EICOSANOID METABOLISM IN BOWEL INFLAMMATION

炎症性肠病(IBD)与过度释放有关 炎性脂质介质[例如PGS、LTB4和血小板激活 导致IBD症状的PAF]，加重组织 损害和延长炎症发作的时间进程。尽管 这些介质在IBD病理生理学中的重要性 知道它们产生过程中涉及的一系列事件，尽管 在其他器官系统和疾病状态中有强有力的证据表明 二十烷类化合物的形成可以通过细胞间代谢来实现。 白三烯的中间体，即白三烯A4(LTA4)。有一种强烈的 显著的“细胞间相互作用”和“跨细胞”的可能性 LTA4到LTB4、脂氧素、LTC4和LTD4的代谢在IBD或 粘膜防御的激活，基于炎性物质的丰富 位于肠黏膜附近的细胞。侵略者 炎性细胞(中性粒细胞、嗜酸性粒细胞、巨噬细胞)可能进一步 加强这种蜂窝通信，并加剧 炎症过程。这项提议旨在解决这一假说 在IBD中有深刻的细胞合作，特别是在 LTA4的跨细胞代谢为LTB4或脂氧素。元胞协作 也可以采取“引爆”的形式，通过这种形式，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 两者(如PAF、fMLP、内毒素、肿瘤坏死因子或其他细胞因子)。相反， 5-脂氧合酶抑制剂、LTB4和PAF等药理制剂 受体拮抗剂可以用来下调这种细胞。 通过抑制5-脂氧合酶或LTB4和PAF与 它们的受体。我们假设细胞间的相互作用在 炎症性肠病由炎症性增多所致 粘膜中的细胞以及它们的高活性，这可能导致 新的炎症介质的产生增加。没有 到目前为止还进行的其他研究，这些研究涉及这些耳壳类动物在 IBD。在这项建议中，我们关注二十烷类化合物的代谢。 细胞与粘膜肥大细胞相互作用过程中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。 发炎。通过提高我们对蜂窝通信的理解， IBD，以及潜在地确定抑制物和 受体拮抗剂我们预计这项建议将导致改善 IBD治疗中的药理学策略。

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.