Eicosanoid regulation of experimental Lyme arthritis

描述(申请人提供)：非类固醇抗炎药(NSAIDs)通常用于缓解类风湿性关节炎和骨关节炎患者的症状。这些药物的新版本(Coxibs)通过抑制环氧合酶(COX)-2酶的活性发挥作用。COX-2负责炎症反应过程中前列腺素的产生，而前列腺素是疼痛和肿胀的主要介质。虽然新药比传统的非甾体抗炎药有了很大的改善，特别是在避免不想要的胃肠道副作用方面，但也有人担心新药的副作用。环氧合酶-2是一个复杂的二十烷类化合物系统的一部分，它调节炎症反应的发展和分解。这些酶和它们的产物通过几个生化途径相互作用，并相互影响彼此的生产。COX-2最初被认为只对炎症的发展起作用。然而，最近的研究表明，COX-2衍生的产物也可能直接或间接地对炎症反应的消退阶段做出贡献。因此，使用新的COX-2抑制药物可能会缓解炎症性疾病的症状，但实际上会阻止潜在炎症的消退和愈合。这项建议使用了由莱姆病病原体伯氏疏螺旋体引起的关节炎的小鼠模型。在一些小鼠品系中，感染这种微生物会导致严重的关节炎，在感染后2-3周达到顶峰，然后自发消退。用抑制COX-2的药物治疗小鼠，然后感染伯氏杆菌，会导致严重的关节炎，但会阻止关节炎的消退。因为二十烷类物质的通路相互作用，所以有几种可能的解释来解释为什么会发生这种情况。在这项提案中，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：特定目标1，确定COX-1是否可以补偿COX-2的丢失，并确定抗炎前列腺素的丢失是否导致关节炎无法解决；特定目标2，确定COX-2的丢失是否导致花生四烯酸分流到白三烯途径；以及特定目标3，确定COX-2活性的丧失是否改变中性粒细胞产生脂素。这些信息将进一步加深我们对炎症是如何调节的理解，并使设计更有效的抗炎治疗成为可能。

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.