Abstract
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.
Footnotes
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This work was supported by the Crohn's and Colitis Foundation of Canada; the Canadian Institutes of Health Research; a Uehara Memorial Foundation Fellowship (Japan); a Canadian Association of Gastroenterology/Canadian Institutes of Health Research/AstraZeneca Fellowship; a Canada Research Chair (Tier II) in Smooth Muscle Pathophysiology; and a Scholarship from the Heart and Stroke Foundation of Canada.
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ABBREVIATIONS: IBD, inflammatory bowel disease; TNF, tumor necrosis factor; CCh, carbachol; TNBS, 2,4,6-trinitrobenzenesulfonic acid; IL, interleukin; STAT, signal transducer and activator of transcription; LC20, regulatory light chains of myosin II; MLCK, myosin light chain kinase; MLCP, myosin light chain phosphatase; ROK, Rho-associated kinase; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; DSS, dextran sulfate sodium; PD98059, 2′-amino-3′-methoxyflavone; SB203580, 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole; U0126, 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene; SB202190, 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole; MPO, myeloperoxidase; NES, normal extracellular solution; KES, K+ extracellular solution; A23187, calcimycin; PAGE, polyacrylamide gel electrophoresis; Y27632, N-(4-pyridyl)-4-(1-aminoethyl)cyclohexanecarboxamid; UC, ulcerative colitis; CD, Crohn disease; MYPT1, myosin target subunit of MLCP; pCa, -log10 [Ca2+].
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↵ The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
- Received June 20, 2008.
- Accepted February 3, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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