Our overall interest is chronic inflammatory lung disease mechanisms in the context of combined alcohol use and cigarette smoking. Some studies report that up to 30% of smokers are heavy alcohol users. The airways of smokers who drink alcohol are more susceptible to bacterial infection and colonization, suggesting a compromise in the protective mucociliary apparatus. We hypothesize that prolonged exposure to the unique combination of cigarette smoking and ethanol consumption results in the impairment of the mucociliary transport apparatus. Large concentrations of malondialdehyde and acetaldehyde are found in the lungs of smoking alcoholics. Accumulation of lung aldehydes results in formation of hybrid aldehyde adducted proteins that produce pro-inflammatory effects parallel to liver necrosis and fibrosis. One such airway protein adduct is the malondialdehyde-acetaldehyde (MAA) adduct. The major mechanism of protein adduct binding to cells is via membrane scavenger receptors. We will explore the relationship between MAA adducts, alcohol consumption, and cigarette smoking with the following specific aims: 1) Determine if co-exposure to the combination of cigarette smoke and alcohol results in unique alterations to the mucociliary transport apparatus. 2) Determine if co-exposure to smoke and alcohol results in the formation of MAA adducts. 3) Identify the scavenger receptor that binds MAA-adducted protein to airway epithelium. 4) Determine the mechanism of action for MAA adduct-mediated cilia slowing. With these aims, we will establish an association between alcohol consumption, cigarette smoking and cilia dysfunction as mediated by MAA adduct formation. While the etiology of chronic inflammatory lung diseases is largely unknown and likely multi-faceted, the study of MAA adduct formation is an innovative approach to the pathologic interaction between cigarette smoke and alcohol. PUBLIC HEALTH SIGNIFICANCE: This study greatly impacts public health. It has long been clinically known that chronic lung disease and lung infections are much more severe in alcoholics. Nearly all alcoholics smoke cigarettes. Our studies seek to define the mechanisms that injure proper lung clearance and health under conditions of combined smoke and alcohol consumption. Understanding the mechanisms of such injury will define the subsequent treatment modalities to restoring normative lung mucociliary clearance function and directly address disease prevention in the approximately 20 million US alcoholics.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA017993-05
Application #
8299082
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Jung, Kathy
Project Start
2008-07-15
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$314,737
Indirect Cost
$100,630
Name
University of Nebraska Medical Center
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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Sapkota, Muna; Kharbanda, Kusum K; Wyatt, Todd A (2016) Malondialdehyde-Acetaldehyde-Adducted Surfactant Protein Alters Macrophage Functions Through Scavenger Receptor A. Alcohol Clin Exp Res 40:2563-2572
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Bell, Wade E; Hallworth, Richard; Wyatt, Todd A et al. (2015) Use of a novel cell adhesion method and digital measurement to show stimulus-dependent variation in somatic and oral ciliary beat frequency in Paramecium. J Eukaryot Microbiol 62:144-8
Poole, Jill A; Anderson, Leigh; Gleason, Angela M et al. (2015) Pattern recognition scavenger receptor A/CD204 regulates airway inflammatory homeostasis following organic dust extract exposures. J Immunotoxicol 12:64-73
Price, Michael E; Pavlik, Jacqueline A; Sisson, Joseph H et al. (2015) Inhibition of protein phosphatase 1 reverses alcohol-induced ciliary dysfunction. Am J Physiol Lung Cell Mol Physiol 308:L577-85

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