PT - JOURNAL ARTICLE AU - Eikichi Ihara AU - Paul L. Beck AU - Mona Chappellaz AU - Josee Wong AU - Shaun A. Medlicott AU - Justin A. MacDonald TI - Mitogen-Activated Protein Kinase Pathways Contribute to Hypercontractility and Increased Ca<sup>2+</sup> Sensitization in Murine Experimental Colitis AID - 10.1124/mol.108.049858 DP - 2009 May 01 TA - Molecular Pharmacology PG - 1031--1041 VI - 75 IP - 5 4099 - http://molpharm.aspetjournals.org/content/75/5/1031.short 4100 - http://molpharm.aspetjournals.org/content/75/5/1031.full SO - Mol Pharmacol2009 May 01; 75 AB - Inflammatory bowel disease (IBD) is associated with intestinal smooth muscle dysfunction. Many smooth muscle contractile events are associated with alterations in Ca2+-sensitizing pathways. The aim of the present study was to assess the effect of colitis on Ca2+ sensitization and the signaling pathways responsible for contractile dysfunction in murine experimental colitis. Colitis was induced in BALB/c mice by providing 5% dextran sulfate sodium (DSS) in drinking water for 7 days. Contractile responses of colonic circular smooth muscle strips to 118 mM K+ and carbachol (CCh) were assessed. DSS induced a TH2 colitis [increased interleukin (IL)-4 and IL-6] with no changes in TH1 cytokines. Animals exposed to DSS had increased CCh-induced contraction (3.5-fold) and CCh-induced Ca2+-sensitization (2.2-fold) responses in intact and α-toxin permeabilized colonic smooth muscle, respectively. The contributions of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) to CCh-induced contractions were significantly increased during colitis. Ca2+-independent contraction induced by microcystin was potentiated (1.5-fold) in mice with colitis. ERK and p38MAPK (but not Rho-associated kinase) contributed to this potentiation. ERK1/2 and p38MAPK expression were increased in the muscularis propria of colonic tissue from both DSS-treated mice and patients with IBD (ulcerative colitis ≫ Crohn's disease). Murine TH2 colitis resulted in colonic smooth muscle hypercontractility with increased Ca2+ sensitization. Both ERK and p38MAPK pathways contributed to this contractile dysfunction, and expression of these molecules was altered in patients with IBD. The American Society for Pharmacology and Experimental Therapeutics