Role of ECM and inflammatory remodeling in alcohol-induced liver and lung damage-diversity supplement

ECM和炎症重塑在酒精性肝肺损伤中的作用-多样性补充

• 批准号: 9121282
• 负责人: Gavin E Arteel
• 金额: $ 2.3万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9121282
• 关键词: Accounting; Acute; Acute Lung Injury; Address; Alcohol abuse; Alcohol consumption; Alcohol-Induced Disorders; Alcoholic Liver Diseases; Alcohols; Animals; Cells; Chronic; Clinical; Data; Deposition; Disease; Endotoxemia; Epithelial Cells; Ethanol; Event; Extracellular Matrix; Fibrin; Fibrinolysis; Functional disorder; Gastrointestinal tract structure; Genetic Engineering; Goals; Health; Hepatic; Hepatotoxicity; Hypoxemia; In Situ; In Vitro; Incidence; Individual; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Intestines; Investigation; Kupffer Cells; Laboratories; Lead; Life; Link; Liver; Lung; Lung Inflammation; Mediating; Mediator of activation protein; Modeling; Morbidity - disease rate; Mus; Nicotinic Receptors; Organ; Peptide Hydrolases; Plasminogen Activator Inhibitor 1; Predisposition; Preparation; Pulmonary Edema; Relative (related person); Risk; Role; Series; Structure of parenchyma of lung; Testing; Tissues; Translating; Up-Regulation; Work; alcohol effect; alcohol exposure; alcohol response; base; in vivo; liver inflammation; liver injury; lung injury; mortality; novel; novel therapeutic intervention; nutrition; problem drinker; response; targeted treatment

DESCRIPTION (provided by applicant): The overarching theme of this project is to study the role of nutrition and gut flora/intestinal dysfunction on alcohol-induced organ injury. We will focus on two organs that are the most common victims of chronic alcohol abuse: liver and lung. Specifically, we will examine how alcohol activates tissue remodeling in liver and lung through the induction of plasminogen activator inhibitor-1 (PAI-1) and the consequences of these events. Novel in vitro and in vivo approaches will be used to address mechanisms of action with the goal of identifying new targets for intervention. We propose that liver and lung share similar mechanisms of organ damage in response to alcohol. We specifically propose that PAI-1 induction and subsequent extracellular matrix (ECM) remodeling are key to the early inflammatory changes in both organs. Considering observations linking the effects of alcohol on tissue remodeling in both organs, we further propose that liver and lung not only share mechanisms of injury in response to alcohol, but that these mechanisms are linked and represent interdependent events. Based on these observations and other preliminary data, this proposal will test the hypothesis that alcohol, through the activation of nicotinic acetylcholine receptors (nAChRs), induces the expression of PAI-1 in both liver (e.g., Kupffer cells) and lung (Type II epithelial cells). This, in turn, triggers a series of downstream events that promote live and lung injury in response to endotoxemia derived from the GI tract. Moreover, we propose that liver-derived mediators further exacerbate lung injury through the induction of inflammation and tissue remodeling enhanced by inhibition of fibrinolysis. These hypotheses will be tested in the following Specific Aims: Aim 1: To explore the role of PAI-1 and nAChRs in the susceptibility of liver and lung to acute injury observed in the setting of chronic alcohol exposure. We hypothesize that alcohol stimulates the expression of PAI-1 in both liver and lung cells through effects on specific nAChRs. This in turn sensitizes both organs to acute injury (e.g. LPS). Aim 2: To test the hypothesis that liver-derived mediators are involved in pulmonary changes caused by chronic alcohol exposure and LPS- related organ damage. We propose that alcohol-induced damage to the liver sensitizes the host to acute lung injury in at-risk individuals. To test this, e plan to evaluate the effects of alcohol on lung injury in animals with reduced hepatotoxicity using genetically engineered and chimeric mice. Aim 3: To determine the role of gut- derived products on alcohol-induced lung damage. Gut changes/injury caused by alcohol consumption could directly or indirectly damage liver and lung tissue. However, how gut:lung or gut:liver:lung interactions are influenced by alcohol remains unknown. We propose to test these concepts, and to explore the effect of novel therapeutic interventions that target the GI tract to protect th lung.

描述（由申请人提供）：该项目的总体主题是研究营养和肠道菌群/肠道功能障碍在酒精引起的器官损伤中的作用。我们将专注于两个器官，这些器官是慢性酒精滥用的最常见受害者：肝脏和肺。具体而言，我们将通过诱导纤溶酶原激活剂抑制剂1（PAI-1）的诱导以及这些事件的后果来研究酒精如何激活肝脏和肺的组织重塑。新型体外和体内方法将用于解决作用机理，目的是确定新的干预目标。我们建议肝脏和肺部对酒精的响应具有相似的器官损伤机制。我们特别建议PAI-1诱导和随后的细胞外基质（ECM）重塑是两个器官早期炎症变化的关键。考虑到将酒精对两个器官组织重塑的影响联系起来的观察结果，我们进一步提出，肝脏和肺部不仅共享响应酒精的损伤机制，而且这些机制是连接的并代表了相互依存的事件。基于这些观察结果和其他初步数据，该提案将检验以下假设：酒精通过激活烟碱乙酰胆碱受体（NACHRS），诱导PAI-1在肝脏（例如Kupffer细胞）和肺（II型上皮细胞）中的表达。反过来，这又触发了一系列下游事件，这些事件促进了胃肠道的内毒素血症，促进了生命和肺部损伤。此外，我们提出，通过诱导炎症和组织重塑，通过抑制纤维蛋白溶解增强了肝脏介质进一步加剧肺损伤。这些假设将在以下特定目的中进行检验：目标1：探索PAI-1和NACHR在肝脏和肺对慢性酒精暴露时观察到的急性损伤的敏感性中的作用。我们假设酒精通过对特定NACHR的影响刺激肝脏和肺细胞中PAI-1的表达。这反过来敏感了两个器官对急性损伤（例如LPS）。目的2：测试以下假设：肝脏衍生的介体参与由慢性酒精暴露和LPS相关器官损伤引起的肺变化。我们建议酒精引起的对肝脏的损害使宿主对处于危险的个体中的急性肺损伤敏感。为了测试这一点，E计划评估酒精对使用肝毒性降低的动物肺损伤的影响 基因工程和嵌合小鼠。目标3：确定肠道衍生产品在酒精引起的肺损伤中的作用。饮酒引起的肠道变化/损伤可能直接或间接损害肝脏和肺组织。但是，肠道：肺或肠道：肝脏：肺相互作用受到酒精的影响仍然未知。我们建议测试这些概念，并探索针对胃肠道保护肺部的新型治疗干预措施的效果。