Cyclooxygenase 2 mediates post-inflammatory colonic secretory and barrier dysfunction.
OBJECTIVE
The colonic epithelium plays a key role in host defence. During colitis, epithelial function is impaired, leading to elevated bacterial translocation and exacerbation of inflammation. We previously documented perturbation of epithelial function, in terms of secretion and as a barrier to bacterial translocation, that persisted long after resolution of a bout of colitis in the rat. The mechanisms underlying the epithelial dysfunction are not completely understood.


METHODS
Given the ability of prostaglandin (PG) D2 to suppress colonic epithelial secretion, we investigated the potential roles of this eicosanoid and of cyclooxygenase 2 (COX-2) in mediating post-colitis epithelial secretory and barrier dysfunction.


RESULTS
Six weeks after induction of colitis with trinitrobenzene sulphonic acid, there was marked elevated synthesis of PGD2 and elevated COX-2 expression. Selective COX-2 inhibition abolished the increase in PGD2 synthesis. Colonic chloride secretory responses (in vitro) were significantly diminished relative to those in controls, a defect that was reversed by pre-exposure to a selective COX-2 inhibitor (celecoxib) but not to a selective COX-1 inhibitor (SC-560). The hyporesponsiveness was mimicked by pre-exposure of normal colonic tissue to PGD2, but not to its metabolite, 15-deoxy-Delta(12-14)PGJ2. The post-colitis rats exhibited a 10-fold increase in bacterial colonisation of the colon, and >3-fold increase in bacterial translocation. Twice daily treatment for one week with a selective COX-2 inhibitor (rofecoxib) did not affect bacterial colonisation but abolished the increase in bacterial translocation.


CONCLUSIONS
These studies demonstrate an important role for COX-2, possibly via generation of PGD2, in mediating the prolonged epithelial secretory and barrier dysfunction after a bout of colitis in the rat.
Zamuner
S R
SR
Mucosal Inflammation Research Group, University of Calgary, Calgary, Alberta, T2N 4N1, Canada.
Warrier
N
N
Buret
A G
AG
MacNaughton
W K
WK
Wallace
J L
JL
D000818:Animals; D018988:Bacterial Translocation / Q000502:physiology; D003092:Colitis / Q000378:metabolism*; D003106:Colon / Q000378:metabolism*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D015230:Prostaglandin D2 / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D015230:Prostaglandin D2