Date on Master's Thesis/Doctoral Dissertation
Pharmacology and Toxicology
Pharmacology and Toxicology, PhD
States, J. Christopher
Background. Individuals who chronically abuse alcohol are almost 4 times more likely to develop Acute Respiratory Distress Syndrome (ARDS), the most severe form of Acute Lung Injury (ALI), but the mechanisms by which alcohol abuse sensitizes the lung to injury are poorly understood. However, the lung appears to share many parallel mechanisms of injury with the liver- a primary target of alcohol abuse. The overarching goal of this dissertation was therefore to expand on established mechanisms of alcohol-induced liver injury to ask innovative questions about mechanisms of alcohol-enhanced acute lung injury, as well as to develop new tools that may be used to gain novel insight into the liver-lung axis of alcoholinduced injury. Methods. Male mice were exposed to ethanol containing liquid diet either chronically (6 weeks) or in a chronic + binge pattern. Some mice were administered lipopolysaccharide (LPS) to induce acute lung injury. Lung injury and inflammation were assessed. To develop an animal model by which liver-lung interactions could be investigated, tamoxifen-loaded polymer nanoparticles were administered intrasplenically to a tamoxifen-inducible, Cre-mediated, dual-fluorescent reporter construct. Results. Chapter III of this dissertation describes a mechanism by which plasminogen activator inhibitor-1 (PAI-1) is involved in alcoholenhanced acute lung injury. Specifically, it was proposed that PAI-1-mediated fibrin accumulation promotes the aggregation of platelets, thereby propagating lung injury and inflammation. Chapter IV of this dissertation characterizes a recently-developed animal model of chronic + binge alcohol exposure, finding that animals exposed to chronic + binge alcohol exposure exhibit pulmonary inflammation and airway hyperresponsiveness. Finally, Chapter V of this dissertation develops an animal model to investigate liver-lung interactions during chronic alcohol exposure. It was found that tamoxifen-loaded polymer nanoparticles, when administered intrasplenically, selectively alter the genetics of hepatic cells, while avoiding other tissues, including the lung. Discussion. The work presented in this dissertation has, in conclusion, uncovered novel mechanisms by which alcohol sensitizes the lung to a second injury, shown that ethanol alone is sufficient to cause lung inflammation, and developed a novel animal method to examine liver-lung interactions during alcohol exposure.
Poole, Lauren G., "Novel insight into the liver-lung axis in alcohol-enhanced acute lung injury." (2017). Electronic Theses and Dissertations. Paper 2794.
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