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

描述（由申请人提供）：本项目的首要主题是研究营养和肠道植物群/肠道功能障碍对酒精诱导的器官损伤的作用。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。具体来说，我们将研究酒精如何激活组织重塑肝脏和肺通过诱导纤溶酶原激活物抑制剂-1（派-1）和这些事件的后果。新的体外和体内方法将用于解决行动机制，目的是确定新的干预目标。我们认为肝脏和肺在酒精引起的器官损伤中有相似的机制。我们特别提出派-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，肝脏和肺不仅共享响应酒精的损伤机制，而且这些机制是相互关联的，代表着相互依赖的事件。基于这些观察结果和其他初步数据，该提议将检验以下假设：酒精通过激活烟碱乙酰胆碱受体（nAChR）诱导两个肝脏中派-1的表达（例如，枯否细胞）和肺（II型上皮细胞）。这反过来又引发了一系列下游事件，这些事件促进了对源自胃肠道的内毒素血症的肝和肺损伤。此外，我们认为肝源性介质通过诱导炎症和抑制纤维蛋白溶解增强的组织重塑进一步加重肺损伤。这些假设将在以下具体目标中进行测试：目标1：探索派-1和nAChR在慢性酒精暴露环境中观察到的肝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定nAChRs的影响刺激肝脏和肺细胞中派-1的表达。这反过来又使两个器官对急性损伤（例如LPS）敏感。目标二：检验肝源性介质参与慢性酒精暴露和LPS相关器官损伤引起的肺变化的假设。我们认为，酒精引起的肝脏损伤使高危个体的宿主对急性肺损伤敏感。为了验证这一点，我们计划用肝毒性降低的动物来评估酒精对肺损伤的影响， 基因工程和嵌合小鼠。目的3：确定肠源性产物在酒精性肺损伤中的作用。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。然而，肠：肺或肠：肝：肺的相互作用如何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的新型治疗干预措施的效果。

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.