EICOSANOID METABOLISM IN BOWEL INFLAMMATION

炎症性肠病（IBD）与过度释放有关 炎症脂质介质[例如Pgs、LTB 4和血小板活化 因子（PAF）]，其有助于IBD的症状，加重组织 损伤并延长炎症发作的时间过程。 尽管 这些介质的重要性，炎症性肠病的病理生理学，很少是 我们知道它们产生的过程，尽管 在其他器官系统和疾病状态中有强有力的证据， 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（LTA 4）。 有很强 显著的“细胞-细胞相互作用”和“跨细胞相互作用” LTA 4向LTB 4、脂氧素、LTC 4和LTD 4的“代谢”发生在IBD中，或 激活粘膜防御，基于炎性细胞的丰度， 在肠粘膜中紧密邻近的细胞。 入侵 炎性细胞（嗜中性粒细胞、嗜酸性粒细胞、巨噬细胞）可进一步 加强这种细胞通信，以及加剧 炎症过程。 这一提议旨在解决假设 IBD中有深刻的细胞合作，特别是在 LTA 4向LTB 4或脂氧素的跨细胞代谢。 细胞合作 也可以采取“启动”的形式，通过这种方式，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，或 两者（例如通过PAF、fMLP、LPS、TNF或其他细胞因子）。 相反地， 药理学试剂如5-脂氧合酶抑制剂、LTB 4和PAF 受体拮抗剂可用于下调这种细胞毒性 合作，通过抑制5-脂氧合酶或结合LTB 4和PAF 他们的受体。 我们假设，细胞间的相互作用是增强， 炎症性肠病是由炎性细胞数量增加引起的。 粘膜中的细胞以及它们的活性增强，这可能导致 新的炎症介质的产生增加。 没有 其他研究还涉及这些autacoids的作用， IBD。 在本提案中，我们重点关注类花生酸代谢， 与粘膜肥大细胞相互作用时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 炎症 通过提高我们对蜂窝通信的理解， IBD，以及潜在地鉴定抑制剂的新功能， 受体拮抗剂，我们预计这一建议将导致改善 治疗IBD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.