Indomethacin worsens and a leukotriene biosynthesis inhibitor accelerates mucosal healing in rat colitis

Abstract

The implication of leukotrienes as mediators of inflammation and recent evidence that prostaglandin analogues provide a beneficial effect during experimental colitis led to the speculation that (i) leukotrienes may be injurious and (ii) prostaglandins may be protective to colonic mucosa. Using a 2% acetic acid induced rat colitis model, we administered specific cyclooxygenase (indomethacin) and leukotriene biosynthesis inhibitors (MK-886) to examine the effect of endogenous prostaglandins and leukotrienes on colonic macroscopic injury, mucosal inflammation as measured by myeloperoxidase activity, net in vivo intestinal fluid absorption, and colonic PGE2 and LTB4 levels as measured by in vivo rectal dialysis. Indomethacin treatment prior to induction of colitis reduced endogenous mucosal PGE2 levels and exacerbated macroscopic ulceration and net fluid absorption. Addition of the exogenous PGE1 analogue misoprostol to the indomethacin-exacerbated colitis completely healed colonic macroscopic ulceration and inflammation but only partially improved fluid absorptive injury. The specific leukotriene biosynthesis inhibitor MK-886 administered prior to induction of colitis healed macroscopic ulceration and inflammation but not fluid absorptive injury. This mucosal reparative effect of MK-886 occurred at a dose that reduced colonic LTB4 synthesis while concomitantly enhancing PGE2 levels. Combining MK-886 with misoprostol treatment improved not only macroscopic ulceration and inflammation but also provided a synergistic effect that maintained net colonic fluid absorption at noncolitic control levels. These studies suggest that, during the induction of experimental colitis, endogenous prostaglandins play a pivotal role in providing a mucosal healing effect, and that leukotriene biosynthesis inhibitor may manifest part of its beneficial effect by shifting arachidonic acid metabolism towards production of prostaglandins.

Fatty Acids and Immune Function: Relevance to Inflammatory Bowel Diseases

“…LTB 4 has distinct pro-inflammatory actions, such as inducing leukocyte infiltration and subsequent release of inflammatory mediators [25], and thus it is highly likely to be playing a pathologic role in inflammatory bowel diseases. This is supported by the reported protective effect on mucosal injury of the LT biosynthesis inhibitor MK-886 in acetic acid-induced rat colitis [30]. This effect was associated with decreased colonic LTB 4 concentrations.…”

“…However, the role of PGE 2 in inflammatory bowel diseases is less certain, and there is evidence that it may be protective. For example, indomethacin, an inhibitor of PG synthesis, worsened mucosal injury in acetic acid-induced rat colitis [30]. Furthermore, the LT synthesis inhibitor not only decreased colonic LTB 4 concentrations but increased those of PGE 2 [30], suggesting that a shift of arachidonic acid metabolism in favor of PGs is beneficial.…”

“…For example, indomethacin, an inhibitor of PG synthesis, worsened mucosal injury in acetic acid-induced rat colitis [30]. Furthermore, the LT synthesis inhibitor not only decreased colonic LTB 4 concentrations but increased those of PGE 2 [30], suggesting that a shift of arachidonic acid metabolism in favor of PGs is beneficial. Recent studies have clearly demonstrated mechanisms by which PGE 2 may act in an anti-inflammatory manner.…”

Mucosal healing in inflammatory bowel diseases: a systematic review

“…It is specifically regulated by soluble (circulating) factors, with phases that might be targeted by pharmacological agents 14. For instance, endogenous prostaglandins promoted mucosal healing in experimental colitis, as did leukotriene biosynthesis inhibitors, by shifting arachidonic acid metabolism towards production of prostaglandins, at least in murine models 15 16…”

Polyunsaturated fatty acids, inflammatory processes and inflammatory bowel diseases

“…Whether these effects are due to ALA itself or relate to conversion of ALA to its longer chain, more unsaturated derivatives, like EPA, is not clear from these studies. Four studies report that dietary fish oil decreases chemically induced colonic damage and inflammation compared with an n-6 PUFA-rich diet [7,74,75,77]. These effects on disease severity were, in all cases, associated with a reduction in production of AA-derived eicosanoids (see Table 2 for details).…”