[Note: COX-2 is an enzyme responsible for inflammation and pain. COX-2 inhibitor products include non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin or ibuprofen. This study suggests COX-2 inhibitors may also inhibit pro-resolution eicosanoids.]
Objective: Recent studies have implicated products of cyclooxygenase 2 (COX-2) in not only induction but also resolution of the inflammatory response; however, the contribution of COX-2 products to the in vivo response to infection is unknown. The aim of this study was to determine the contribution of COX-2 to temporal regulation of the inflammatory response to infection in a murine model of Lyme arthritis.
Methods: Experimental Lyme disease was induced in both arthritis-resistant DBA/2J and arthritis-susceptible C3H/HeJ mice by inoculation in the hind footpads with Borrelia burgdorferi.
COX-2 inhibitors were administered daily, and their effect on arthritis pathology was assessed at various time points post-infection.
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The COX-2 deficiency was also backcrossed onto both DBA and C3H backgrounds to confirm the findings from COX-2 inhibitor-treated mice.
- In COX-2 inhibitor-treated or COX-2(-/-) C3H mice, arthritis developed normally but did not resolve.
- Cessation of COX-2 inhibitor treatment on day 14 post-infection did not induce resolution of arthritis, indicating an early onset for the molecular mechanisms governing resolution.
- The lack of resolution of arthritis correlated with altered COX-2 and cytosolic phospholipase A(2) messenger RNA levels in the joints of C3H mice. In addition, the proresolution lipid molecule 15-deoxy-Delta(12,14)-prostaglandin J(2) was produced in response to B burgdorferi infection, and its production was attenuated by the inhibition of COX-2.
Conclusion: Our results demonstrate:
- That early production of COX-2 products is necessary for resolution of the inflammatory arthritis induced by Borrelia infection,
- And that COX-2 inhibition may result in prolonged inflammatory states, possibly by inhibition of pro-resolution eicosanoids [‘signaling molecules’ made by oxygenation of the omega-3 essential fatty acid EPA (found in fish oil), and influencing inflammation/immunity].
Source: Arthritis and Rheumatism, April 2008;58(5):1485-1495. PMID: 18438879 [E-publication ahead of print] by Blaho VA, Jefferson Mitchell W, Brown CR. University of Missouri, Columbia, Missouri, USA.