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.
