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Impact of alcohol intoxication on lymphatic contractile mechanisms

酒精中毒对淋巴收缩机制的影响

基本信息

批准号：
8620599
负责人：
Flavia Moreira Souza
金额：
$ 5.7万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-15 至 2015-08-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8620599
关键词：
Acute Affect Alcohol abuse Alcoholic Intoxication Alcohols Antigens Area Award Binding Biochemical Blood Circulation Blood alcohol level measurement Cardiac Cardiovascular Physiology Clinical Communication Critical Thinking Data Development Development Plans Emergency Situation Environment Ethanol Metabolism Faculty Fluid Balance Frequencies Fura-2 Gastrointestinal tract structure Heart Homeostasis Host Defense Image Immune Immune response Immune system Immunity Immunologic Monitoring Immunologics Impairment Incidence Infection Infection prevention Injury Intervention Intestines Knowledge Laboratories Length of Stay Lipids Liquid substance Lung Lymph Lymphatic Lymphatic vessel Measures Mesentery Methods Modeling Molecular Morbidity - disease rate Mucosal Immunity Muscle Contraction Nature Organ Pattern Phase Positioning Attribute Prospective Studies Proteins Protocols documentation Pump Rattus Recovery Reporting Research Retrospective Studies Role Signaling Molecule Smooth Muscle Stretching Stroke Volume System Testing Therapeutic Tissues Trauma Work Writing alcohol effect alcohol testing base constriction cost driving force gastrointestinal health care delivery improved indexing injured injury prevention lymph flow lymph nodes lymphatic pump mortality myosin phosphatase novel pathogen patient population pressure pulmonary function response rho skills therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Alcohol intoxication complicates injury and infection by impairing cardiovascular function, fluid homeostasis, and host defense. The lymphatics of the gut are a multifunctional transport system that normally serves as a delivery and surveillance system for potentially harmfull antigens, optimizing mucosal innate and adaptative immunity. Alcohol increases mesenteric lymph flow, which could potentially be harmful if gut barrier function is compromised, such as after traumatic injury. In such cases increased lymph flow could facilitate delivery of an overwhelming number of pathogens to the lymph node barrier, allowing entry to the systemic circulation, and infection of the heart, lungs and other organs. We recently showed that alcohol modulates the intrinsic contractile cycle of mesenteric lymphatics that provides the driving force for lymph flow. We aim to discover the molecular mechanisms by which alcohol enhances intrinsic lymphatic pumping. Because of the known importance of Ca2+ in smooth muscle contraction, we developed a novel method to measure cytosolic [Ca2+] in isolated rat collecting lymphatics. Our preliminary data indicate that alcohol modulates phasic contractions of lymphatic vessels by decreasing the frequency yet increasing the magnitude of cyclic mobilizations of Ca2+ from internal stores. Alcohol also inhibits the lymphatic myogenic constriction in response to increases in luminal pressure. However, alcohol does not inhibit the associated gradual increase in cytosolic [Ca2+] during the diastolic phase of the contractile cycle, which suggests that the inhibition of myogenic constriction may instead be due to impaired sensitivity to Ca2+. We hypothesize that alcohol decreases the frequency and increases the magnitude of Ca2+ mobilization in lymphatic smooth muscle to cause less frequent but larger contractions, and in addition decreases mesenteric lymphatic tone by inhibiting Ca2+-sensitizing mechanisms. We will test this hypothesis with two Specific Aims: 1) to test the prediction that acute alcohol intoxication induced-changes in the lymphatic phasic contraction pattern are caused by an altered cyclic mobilization of Ca2+, and 2) to demonstrate that alcohol intoxication inhibits Ca2+ sensitization in lymphatic smooth muscle, causing a decrease in tone and loss of myogenic responsiveness. We will utilize an established rat model of acute alcohol intoxication in combination with our novel method to simultaneously track changes in cytosolic [Ca2+] and intrinsic pump function in isolated mesenteric lymphatics. In addition, pharmacological interventions will be combined with biochemical analyses of key signaling molecules to determine the underlying Ca2+- dependent and Ca2+-sensitizing mechanisms impacted by alcohol intoxication. The successful completion of these studies will reveal the lymphatic contractile mechanisms impacted by alcohol intoxication, this will advance our knowledge on how alcohol intoxication disrupts immunity in the digestive tract. This information will also enable development of useful therapeutic strategies to prevent infections that hamper cardio- pulmonary function in alcohol-intoxicated trauma victims.

描述（由申请人提供）：酒精中毒会损害心血管功能、体液稳态和宿主防御，从而使损伤和感染复杂化。肠道淋巴管是一个多功能运输系统，通常充当潜在有害抗原的传递和监视系统，优化粘膜先天性和适应性免疫。酒精会增加肠系膜淋巴流量，如果肠道屏障功能受损（例如外伤后），这可能会有害。在这种情况下，淋巴流量增加可能会促进大量病原体输送到淋巴结屏障，从而进入体循环，并感染心脏、肺和其他器官。我们最近表明，酒精调节肠系膜淋巴管的内在收缩周期，为淋巴液流动提供驱动力。我们的目标是发现酒精增强内在淋巴泵的分子机制。由于已知 Ca2+ 在平滑肌收缩中的重要性，我们开发了一种新方法来测量离体大鼠收集淋巴管中的胞质 [Ca2+]。我们的初步数据表明，酒精通过降低内部储存的 Ca2+ 循环动员的频率并增加其幅度来调节淋巴管的阶段性收缩。酒精还会抑制淋巴管因管腔压力增加而发生肌源性收缩。然而，酒精不会抑制收缩周期舒张期相关的胞质 [Ca2+] 逐渐增加，这表明肌源性收缩的抑制可能是由于对 Ca2+ 的敏感性受损。我们假设酒精会降低淋巴平滑肌中 Ca2+ 动员的频率并增加其幅度，从而导致频率降低但幅度更大的收缩，此外还通过抑制 Ca2+ 敏化机制来降低肠系膜淋巴张力。我们将通过两个具体目标来检验这一假设：1) 检验急性酒精中毒引起的淋巴相收缩模式变化是由 Ca2+ 循环动员改变引起的预测，2) 证明酒精中毒抑制淋巴平滑肌中的 Ca2+ 敏化，导致张力降低和肌源性反应性丧失。我们将利用已建立的急性酒精中毒大鼠模型与我们的新方法相结合，同时跟踪离体肠系膜淋巴管中胞质 [Ca2+] 和内在泵功能的变化。此外，药物干预措施将与关键信号分子的生化分析相结合，以确定酒精中毒影响的潜在 Ca2+ 依赖性和 Ca2+ 敏化机制。这些研究的成功完成将揭示酒精中毒影响的淋巴收缩机制，这将增进我们对酒精中毒如何破坏消化道免疫力的认识。这些信息还将有助于制定有用的治疗策略，以预防妨碍酒精中毒创伤受害者心肺功能的感染。