TNF, Vagal Tone and Gastric Motility

描述（由申请方提供）：免疫效应细胞产生的细胞因子是宿主对抗原激发、创伤或辐射应答的一部分。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，这些损伤后促炎性细胞因子肿瘤坏死因子-α（TNF）的升高也与胃停滞、恶心、呕吐和厌食症的发作相关。胃肠、体液和营养平衡控制的退化除了由原发疾病过程引起的发病率和死亡率外，还引起显著的发病率和死亡率。a）通过外周免疫攻击启动胃抑制依赖于TNF合成，B）外周产生的细胞因子抑制CNS命令，迷走神经介导的胃运动性增加，以及c）TNF可以直接作用于脑干的背侧迷走神经复合体[DVC]的神经元以产生深度胃抑制。这些结果满足了项目的最初目标，即，明确证明了背侧延髓和迷走神经控制回路在TNF介导的胃停滞中的作用，现在我们希望研究TNF显著改变胃迷走神经控制的生理机制。目前的建议集中在三个特定的目的：1）迷走神经传出通路（一个或多个）被激活的中央TNF行动，2）脑干神经元（一个或多个）的特定表型激活的TNF和3）的细胞机制激活的DVC内的TNF。我们预期TNF通过作用于延髓迷走神经-迷走神经反射回路内的几个部位来抑制胃运动。我们预测：1）TNF增强迷走传入神经和孤束核之间的谷氨酸神经传递，2）TNF直接影响控制迷走传出[DMN]神经元活动的孤束神经元的特定表型的兴奋性，3）这些DMN神经元（最终控制胃运动）也可能受到TNF的直接影响。TNF可能通过同时作用于DVC中的几个点而产生对胃运动的深刻而持久的抑制（以及可能产生恶心、呕吐和进食抑制）。将使用体内和体外神经生理学方法的组合来测试这些假设。

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.