Vascular anatomy defines sites of indomethacin induced jejunal ulceration along the mesenteric margin

Abstract

Background-Indomethacin induces ulceration in the rat jejunum with sparing of the ileum. The ulcers localise between vasa recta along the mesenteric margin of the bowel, observations that have not been fully explained. Aim-To examine the relationship between the localisation of experimental ulcers and the vascular anatomy of the rat small intestine. Methods-The normal vascular anatomy of the rat jejunum and ileum was studied and compared using arterial carbon ink perfusion. The anatomical localisation of early and advanced lesions induced by indomethacin was examined with particular reference to the vasculature. Mucosal injury induced by feeding vessel ligation for 24 hours or brief ischaemiareperfusion injury was examined. The existence of anatomically sensitive sites to indomethacin was tested in a two dose study. Results-In the rat jejunum, poorly vascularised sites along the mesenteric margin were highly susceptible to indomethacin induced injury, such sites being absent from the ileum. Villous contraction was a feature of both early indomethacin injury and ischaemia-reperfusion injury in the rat jejunum. Twenty four hour ligation of jejunal vasa brevia selectively induced ischaemic injury along the mesenteric margin. Two doses of indomethacin to rats did not induce greater injury than a single dose. Conclusions-Results support the hypothesis that the rat jejunum possesses vascularly compromised sites along the mesenteric margin that are susceptible to indomethacin induced injury. Indomethacin may cause ischaemia-reperfusion injury selectively at these sites.

Small bowel injury induced by selective cyclooxygenase-2 inhibitors: a prospective, double-blind, randomized clinical trial comparing celecoxib and meloxicam

“…It has been confirmed that NSAIDs increase intestinal permeability through enterocytic mitochondrial damage and a decrease in prostaglandin synthesis, and, as a consequence, the intestinal mucosa becomes more susceptible to the actions of luminal agents such as bile acid, bacterial flora, and ingested foods [34][35][36][37]. Changes in the composition of bile acids and an increase in bacterial flora in the ileum may explain the more severe mucosal damage at this site [37].…”

“…It has been confirmed that NSAIDs increase intestinal permeability through enterocytic mitochondrial damage and a decrease in prostaglandin synthesis, and, as a consequence, the intestinal mucosa becomes more susceptible to the actions of luminal agents such as bile acid, bacterial flora, and ingested foods [34][35][36][37]. Changes in the composition of bile acids and an increase in bacterial flora in the ileum may explain the more severe mucosal damage at this site [37]. A similar trend in the distribution of mucosal injuries has been confirmed in recent studies using other NSAIDs [26,38,39], indicating that the ileum seems to be the predominant site prone to mucosal injury in patients taking NSAIDs or COX-2 inhibitors.…”

Pathogenic Importance of Intestinal Hypermotility in NSAID-Induced Small Intestinal Damage in Rats

“…Thus, inhibition of the intestinal hypermotility response by atropine as well as dmPGE 2 may strengthen the barrier against luminal pathogens, resulting in suppression of bacterial invasion and inhibition of neutrophil recruitment as well as the upregulation of iNOS expression, and by so doing prevent the occurrence of intestinal damage following indomethacin. On the other hand, Anthony et al [25, 26]reported that intestinal hypermotility causes mucosal hypoxia and microvascular injury due to smooth muscle contraction, leading to neutrophil infiltration and the release of various cytokines. Since the inhibition of intestinal hypermotility may lead to prevention of microvascular disturbances due to contraction of the intestinal wall, it is speculated that these agents contribute to maintaining mucosal blood flow in the presence of indomethacin.…”

Soluble Dietary Fiber Protects Against Nonsteroidal Anti-inflammatory Drug-Induced Damage to the Small Intestine in Cats

“…Several different factors related to the pathogenesis of NSAID-induced small intestinal ulcers have been reported [6][7][8], such as decreased mucosal mucus [9] and blood flow [10,11]; infiltration of inflammatory cells [12], intestinal bacteria [13,14], and bile acids [15]; dietary fibers [16]; and increased intestinal motility [17,18].…”