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

描述(申请人提供)：本项目的主要主题是研究营养和肠道菌群/肠道功能障碍在酒精诱导的器官损伤中的作用。我们将重点关注慢性酒精滥用最常见的两个器官：肝脏和肺。具体地说，我们将研究酒精如何通过诱导纤溶酶原激活物抑制物-1(PAI-1)激活肝脏和肺的组织重塑以及这些事件的后果。新的体外和体内方法将被用来解决作用机制，目的是确定新的干预目标。我们认为，肝脏和肺在对酒精的反应中具有相似的器官损伤机制。我们特别提出，PAI-1的诱导和随后的细胞外基质(ECM)重构是这两个器官早期炎症变化的关键。考虑到酒精对两个器官组织重塑的影响，我们进一步提出，肝脏和肺不仅分享酒精反应的损伤机制，而且这些机制是相互联系的，代表相互依赖的事件。基于这些观察和其他初步数据，这项建议将检验以下假设：酒精通过激活烟碱型乙酰胆碱受体(NAChRs)，诱导肝脏(例如Kupffer细胞)和肺(II型上皮细胞)中PAI-1的表达。这反过来会触发一系列下游事件，促进肝脏和肺损伤，以应对源自胃肠道的内毒素血症。此外，我们认为肝源性介质通过诱导炎症和组织重塑而进一步加重肺损伤，这些炎症和组织重塑通过抑制纤溶而增强。这些假说将在以下特定目标进行验证：目的1：探讨PAI-1和nAChRs在慢性酒精暴露下肝脏和肺对急性损伤的易感性中的作用。我们假设酒精通过对特异性nAChRs的作用刺激肝和肺细胞PAI-1的表达。这反过来又使两个器官对急性损伤(如脂多糖)敏感。目的：验证肝源性介质参与慢性酒精暴露和内毒素相关脏器损伤所致肺损伤的假说。我们认为，酒精对肝脏的损伤会使高危个体的宿主对急性肺损伤敏感。为了测试这一点，我们计划评估酒精对肝毒性降低的动物的肺损伤的影响。 基因工程和嵌合小鼠。目的3：探讨肠源性物质在酒精性肺损伤中的作用。饮酒引起的肠道改变/损伤可直接或间接损害肝脏和肺组织。然而，酒精如何影响肠道：肺或肠道：肝脏：肺的相互作用仍不清楚。我们建议测试这些概念，并探索以胃肠道为靶点的新型治疗干预措施保护肺的效果。

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.