Proinflammatory cytokines alter/reduce esophageal circular muscle contraction in experimental cat esophagitis
Proinflammatory cytokines alter/reduce esophageal circular muscle contraction in experimental cat esophagitis
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DOI：
10.1152/ajpgi.00216.2004
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发表时间：
2004-12-01
影响因子：
4.5
通讯作者：
Harnett, KM
中科院分区：
文献类型：
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作者：
Cao, WB;Cheng, L;Harnett, KM
胆碱能机制在很大程度上导致吞咽或体外电场刺激(EFS)引起的食道收缩。反复灌酸诱导实验性食管炎后，吞咽反应和EFS反应显著降低，而ACh的收缩反应无明显改变，提示酸灌流损伤了胆碱能机制，但对肌源性机制无影响。对EFS反应的ACh释放的测量证实，与正常对照组相比，食管炎患者ACh的释放减少。为了研究导致这种神经病变的因素，将正常的食管条与促炎细胞因子IL-1β(100U/ml)、IL-6(1 ng/ml)或肿瘤坏死因子-α(1 ng/ml)孵育1-2小时。Western印迹分析显示，与正常环状肌相比，食管炎患者IL-1β和IL-6水平升高。IL-1β和IL-6抑制EFS(2-10 Hz，0.2ms)引起的收缩，但不影响ACh的收缩，提示这些细胞因子抑制ACh的释放而不影响肌源性收缩机制。经IL-1β或IL-6孵育后，EFS诱导的正常食管条ACh释放明显减少，提示它们可能参与了食管条收缩功能的改变。然而，1 ng/ml的肿瘤坏死因子-α不影响对ACh和电刺激的反应，但在较高浓度时对两者都有抑制作用。正常肌肉组织中肿瘤坏死因子-α水平较低，且不随食管炎而升高。这些数据表明，促炎细胞因子IL-1β和IL-6通过抑制肌间神经元ACh的释放而减少了食道收缩。
Cholinergic mechanisms are largely responsible for esophageal contraction in response to swallowing or to in vitro electrical field stimulation (EFS). After induction of experimental esophagitis by repeated acid perfusion, the responses to swallowing and to EFS were significantly reduced but contraction in response to ACh was not affected, suggesting that cholinergic mechanisms are damaged by acid perfusion but that myogenic mechanisms are not. Measurements of ACh release in response to EFS confirmed that release of ACh was reduced in esophagitis compared with normal controls. To examine factors contributing to this neuropathy, normal esophageal strips were incubated for 1 - 2 h with the proinflammatory cytokines IL-1beta (100 U/ml), IL-6 ( 1 ng/ml), or TNF-alpha (1 ng/ml). IL-1beta and IL-6 levels, measured by Western blot analysis, increased in esophagitis compared with normal circular muscle. IL-1beta and IL-6 reduced contraction in response to EFS (2 - 10 Hz, 0.2 ms) but did not affect ACh-induced contraction, suggesting that these cytokines inhibit ACh release without affecting myogenic contractile mechanisms. EFS-induced ACh release was significantly reduced in normal esophageal strips by incubation in IL-1beta or IL-6, suggesting that they may contribute to the contractility changes. TNF-alpha at 1 ng/ml, however, did not affect the response to ACh or to electrical stimulation but inhibited both at higher concentrations. TNF-alpha levels were low in normal muscle and did not increase with esophagitis. The data suggest that the proinflammatory cytokines IL-1beta and IL-6 contribute to reduced esophageal contraction by inhibiting release of ACh from myenteric neurons.