EICOSANOID METABOLISM IN BOWEL INFLAMMATION

肠道炎症中的类二十烷酸代谢

• 批准号: 3242616
• 负责人: PATRICK Y-K WONG
• 金额: $ 15.41万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 1996-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3242616
• 关键词: cell cell interaction; colitis; disease /disorder model; eicosanoid metabolism; enzyme activity; eosinophil; epoxide hydrolase; fatty acid metabolism; gas chromatography; ileitis; immunologic assay /test; inflammatory bowel diseases; laboratory rat; leukotrienes; mass spectrometry; membrane permeability; neutrophil; phospholipids

Inflammatory bowel disease (IBD) is associated with an exaggerated release of inflammatory lipid mediators [e.g. Pgs, LTB4 and platelet- activating factor (PAF) ] which contribute to the symptoms of IBD, exacerbate tissue damage and prolong the time-course of inflammatory episodes. Despite the importance of these mediators to the pathophysiology of IBD, little is known about the sequence of events involved in their generation, although there is strong evidence in other organ systems and disease states that eicosanoid formation can occur by "transcellular metabolism" of an intermediate of leukotrienes i.e. leukotrieneA4 (LTA4). There is a strong likelihood that significant "cell-cell interaction" and "transcellular metabolism" of LTA4 to LTB4, lipoxins, LTC4 and LTD4 occurs in IBD or activation of mucosal defenses, based on the abundance of inflammatory cells resident in close proximity in the intestinal mucosa. Invading inflammatory cells (neutrophils, eosinophils, macrophages) may further potentiate this cellular communication as well as exacerbate the inflammatory process. This proposal is designed to address the hypothesis that there is profound cellular cooperation in IBD, specifically in the transcellular metabolism of LTA4 to LTB4 or lipoxins. Cellular cooperation may also take the form of "priming", through which this process can be up- regulated by enhancing the activity of the donor or recipient cell type or both (e.g. by PAF, fMLP, LPS, TNF or other cytokines). Conversely, pharmacological agents such as 5-lipoxygenase inhibitor, LTB4 and PAF receptor antagonists may be used to down-regulate this cellular cooperation, by inhibiting 5-lipoxygenase or binding of LTB4 and PAF to their receptors. We hypothesize that cell-cell interaction is enhanced in inflammatory bowel disease by an increase in the number of inflammatory cells in the mucosa as well as in their heightened activity, which may lead to the increased production of novel inflammatory mediators. There are no other investigations as yet which address the role of these autacoids in IBD. In this proposal we focus on eicosanoids metabolism by and in neutrophils and eosinophils during cell-cell interaction with mucosal mast cell, and evaluate the effects of these mediators in the bowel inflammation. By improving our understanding of cellular communication in IBD, as well as potentially identifying novel functions of inhibitors and receptor antagonists we anticipate that this proposal will lead to improved pharmacological strategies in the treatment of IBD.

炎症性肠病 (IBD) 与过度释放有关 炎症脂质介质[例如Pgs、LTB4 和血小板活化 因子 (PAF)] 导致 IBD 症状，加剧组织 损害并延长炎症发作的时间。 尽管 这些介质对 IBD 病理生理学的重要性，但人们对此知之甚少。 知道他们这一代所涉及的事件的顺序，尽管 其他器官系统和疾病状态中有强有力的证据表明 类二十烷酸的形成可以通过“跨细胞代谢”发生 白三烯的中间体，即白三烯A4 (LTA4)。 有一种强烈的 显着的“细胞间相互作用”和“跨细胞相互作用”的可能性 LTA4 代谢为 LTB4、脂氧素、LTC4 和 LTD4 发生在 IBD 或 基于炎症的丰富程度激活粘膜防御 细胞驻留在肠粘膜附近。 入侵 炎症细胞（中性粒细胞、嗜酸性粒细胞、巨噬细胞）可能进一步 增强这种细胞通讯并加剧 炎症过程。 该提案旨在解决以下假设 IBD 中存在着深刻的细胞合作，特别是在 LTA4 跨细胞代谢为 LTB4 或脂氧素。 蜂窝合作 也可以采取“启动”的形式，通过它这个过程可以向上- 通过增强供体或受体细胞类型的活性来调节或 两者（例如 PAF、fMLP、LPS、TNF 或其他细胞因子）。 反过来， 药物，例如 5-脂氧合酶抑制剂、LTB4 和 PAF 受体拮抗剂可用于下调这种细胞 通过抑制 5-脂氧合酶或 LTB4 和 PAF 的结合来合作 他们的受体。 我们假设细胞与细胞的相互作用在 炎症性肠病是由于炎症细胞数量增加所致 粘膜细胞及其活性增强，这可能会导致 增加新型炎症介质的产生。 没有 迄今为止，其他研究还探讨了这些自体激素在 炎症性肠病。 在本提案中，我们重点关注类二十烷酸的代谢 细胞间与粘膜肥大相互作用期间的中性粒细胞和嗜酸性粒细胞 细胞，并评估这些介质在肠道中的作用 炎。 通过提高我们对细胞通信的理解 IBD，以及潜在地识别抑制剂和药物的新功能 受体拮抗剂，我们预计该提案将导致改善 IBD 治疗的药理学策略。