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NEUROREGULATION AND MOTILITY

Gene plasticity in colonic circular smooth muscle cells underlies motility dysfunction in a model of postinfective IBS

The University of Texas Medical Branch at Galveston, Enteric Neuromuscular Disorders and Visceral Pain Center, Division of Gastroenterology, Departments of ¹Internal Medicine and ²Neuroscience and Cell Biology, Galveston, Texas

Submitted 25 November 2008 ; accepted in final form 30 December 2008

The cellular mechanisms of motility dysfunction in postinfectious irritable bowel syndrome (PI-IBS) are not known. We used a rat model of neonatal inflammation to test the hypothesis that gene plasticity in colonic circular smooth muscle cells underlies motility dysfunction in PI-IBS. Mild/moderate or severe inflammation was induced in neonatal and adult rats. Experiments were performed in tissues obtained at 7 days (short term) and 6–8 wk (long term) after the induction of inflammation. Severe inflammation in neonatal rats induced persistent long-term smooth muscle hyperreactivity to acetylcholine (ACh), whereas that in adult rat caused smooth muscle hyporeactivity that showed partial recovery in the long term. Mild/moderate inflammation had no effect in neonatal rats, but it induced smooth muscle hyporeactivity to ACh in adult rats, which recovered fully in the long term. Smooth muscle hyperreactivity to ACh resulted in accelerated colonic transit and increase in defecation rate, whereas hyporeactivity had opposite effects. Smooth muscle hyperreactivity to ACh was associated with increase in transcription rate of key cell-signaling proteins of the excitation-contraction coupling _1C subunit of Ca_v1.2 (L-type) calcium channels, G_q, and 20-kDa myosin light chain (MLC₂₀), whereas hyporeactivity was associated with their suppression. Inflammation in adult rats induced classical inflammatory response, which was absent in neonatal rats. Severe neonatal inflammation enhanced plasma norepinephrine and muscularis propria vasoactive intestinal polypeptide in the long term. We conclude that severe, but not mild/moderate, inflammation in a state of immature or impaired stress and immune response systems alters the transcription rate of key cell-signaling proteins of excitation-contraction coupling in colonic circular smooth muscle cells to enhance their contractility and accelerate colonic transit and defecation rate.

irritable bowel syndrome; enteric nervous system; gastrointestinal motility; neurotransmitters; gene expression

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