Autonomic neuropathy, gastrointestinal motility, and inflammation in HIV

HIV 的自主神经病变、胃肠道运动和炎症

• 批准号: 9110258
• 负责人: Jessica Robinson-Papp
• 金额: $ 20.78万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9110258
• 关键词: AIDS/HIV problem; Acetylcholine; Acetylcholinesterase Inhibitors; Address; Anti-Inflammatory Agents; Anti-inflammatory; Autonomic Dysfunction; Autonomic nervous system; Autonomic nervous system disorders; Blood Pressure; Breath Tests; Cells; Chronic; Complex; Constipation; Data; Digestion; Disease; Disease Progression; FDA approved; Functional disorder; Gastric Emptying; Gastrointestinal Motility; Gastrointestinal Transit; Gastrointestinal tract structure; HIV; Health; Heart Rate; Hydrogen; Immune; Immunologic Markers; Individual; Inflammation; Inflammatory; Inflammatory Response; Interleukin-6; Intestines; Life; Lipopolysaccharides; Measures; Mediating; Morbidity - disease rate; Nausea and Vomiting; Nervous System control; Neurotransmitters; Oral; Organ; Participant; Pathway interactions; Patients; Pharmaceutical Preparations; Plasma; Radionuclide Imaging; Recruitment Activity; Research; T-Cell Activation; Testing; Vagus nerve structure; alpha-bungarotoxin receptor; antiretroviral therapy; autonomic neuropathy; cell motility; cholinergic; effective therapy; gastrointestinal; gastrointestinal function; gastrointestinal symptom; heart rate variability; immune activation; immune function; improved; macrophage; meetings; microbial; motility disorder; pyridostigmine; standardize measure; study population

 DESCRIPTION (provided by applicant): HIV-infected patients commonly develop autonomic neuropathy (HIV-AN), which is a heterogeneous disorder characterized by varying degrees of both sympathetic and vagal dysfunction. We hypothesize that the vagal component of HIV-AN contributes to chronic inflammation, both directly via loss of cholinergic activity, and indirectlyvia effects on the gastrointestinal (GI) tract, and that these effects will be treatable using the acetylcholinesterase inhibitor pyridostigmine. The autonomic nervous system controls the inflammatory response to lipopolysaccharide (LPS) via the cholinergic anti-inflammatory pathway. This pathway is mediated by the vagus nerve, and is therefore likely impaired in HIV-AN with vagal dysfunction. Vagal dysfunction also causes slowed GI transit, which could exacerbate LPS-driven inflammation by promoting bacterial overgrowth. However, the anti-inflammatory impact of cholinergic pathways is almost completely unstudied in HIV, despite the known importance of inflammation in HIV disease progression. Therefore, in this exploratory pilot, we seek to establish associations between vagal dysfunction, GI motility and inflammation in virally suppressed, CART- treated individuals with HIV-AN. Specific Aim 1: To determine whether vagal dysfunction is associated with immune activation in CART- treated participants with HIV-AN, and if so to estimate the extent to which this association is mediated by GI effects (i.e. slowed motility, bacterial overgrowth, microbial translocation) versus direct effects of vaga dysfunction. Specific Aim 2: In a subset of participants who have both vagal and GI dysfunction, to investigate whether 8 weeks of pyridostigmine: a) reduces immune activation, and b) improves GI motility; and if the immune effect depends on the GI effect. To achieve these aims, we will recruit 80-100 participants with HIV-AN and GI symptoms who will be assessed for: vagal dysfunction (heart rate variability); GI dysmotility (gastric emptying scintigraphy); small intestinal bacterial overgrowth (breath testing); microbial translocation (LPS and sCD14); and immune activation (IL-6 and CRP). Participants meeting threshold criteria for both vagal and GI dysfunction will then be treated with pyridostigmine for 8 weeks, after which GI and immune measures will be reassessed.

 描述（由适用提供）：感染HIV的患者通常会出现自主神经病（HIV-AN），这是一种以不同程度的交感神经和迷走性功能障碍为特征的异质性疾病。我们假设HIV的迷走神经成分 - 既直接通过胆碱能活性的丧失，又导致慢性感染，以及对胃肠道（GI）区域的间接影响，并且将使用乙酰胆碱酯酶抑制剂吡啶家治疗这些作用。自主神经系统通过胆碱能抗炎途径控制对脂多糖（LPS）的炎症反应。该途径是由迷走神经介导的，因此可能在HIV-AN中受到迷走神经功能障碍的损害。迷走神经功能障碍还会导致胃肠道转移减慢，这可能通过促进细菌过度生长来加剧LPS驱动的炎症。然而，胆碱能途径的抗炎作用几乎完全未被研究，在HIV中，炎症在HIV疾病进展中已知的重要性。因此，在这种探索性飞行员中，我们寻求在病毒抑制，接受过HIV-AN的手推车治疗的个体中建立迷走神经功能障碍，胃肠道运动和炎症之间的关联。具体目的1：确定迷走神经功能障碍是否与接受HIV-AN的手推车处理的参与者的免疫激活有关，如果是这样估算了该关联是由GI效应（即缓慢的运动性，细菌过度生长，微生物易位）与Vaga功能障碍的直接效应介导的程度。具体目的2：在具有迷走神经和胃肠道功能障碍的参与者的一部分中，以研究8周的吡啶甲胺：a）减少免疫活化，b）提高GI运动性；如果免疫作用取决于胃肠道效应。为了实现这些目标，我们将招募80-100名患有HIV-AN和GI症状的参与者，他们将被评估为：迷走功能障碍（心率变异性）；胃肠道不良症（胃清空闪烁显像）；小肠细菌过度生长（呼吸测试）；微生物易位（LPS和SCD14）;和免疫激活（IL-6和CRP）。符合迷走神经和胃肠道功能障碍的阈值标准的参与者将用吡啶降氨酸治疗8周，然后将重新评估GI和免疫措施。