Gene plasticity in colonic circular smooth muscle cells underlies motility dysfunction in a model of postinfective IBS.
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 alpha1C subunit of Cav1.2 (L-type) calcium channels, Galphaq, 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.
Choudhury
Barun K
BK
Enteric Neuromuscular Disorders and Visceral Pain Center, Department of Internal Medicine, The University of Texas Medical Branch at Galveston, 9.138 Medical Research Bldg., Galveston, TX 77555-1064, USA.
Shi
Xuan-Zheng
XZ
Sarna
Sushil K
SK
D000109:Acetylcholine / Q000494:pharmacology; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D020746:Calcium Channels, L-Type / Q000235:genetics; D018678:Cholinergic Agents / Q000494:pharmacology; D003106:Colon / Q000166:cytology / Q000294:innervation / Q000502:physiology*; D003672:Defecation / Q000502:physiology; D004195:Disease Models, Animal; D017615:Enteric Nervous System / Q000502:physiology; D004751:Enteritis / Q000235:genetics / Q000276:immunology / Q000503:physiopathology*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D018836:Inflammation Mediators / Q000378:metabolism; D043183:Irritable Bowel Syndrome / Q000235:genetics / Q000276:immunology / Q000503:physiopathology*; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D018994:Myosin Light Chains / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000502:physiology; D014660:Vasoactive Intestinal Peptide / Q000037:antagonists & inhibitors / Q000378:metabolism
C514350:CACNA1C protein, mouse; D020746:Calcium Channels, L-Type; D018678:Cholinergic Agents; D018836:Inflammation Mediators; D018994:Myosin Light Chains; D014660:Vasoactive Intestinal Peptide; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D000109:Acetylcholine