Mechanisms underlying the maintenance of muscle hypercontractility in a model of postinfective gut dysfunction

Background & Aims; Acute gastroenteritis is a strong risk factor for the development of irritable bowel syndrome (IBS). We have developed an animal model in which transient acute infection leads to persistent muscle hypercontractility. Here, we investigate the mechanisms underlying the maintenance of this hypercontractility in the postinfective (PI) state. Methods: Muscle contraction and messenger RNA (mRNA) or protein expression of cytokines were examined from jejunal longitudinal muscle cells of NIH Swiss mice infected with Trichinella spiralis or incubated with or without cytokines. Results: During acute infection, interleukin (IL)-4 or IL-13, transforming growth factor (TGF)-beta 1, and cyclooxygenase (COX)-2 were increased in the muscle layer (P < .05). In the PI phase of the model, T helper (Th)2 cytokines returned to normal, but TGF-beta 1 remained in the muscle (P < .05). Exposure of muscle cells to IL-4 or IL-13 increased TGF-beta 1 (P < .01), COX-2 protein, and prostaglandin (PG)E-2. Exposure of muscle cells to TGF-beta 1 increased PGE(2) (P < .05) and COX-2 protein. Incubation of tissue with IL-4, IL-13, TGF-beta 1, or PGE2 enhanced carbachol-induced muscle cell contractility (P < .05). COX-2 inhibitor attenuated TGF-beta 1-induced muscle hypercontractility (P < .05). Conclusions: These results support the hypothesis that Th2 cytokines induce muscle hypercontractility during infection by a direct action on smooth muscle. The maintenance of hypercontractility results from Th2 cytokine-induced expression of TGF-beta 1 and the subsequent up-regulation of COX-2 and PGE2 at the level of the smooth muscle cell. We propose that PI gut dysfunction reflects mediator production in the neuromuscular tissues and that this may occur in PHBS.