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

Abstract

Choudhury BK, Shi X-Z, Sarna SK. Gene plasticity in colonic circular smooth muscle cells underlies motility dysfunction in a model of postinfective IBS. Am J Physiol Gastrointest Liver Physiol 296: G632-G642, 2009. First published January 8, 2009 doi:10.1152/ajpgi.90673.2008.-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 Cav1.2 (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 excitationcontraction 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 MOTILITY DYSFUNCTION RESULTING in diarrhea, constipation, or alternating diarrhea and constipation and visceral hypersensitivity are the defining symptoms of irritable bowel syndrome (IBS). Motility dysfunction in IBS is thought to be attributable to defects in smooth muscle and/or enteric neuronal regulatory systems. However, the cellular and molecular mechanisms of these defects in the absence of an organic disease, infection, or structural abnormality are not known.Clinical observations indicate that a subset (about 10 -25%) of the subjects exposed to enteric infections in an individual or a community setting go on to develop predominantly the symptoms of diarrhea-predominant IBS (IBS-D) (8, 15-17, 23, 28, 30). Why only l...

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