 在一些动物疾病模型中， 在血管平滑肌中出现了不同的受体， des-Arg 9-BK，通常是一种无活性的BK代谢物， 激动剂 有证据表明，白细胞介素-I（IL-1），一种细胞因子， 负责诱导这些B1受体。 同样在 几种人类病理学模型，以及来自患有 被认为是由IL-1、BK 响应性显著提高。 此外，如果健康 组织用IL-1处理，对BK的应答增加。 因此，IL- l使组织对BK的作用敏感，并可通过 B1受体的诱导。 NOVA目前正在开发BK 拮抗剂的基础上筛选的B2受体。 B1受体 然而，（由IL-1诱导的），可能在几种情况下更重要， 炎症性疾病。 因此，另一个潜在的非常重要的 方法可能是开发IL- 1抑制剂，并提供一种治疗方法。 治疗炎性疾病的新的治疗方法。 该阶段I提案寻求对IL-1的阐明的支持， 在增加组织对BK的反应性中的作用，特别是 其在诱导B1受体中的作用。 它还寻求支持， 开发一个程序来鉴定非肽IL-1 拮抗剂/抑制剂。 方法将包括生物化学和 分离的组织研究，以及整个动物实验。 化合物将从NOVA的当前目录中选择 化学品 具有IL-1抑制活性的试剂将提供 领导结构在第二阶段启动综合努力。

Bradykinin (BK), synthesized following many pathological insults, causes smooth muscle contraction, increased vascular permeability and stimulation of neuronal pain receptors, actions generally mediated through B2 receptors. In some animal disease models, there appears in vascular smooth muscle a different receptor, on which des-Arg9-BK, normally an inactive BK metabolite, is an agonist. Evidence suggests that interleukin-l (IL-l), a cytokine, is responsible for inducing these B1 receptors. Similarly, in several models of human pathology, and in tissue from patients with diseases thought to be mediated by overproduction of IL-l, BK responsiveness is dramatically increased. Moreover, if healthy tissue is treated with IL-l, responses to BK increase. Thus, IL- l sensitizes tissues to the action of BK and may do so through induction of B1 receptors. NOVA is currently developing BK antagonists based on screens of B2 receptors. The B1 receptor (induced by IL-l), however, may be more important in several inflammatory diseases. Thus, another potentially very important approach may be development of an IL- 1 inhibitor, and provide a novel therapeutic approach to treating inflammatory diseases. This Phase I proposal seeks support for the elucidation of IL-l's role in increasing tissue responsiveness to BK, and in particular its role in inducing B1 receptors. It also seeks support to develop a program to identify nonpeptide IL-l antagonists/inhibitors. Methods will include biochemical and isolated tissue studies, as well as whole animal experiments. Compounds will be selected from NOVA's current directory of chemicals. Agents having IL-l inhibitory activity will provide lead structures to initiate synthetic efforts in Phase II.