Cyclooxygenase 2 mediates post-inflammatory colonic secretory and barrier dysfunction

Abstract

Background and aims: 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) D 2 to suppress colonic epithelial secretion, we investigated the potential roles of this eicosanoid and of cyclooxygenase 2 (COX-2) in mediating postcolitis epithelial secretory and barrier dysfunction. Results: Six weeks after induction of colitis with trinitrobenzene sulphonic acid, there was marked elevated synthesis of PGD 2 and elevated COX-2 expression. Selective COX-2 inhibition abolished the increase in PGD 2 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 PGD 2 , but not to its metabolite, 15-deoxy-D 12-14 PGJ 2 . 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 PGD 2 , in mediating the prolonged epithelial secretory and barrier dysfunction after a bout of colitis in the rat.

A pro-resolution mediator, prostaglandin D 2 , is specifically up-regulated in individuals in long-term remission from ulcerative colitis

“…As reported in models of self-resolving inflammation (9) and experimental colitis (7), the use of selective inhibitors of DP1 has been shown to abrogate the protective effects of PGD 2 , resulting in an increase in inflammatory-cell infiltration and an imbalance in pro-and antiinflammatory cytokines. However, some of the long-term detrimental effects of PGD 2 after resolution of colitis in rats, which included enhancement of epithelial proliferation and increased barrier permeability, could be reversed by treatment with a DP1 receptor antagonist (14). Likewise, the increased susceptibility to chemically induced colon cancer in rats that had recovered from a bout of colitis was reversed by treatment with a DP1 receptor antagonist.…”

“…Previous animal studies have documented an important role of PGD 2 in reducing infiltration of leukocytes into the inflamed colon (7) and promoting resolution of inflammation and healing of damaged tissue (8,9,14). In rats, colonic PGD 2 synthesis remained elevated for several weeks after resolution of colonic injury that had been induced by trinitrobenzene sulfonic acid (14,15).…”

“…As mentioned above, a role for PGD 2 in the resolution of experimental colitis has been shown in several studies (6,14,15). This prostanoid has also been shown to be a critical mediator of the resolution of inflammation in experimental pleurisy (8).…”

“…In rats, colonic PGD 2 synthesis remained elevated for several weeks after resolution of colonic injury that had been induced by trinitrobenzene sulfonic acid (14,15). The elevated colonic PGD 2 synthesis, along with elevated expression of DP1 receptors, mediated some of the long-term consequences of colitis in rats, including elevated epithelial proliferation and an increased susceptibility to colon cancer (14,15). In the present study, we examined the synthesis of PGD 2 in biopsies of colon from patients with UC (active or in medically induced remission) and did not observe any significant changes relative to biopsies from healthy controls.…”

“…In UC and experimental colitis, the predominant source of PGs seems to be COX-2 (12,13). Several studies of experimental colitis suggest important roles of PGD 2 in promoting the resolution of inflammation and long-term alterations in colonocyte and barrier function (7,14,15), but little is known about the roles of this eicosanoid in human colitis. In the present study, we have examined PGD 2 levels in biopsies from UC patients, comparing them with those from healthy individuals who had no prior history of UC or those from healthy individuals who had experienced a prior bout of UC but had been in remission without medication for >4 y.…”