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.

Public Health Relevance

Alcohol-induced organ damage is a major health concern. The liver and lungs are major target organs of alcohol damage, but the mechanisms of injury remain unclear and there are no therapies for these diseases. This project test the overall hypothesis that liver and lung inflammation caused by ethanol is mediated by fibrin ECM deposition. Taken together, these studies will establish new models of alcoholic injury, explore multiple overlapping mechanisms and provide novel targets for therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
1R01AA021978-01
Application #
8435101
Study Section
Special Emphasis Panel (ZRG1-DKUS-D (03))
Program Officer
Radaeva, Svetlana
Project Start
2014-02-01
Project End
2019-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
1
Fiscal Year
2014
Total Cost
$337,500
Indirect Cost
$112,500
Name
University of Louisville
Department
Pharmacology
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292