Differential immune and genetic responses in rat models of Crohn's colitis and ulcerative colitis.
Crohn's disease and ulcerative colitis are clinically, immunologically, and morphologically distinct forms of inflammatory bowel disease (IBD). However, smooth muscle function is impaired similarly in both diseases, resulting in diarrhea. We tested the hypothesis that differential cellular, genetic, and immunological mechanisms mediate smooth muscle dysfunction in two animal models believed to represent the two diseases. We used the rat models of trinitrobenzene sulfonic acid (TNBS)- and dextran sodium sulfate (DSS)-induced colonic inflammations, which closely mimic the clinical and morphological features of Crohn's disease and ulcerative colitis, respectively. DSS inflammation induced oxidative stress initially in mucosa/submucosa, which then propagated to the muscularis externa to impair smooth muscle function. The muscularis externa showed no increase of cytokines/chemokines. On the other hand, TNBS inflammation almost simultaneously induced oxidative stress, recruited or activated immune cells, and generated cytokines/chemokines in both mucosa/submucosa and muscularis externa. The generation of cytokines/chemokines did not correlate with the recruitment and activation of immune cells. Consequently, the impairment of smooth muscle function in DSS inflammation was primarily due to oxidative stress, whereas that in TNBS inflammation was due to both oxidative stress and proinflammatory cytokines. The impairment of smooth muscle function in DSS inflammation was due to suppression of Gα(q) protein of the excitation-contraction coupling. In TNBS inflammation, it was due to suppression of the α(1C)1b subunit of Ca(v)1.2b channels, CPI-17 and Gα(q). TNBS inflammation increased IGF-1 and TGF-β time dependently in the muscularis externa. IGF-1 induced smooth muscle hyperplasia; both IGF-1 and TGF-β induced hypertrophy. In conclusion, both TNBS and DSS induce transmural inflammation, albeit with different types of inflammatory mediators. The recruitment or activation of immune cells does not correlate directly with the intensity of generation of inflammatory mediators. The inflammatory mediators in TNBS and DSS inflammations target different genes to impair smooth muscle function.
Enteric Neuromuscular Disorders and Visceral Pain Center, Division of Gastroenterology, Department of Internal Medicine, The University of Texas Medical Branch at Galveston, Galveston, Texas 77555-1064, USA.
Xuan-Zheng
XZ
Shi
John H
JH
Winston
Sushil K
SK
Sarna
D000818:Animals; D003092:Colitis / Q000139:chemically induced; D003093:Colitis, Ulcerative / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D016207:Cytokines / Q000009:adverse effects; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D006965:Hyperplasia; D006984:Hypertrophy; D007249:Inflammation / Q000473:pathology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D009130:Muscle, Smooth / Q000473:pathology / Q000503:physiopathology*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D014302:Trinitrobenzenesulfonic Acid
D016207:Cytokines; D018836:Inflammation Mediators; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate