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Alveolar Macrophage Gene Expression Is Altered in the Setting of Alcohol Use Disorders

Authors

  • Ellen L. Burnham,

    1. From the Department of Medicine (ELB, TLP, RH, RWV, MM, JG), Division of Pulmonary Sciences and Critical Care Medicine; Department of Psychiatry (RH), University of Colorado School of Medicine, Denver, Colorado.
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  • Tzu L. Phang,

    1. From the Department of Medicine (ELB, TLP, RH, RWV, MM, JG), Division of Pulmonary Sciences and Critical Care Medicine; Department of Psychiatry (RH), University of Colorado School of Medicine, Denver, Colorado.
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  • Robert House,

    1. From the Department of Medicine (ELB, TLP, RH, RWV, MM, JG), Division of Pulmonary Sciences and Critical Care Medicine; Department of Psychiatry (RH), University of Colorado School of Medicine, Denver, Colorado.
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  • R. William Vandivier,

    1. From the Department of Medicine (ELB, TLP, RH, RWV, MM, JG), Division of Pulmonary Sciences and Critical Care Medicine; Department of Psychiatry (RH), University of Colorado School of Medicine, Denver, Colorado.
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  • Marc Moss,

    1. From the Department of Medicine (ELB, TLP, RH, RWV, MM, JG), Division of Pulmonary Sciences and Critical Care Medicine; Department of Psychiatry (RH), University of Colorado School of Medicine, Denver, Colorado.
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  • Jeanette Gaydos

    1. From the Department of Medicine (ELB, TLP, RH, RWV, MM, JG), Division of Pulmonary Sciences and Critical Care Medicine; Department of Psychiatry (RH), University of Colorado School of Medicine, Denver, Colorado.
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Reprint requests: Ellen L. Burnham, MD, MS, 12700 E. 19th Ave, Mailstop C272, Aurora, CO 80045; Tel: 303-724-6078; Fax: 303-724-6042; E-mail:ellen.burnham@ucdenver.edu

Abstract

Background:  Alcohol use disorders (AUDs) are associated with an increased susceptibility to a variety of common and devastating pulmonary diseases including community- and hospital-acquired pneumonias, as well as the acute respiratory distress syndrome (ARDS). Alveolar macrophages play an important role in preventing the development of these disorders through maintaining lung sterility and resolving lung inflammation. Although alcohol exposure has been associated with aberrant alveolar macrophage function in animal models, the clinical relevance of these observations in humans is not established. Therefore, we sought to determine the effects of AUDs on human alveolar macrophage gene expression.

Methods:  Whole genome microarray analysis was performed on alveolar macrophages obtained by bronchoalveolar lavage from a test cohort of subjects with AUDs (n = 7), and controls (n = 7) who were pair-matched on age, gender, and smoking. Probe set expression differences in this cohort were validated by real-time reverse transcription-polymerase chain reaction (RT RT-PCR). Functional analysis with web-based bioinformatics tools was utilized with microarray data to assess differentially expressed candidate genes (p < 0.01) based on alcohol consumption. Alveolar macrophage mRNA samples from a second cohort of subjects with AUDs (n = 7) and controls (n = 7) were used to confirm gene expression differences related to AUDs.

Results:  In both the test and the confirmatory cohorts, AUDs were associated with upregulation of alveolar macrophage gene expression related to apoptosis, including perforin-1, granzyme A, and CXCR4 (fusin). Pathways governing the regulation of progression through cell cycle and immune response were also affected, as was upregulation of gene expression for mitochondrial superoxide dismutase. Overall, 12 genes’ expression was affected by AUDs independent of smoking.

Conclusions:  Alcohol use disorders are associated with unique changes in human alveolar macrophage gene expression. Novel therapies targeting alveolar macrophage gene expression in the setting of AUDs may prove to be clinically useful in limiting susceptibility for pulmonary disorders in these individuals.

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