Do eicosanoids cause colonic dysfunction in experimental E coli O157:H7 (EHEC) infection?

Abstract

Background: The pathophysiology of enterohaemorrhagic Escherichia coli (EHEC) infection remains unclear. Eicosanoids have been implicated as pathophysiological mediators in other colitides.

Aims: To determine if prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)) contribute to mucosal inflammation and dysfunction in EHEC colitis.

Methods: Ten day old rabbits were infected with EHEC. For five days after infection, mucosal synthesis of PGE(2) and LTB(4) was measured in distal colonic tissue from control and infected animals and (51)Cr-EDTA permeability was assessed in vivo. Myeloperoxidase activity was measured and histological inflammation and damage were assessed at five days in control and infected animals and after treatment of infected animals with the LTB(4) synthesis inhibitor MK-886. In separate experiments, ion transport was measured in Ussing chambers, before and after in vitro addition of the cyclooxygenase inhibitor indomethacin.

Results: LTB(4) synthesis was increased from day 2 after infection onwards and PGE(2) synthesis was increased on day 3. Mucosal permeability did not increase until day 5 after infection. MK-886 inhibited colonic LTB(4) production but did not reduce diarrhoea, inflammation, or mucosal damage. Electrolyte transport was not significantly altered on day 3 after infection. However, both Cl secretion and reduced Na absorption found on day 5 were partially reversed by indomethacin.

Conclusions: Tissue synthesis of PGE(2) and LTB(4) did not correlate temporally with EHEC induced inflammation or changes in mucosal permeability and ion transport. Cyclooxygenase inhibition partially reversed ion transport abnormalities but lipoxygenase inhibition did not affect mucosal inflammation or histological damage. We conclude that the contribution of eicosanoids to mucosal injury and dysfunction is more complex than previously suggested.

Figure 1

(A) Distal colonic mucosal PGE₂ synthetic capacity in uninfected control rabbits and in EHEC infected rabbits 1-5 days after inoculation. Data are mean (SEM), n=12 per group. *p<0.05 compared with control, day 1 infected, and day 2 infected values. (B) Distal colonic mucosal LTB₄ synthetic capacity in uninfected control rabbits and in EHEC infected rabbits 1-5 days after inoculation. Data are mean (SEM), n=12 per group. *p<0.05 compared with control and day 1 infected values. (C) Distal colonic mucosal ⁵¹Cr-EDTA permeability in uninfected control rabbits and in EHEC infected rabbits 2-5 days after inoculation. Data are mean (SEM), n=4 per group. *p<0. 05 compared with control and other infected values. Lower panels show Cl transport and infiltration of the mucosa by neutrophils. Abs'n, absorption.