TNF, Vagal Tone and Gastric Motility

描述(由申请人提供)：免疫效应细胞产生的细胞因子构成宿主对抗原挑战、创伤或辐射反应的一部分。对宿主的保护依赖于细胞因子的释放来刺激：对病原体的免疫攻击、伤口愈合、组织重塑和能量动员。然而，在这些侮辱之后，促炎症细胞因子肿瘤坏死因子-α(TNF)的升高也与胃淤滞、恶心、呕吐和厌食症的发生有关。我们的工作表明：a)外周免疫攻击引起的胃抑制依赖于TNF的合成，b)外周产生的细胞因子抑制中枢神经系统控制的迷走神经介导的胃动力增加，c)TNF可以直接作用于脑干迷走神经背侧复合体[DVC]的神经元，产生深刻的胃抑制。这些结果满足了项目的最初目标，即明确展示了延髓背侧和迷走神经控制回路在肿瘤坏死因子介导的胃静止中的作用。现在，我们希望研究肿瘤坏死因子显著改变迷走神经对胃的控制的生理机制。本研究的目的主要集中在三个方面：1)中枢肿瘤坏死因子激活迷走神经传出通路(S)；2)肿瘤坏死因子激活脑干神经元(S)的特殊表型；3)肿瘤坏死因子激活下丘脑室旁核的细胞机制。我们认为，肿瘤坏死因子通过作用于延髓迷走神经反射回路中的多个部位而抑制胃动力。我们预测：1)肿瘤坏死因子增强迷走神经传入与孤束核之间的谷氨酸神经传递；2)肿瘤坏死因子直接影响控制迷走神经传出神经元活动的特定表型孤束神经元的兴奋性；3)这些最终控制胃运动的孤束神经元也可能受到肿瘤坏死因子的直接影响。也许，肿瘤坏死因子通过同时作用于DVC的多个点而产生对胃运动的深刻而持久的抑制(可能还会产生恶心、呕吐和进食抑制)。这些假说将使用体内和体外神经生理学方法相结合的方法进行验证。

DESCRIPTION (provided by applicant): Cytokine production by immune effector cells forms part of the host response to antigenic challenge, trauma or irradiation. Protection of the host relies on cytokine release to stimulate: immune attack on pathogens, wound healing, tissue remodeling and energy mobilization. However, elevation of the proinflammatory cytokine, tumor necrosis factor-alpha (TNF], following these insults is also associated with the onset of gastric stasis, nausea, vomiting and anorexia. Degradation of the control of gastrointestinal, fluid and nutritional homeostasis causes significant morbidity and mortality apart from that caused by the primary disease process.Our work has shown that: a) initiation of gastric inhibition by peripheral immune challenge is dependent on TNF synthesis, b) peripherally generated cytokines suppress CNS-commanded, vagally mediated increases in gastric motility and c) TNF can operate directly on neurons of the dorsal vagal complex [DVC] of the brainstem to produce profound gastroinhibition. These results satisfied the initial goals of the project, i.e., the unambiguous demonstration of a role for the dorsal medulla and vagal control circuitry in TNF-mediated gastric stasis.Now we wish to investigate the physiological mechanisms by which TNF dramatically alters vagal control of the stomach. The present proposal focuses on three Specific Aims: 1) which vagal efferent pathway(s) are invoked by central TNF action, 2) the specific phenotype of brainstem neuron(s) activated by TNF and 3) the cellular mechanisms activated within the DVC by TNF. We expect that TNF suppresses gastric motility by acting at several sites within vago-vagal reflex circuits in the medulla. We predict that: 1) TNF enhances glutamate neurotransmission between vagal afferents and the solitary nucleus, 2) TNF directly affects the excitability of specific phenotypes of solitary neurons which control the activity of vagal efferent [DMN] neurons, and 3) these DMN neurons (which ultimately control gastric motility) are also likely to be under the direct influence of TNF. Perhaps TNF produces its profound and prolonged inhibition of gastric motility, (and, perhaps, the generation of nausea, emesis and suppression of feeding) by acting at several points in the DVC simultaneously. These hypotheses will be tested using a combination of in vivo and in vitro neurophysiological methods.