LPS-induced suppression of gastric motility relieved by TNFR:Fc construct in dorsal vagal complex
LPS-induced suppression of gastric motility relieved by TNFR:Fc construct in dorsal vagal complex
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DOI：
10.1152/ajpgi.00412.2001
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发表时间：
2002-09-01
影响因子：
4.5
通讯作者：
Rogers, RC
中科院分区：
文献类型：
--
作者：
Hermann, GE;Tovar, CA;Rogers, RC
我们以前的研究表明，细胞因子肿瘤坏死因子-α（TNF-α）可能在延髓背侧迷走神经复合体（DVC）的神经回路中起作用，影响胃功能的变化，如胃停滞，食欲不振，恶心和呕吐。内源性产生的TNF-α能够通过DVC回路影响胃功能的明确证明由于缺乏TNF-α拮抗剂而受到阻碍。本研究使用TNF吸附构建体（TNFR：Fc; TNF受体与人免疫球蛋白IgG 1的Fc部分连接）的局部中枢神经系统应用，试图中和内源性产生的TNF-α的抑制作用。在全身给予脂多糖（LPS）诱导TNF-α产生后，监测硫代丁巴比妥麻醉大鼠的胃运动。用TNFR：Fc连续灌注第四脑室底部逆转了LPS诱导的有效胃抑制，即，中枢促甲状腺激素释放肽诱导的运动性增加没有受到抑制。在静脉内给予类似剂量的TNFR：Fc或心室应用人免疫球蛋白Fc片段后，未观察到胃停滞的解除抑制。这些结果证实了我们以前的研究，表明循环TNF-α可能直接作用于DVC内，影响各种病理生理状态下的胃功能。
Our previous studies suggested that the cytokine tumor necrosis factor-alpha (TNF-alpha) may act within the neural circuitry of the medullary dorsal vagal complex (DVC) to affect changes in gastric function, such as gastric stasis, loss of appetite, nausea, and vomiting. The definitive demonstration that endogenously generated TNF-alpha is capable of affecting gastric function via the DVC circuitry has been impeded by the lack of an antagonist for TNF-alpha. The present studies used localized central nervous system applications of the TNF-adsorbant construct (TNFR: Fc; TNF-receptor linked to the Fc portion of the human immunoglobulin IgG1) to attempt to neutralize the suppressive effects of endogenously produced TNF-alpha. Gastric motility of thiobutabarbital-anesthetized rats was monitored after systemic administration of lipopolysaccharide (LPS) to induce TNF-alpha production. Continuous perfusion of the floor of the fourth ventricle with TNFR: Fc reversed the potent gastroinhibition induced by LPS, i.e., central thyrotropin-releasing hormone-induced increases in motility were not inhibited. This disinhibition of gastric stasis was not seen after intravenous administration of similar doses of TNFR: Fc nor ventricular application of the Fc fragment of human immunoglobulin. These results validate our previous studies that suggest that circulating TNF-alpha may act directly within the DVC to affect gastric function in a variety of pathophysiological states.