Arthritis develops but fails to resolve during inhibition of cyclooxygenase 2 in a murine model of Lyme disease.
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 postinfection. The COX-2 deficiency was also backcrossed onto both DBA and C3H backgrounds to confirm the findings from COX-2 inhibitor-treated mice.


RESULTS
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 postinfection 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 A2 messenger RNA levels in the joints of C3H mice. In addition, the proresolution lipid molecule 15-deoxy-Delta12,14-prostaglandin J2 was produced in response to B burgdorferi infection, and its production was attenuated by the inhibition of COX-2.


CONCLUSIONS
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 proresolution eicosanoids.
Blaho
Victoria A
VA
University of Missouri, Columbia, MO 65211, USA.
Mitchell
W Jefferson
WJ
Brown
Charles R
CR
D000818:Animals; D001170:Arthritis, Infectious / Q000188:drug therapy* / Q000201:enzymology* / Q000382:microbiology; D025065:Borrelia burgdorferi; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000502:physiology*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D008193:Lyme Disease; D051379:Mice; D008809:Mice, Inbred C3H; D008811:Mice, Inbred DBA; D054467:Phospholipases A2 / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D017211:Treatment Failure
D016861:Cyclooxygenase Inhibitors; D012333:RNA, Messenger; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D054467:Phospholipases A2