Eicosanoid regulation of experimental Lyme arthritis

描述（由申请人提供）：非甾体抗炎药（NSAID）通常用于缓解类风湿和骨关节炎患者的症状。这些药物的新版本（coxib）通过抑制环氧合酶（考克斯）-2酶的活性起作用。考克斯-2负责炎症反应期间产生的异甘草素;异甘草素是疼痛和肿胀的主要介质。虽然新药代表了对传统NSAID的显着改进，特别是在避免不必要的胃肠道副作用方面，但也存在对新药副作用的担忧。考克斯-2是调节炎症反应的发展和消退的复杂类二十烷酸系统的一部分。这些酶及其产物通过几种生化途径相互作用，并影响彼此的生产。考克斯-2最初被认为只促进炎症的发展。然而，最近的研究表明，考克斯-2衍生的产物也可能直接或间接地促进炎症反应的消退阶段。因此，使用新的考克斯-2抑制药物可以减轻炎性疾病的症状，但实际上阻止了潜在炎症的消退和愈合。该提案使用了由莱姆病病原体伯氏疏螺旋体引起的关节炎小鼠模型。在某些小鼠品系中，感染这种微生物会导致严重关节炎的发展，在感染后2至3周达到高峰，然后自发消退。用考克斯-2抑制药物治疗小鼠，然后用B感染。burgdorferi引起严重关节炎的发展，但阻止关节炎的解决。由于类花生酸途径相互作用，有几种可能的解释为什么会发生这种情况。在这个建议中，我们设计了具体的目标，使我们能够确定哪些其他途径参与了这一反应。我们将：具体目标1，确定考克斯-1是否可以补偿考克斯-2的损失，并确定抗炎前列腺素的损失是否是关节炎不消退的原因;具体目标2，确定考克斯-2的损失是否导致花生四烯酸分流到白细胞三烯途径中;具体目标3，确定考克斯-2活性的损失是否改变中性粒细胞的脂氧素产生。这些信息将进一步了解炎症是如何调节的，并允许设计更有效的抗炎治疗。

DESCRIPTION (provided by applicant): Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed to relieve the symptoms of rheumatoid and osteoarthritis patients. New versions of these drugs (coxibs) act by inhibiting the activity of the cyclooxygenase (COX)-2 enzyme. COX-2 is responsible for the production of prostaglandins during inflammatory responses; which are the primary mediators of pain and swelling. While the new drugs represent a significant improvement over traditional NSAIDs, especially in avoiding unwanted gastrointestinal side-effects, there are concerns about side-effects with the new drugs as well. COX-2 is part of a complex system of eicosanoids that regulate the development and resolution of inflammatory responses. These enzymes and their products interact through several biochemical pathways and influence each others production. COX-2 was originally thought to contribute only to the development of inflammation. Recent studies, however, have suggested that COX-2-derived products may also contribute either directly or indirectly to the resolution phase of the inflammatory response. Thus, use of the new COX-2-inhibiting drugs may alleviate the symptoms of inflammatory diseases, but actually prevent resolution and healing of the underlying inflammation. This proposal uses a mouse model of arthritis caused by the spirochete, Borrelia burgdorferi, the agent of Lyme disease. In some mouse strains infection with this organism causes the development of a severe arthritis that peaks 2 to 3 weeks after infection, and then spontaneously resolves. Treatment of mice with the COX-2-inhibiting drugs, followed by infection with B. burgdorferi, causes the development of severe arthritis but prevents arthritis resolution. Because the eicosanoid pathways interact, there are several possible explanations for why this might occur. In this proposal we have designed specific aims that will allow us to determine which other pathways are involved in this response. We will: Specific Aim 1, determine if COX-1 can compensate for the loss of COX-2, and determine if the loss of anti-inflammatory prostaglandins are responsible for arthritis non-resolution; Specific Aim 2, determine if the loss of COX-2 causes a shunt of arachidonic acid into the leukotriene pathway; and Specific Aim 3, determine if the loss of COX-2 activity alters lipoxin production by neutrophils. This information will further our understanding of how inflammation is regulated and allow the design of more effective anti-inflammatory treatments.