Mitogen-Activated Protein Kinase Pathways Contribute to Hypercontractility and Increased Ca2+ Sensitization in Murine Experimental Colitis
Mitogen-Activated Protein Kinase Pathways Contribute to Hypercontractility and Increased Ca2+ Sensitization in Murine Experimental Colitis
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DOI：
10.1124/mol.108.049858
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发表时间：
2009-05-01
影响因子：
3.6
通讯作者：
MacDonald, Justin A.
中科院分区：
文献类型：
--
作者：
Ihara, Eikichi;Beck, Paul L.;MacDonald, Justin A.
炎症性肠病（IBD）与肠平滑肌功能障碍有关。许多平滑肌收缩事件与Ca2+敏化途径的改变有关。本研究的目的是评估结肠炎对小鼠实验性结肠炎Ca2+致敏和负责收缩功能障碍的信号通路的影响。用5%葡聚糖硫酸钠（DSS）灌胃BALB/c小鼠，连续7天诱导结肠炎。评估结肠圆形平滑肌条对118 mM K+和氯巴酚（CCh）的收缩反应。DSS诱导T(H)2结肠炎[白细胞介素(IL)-4和IL-6升高]，但T(H)1细胞因子无变化。暴露于DSS的动物在完整和α毒素渗透的结肠平滑肌中分别增加了cch诱导的收缩（3.5倍）和cch诱导的Ca2+致敏（2.2倍）反应。结肠炎期间，细胞外信号调节激酶（ERK）和p38丝裂原活化蛋白激酶（MAPK）对cch诱导的收缩的贡献显著增加。微囊藻毒素诱导的Ca2+非依赖性收缩在结肠炎小鼠中增强（1.5倍）。ERK和p38MAPK（而不是rho相关激酶）促进了这种增强。dss治疗小鼠和IBD（溃疡性结肠炎）患者结肠组织固有肌层中ERK1/2和p38MAPK的表达均升高。小鼠T(H)2结肠炎导致结肠平滑肌过度收缩并增加Ca2+敏化。ERK和p38MAPK通路都参与了这种收缩功能障碍，并且这些分子的表达在IBD患者中发生了改变。
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 T(H)2 colitis [increased interleukin (IL)-4 and IL-6] with no changes in T(H)1 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 alpha-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 T(H)2 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.