Mitogen-activated protein kinase pathways contribute to hypercontractility and increased Ca2+ sensitization in murine experimental colitis

Eikichi Ihara, Paul L. Beck, Mona Chappellaz, Josee Wong, Shaun A. Medlicott, Justin A. MacDonald

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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 Ca 2+-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.

Original languageEnglish
Pages (from-to)1031-1040
Number of pages10
JournalMolecular Pharmacology
Volume75
Issue number5
DOIs
Publication statusPublished - May 1 2009
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Molecular Medicine

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