Chronic alcohol abuse increases patients'risk of developing Acute Respiratory Distress Syndrome (ARDS) and respiratory infections. In the lung, chronic alcohol ingestion reduces peroxisome proliferator- activated receptor gamma (PPARg) levels and increases transforming growth factor beta-1 (TGF21) expression, leading to alveolar macrophage (AM) alternative activation and dysfunction. These alcohol- induced derangements can be reversed by treatment with PPARg ligands, such as pioglitazone and rosiglitazone. The studies outlined in this proposal will examine the effect of alcohol on AM PPARg expression and activity as modulated by microRNAs (Aim 1). Then, we will determine the capacity of PPARg ligands to reverse alcohol-mediated AM dysfunction (Aim 2). These hypotheses will be investigated by performing various experiments on a murine model of chronic alcohol consumption and an in vitro ethanol exposed mouse AM cell line, MH-S. We will evaluate whether chronic alcohol exposure compromises PPARg signaling in AMs, how ethanol-induced alterations in microRNAs modulate PPARg, and whether treatment with PPARg ligands can upregulate ethanol-mediated reductions in AM PPARg. Further, we will determine whether PPARg ligands can attenuate ethanol-induced AM TGF21, alternative activation and dysfunction. The studies outlined in this proposal will demonstrate that treatment with PPARg ligands has potential to identify a novel therapeutic approach to ameliorating alcohol-mediated AM dysfunction and associated susceptibility to lung injury and infection. If successful, this line of investigation could have considerable translational impact on the management of patients with alcohol abuse disorders. With support from this NRSA grant, mentorship by well-established researchers, and opportunities and resources available at Emory University's Alcohol and Lung Biology Center, the next one year will be used to hone my molecular biology techniques by attending courses offered at Emory University, collect critical preliminary data for subsequent K-series grant applications, present research findings at national meetings, and gain experience in manuscript writing and grant preparation, with the ultimate goal of progressing towards a career as an independent scientist in biomedical research.
Alcoholics have an increased risk of developing respiratory infections, such as bronchitis and pneumonia, due to impaired function of alveolar macrophages to clear infectious particles. PPARg receptor ligands, which include synthetic thiazolidinedione (TZD) medications such as pioglitazone and rosiglitazone, have been found to reduce chronic alcohol-induced hepatic steatosis and inflammation involving Kupffer cells. The studies outlined in this proposal will determine whether PPARg ligand treatment can upregulate PPARg to improve alcohol-induced alveolar macrophage dysfunction and be a novel therapy in reducing respiratory infections among patients with a history of alcohol abuse.
|Yeligar, Samantha M; Ward, Janine M; Harris, Frank L et al. (2017) Dysregulation of Alveolar Macrophage PPAR?, NADPH Oxidases, and TGF?1 in Otherwise Healthy HIV-Infected Individuals. AIDS Res Hum Retroviruses 33:1018-1026|
|Yeligar, Samantha M; Mehta, Ashish J; Harris, Frank L et al. (2016) Peroxisome Proliferator-Activated Receptor ? Regulates Chronic Alcohol-Induced Alveolar Macrophage Dysfunction. Am J Respir Cell Mol Biol 55:35-46|
|Yeligar, Samantha M; Harris, Frank L; Hart, C Michael et al. (2014) Glutathione attenuates ethanol-induced alveolar macrophage oxidative stress and dysfunction by downregulating NADPH oxidases. Am J Physiol Lung Cell Mol Physiol 306:L429-41|