Eicosanoid regulation of experimental Lyme arthritis

描述（由申请人提供）：非甾体抗炎药（NSAIDs）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（coxibs）通过抑制环氧化酶(COX)-2酶的活性起作用。COX-2在炎症反应中负责前列腺素的产生；它们是疼痛和肿胀的主要媒介。虽然这些新药比传统的非甾体抗炎药有了显著的改进，尤其是在避免不必要的胃肠道副作用方面，但人们也担心新药的副作用。COX-2是一个复杂的类二十烷系统的一部分，调节炎症反应的发展和解决。这些酶及其产物通过几种生化途径相互作用，并相互影响生产。COX-2最初被认为只有助于炎症的发展。然而，最近的研究表明，cox -2衍生产品也可能直接或间接地参与炎症反应的消退阶段。因此，使用新的cox -2抑制药物可能减轻炎症性疾病的症状，但实际上阻止了潜在炎症的消退和愈合。这个提议使用了一个由螺旋体引起的关节炎的小鼠模型，伯氏疏螺旋体是莱姆病的病原体。在某些小鼠株中，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周达到顶峰，然后自行消退。用cox -2抑制药物治疗小鼠，然后感染伯氏疏螺旋体，导致严重关节炎的发展，但阻止关节炎的消退。因为类二十烷酸途径相互作用，有几种可能的解释为什么会发生这种情况。在这项建议中，我们设计了具体目标，使我们能够确定这种反应涉及哪些其他途径。我们将：具体目标1，确定COX-1是否可以补偿COX-2的损失，并确定抗炎前列腺素的损失是否与关节炎不消退有关；特异性目的2：确定COX-2的缺失是否会导致花生四烯酸进入白三烯通路；特异性目的3，确定COX-2活性的丧失是否会改变中性粒细胞产生的脂素。这些信息将进一步加深我们对炎症是如何调节的理解，并允许设计更有效的抗炎治疗方法。

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.