Alcohol use disorders are a major burden to society. The medical consequences for alcoholism include an increased susceptibility to lung injury and infection. Currently, there are no therapeutic options for the pulmonary complications of alcohol abuse, but animal models have suggested that chronic alcohol ingestion impairs the absorption and distribution of zinc to the lung. This pulmonary zinc deficiency impairs function of the alveolar macrophage, which is the resident immune cell of the lower airways. However, human studies are lacking. The objective of this research project is to better characterize zinc status and immune function in the lung among individuals who abuse alcohol. Otherwise healthy alcoholic subjects (n=17) and matched non-alcoholic subjects (n=17) were recruited to receive a blood draw for serum zinc measurement and to undergo bronchoscopy for collection of alveolar macrophages. These isolated phagocytes were analyzed for intracellular zinc and immune function, which was determined by measuring phagocytic capacity and cell surface expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor. Alcoholic subjects had normal serum zinc values, but alcohol abuse was associated with significantly lower alveolar macrophage intracellular zinc levels even after adjustments are made for important confounders such as cigarette smoking (adjusted mean difference (se) = -277.8 (121.7) RFU/cell; p = 0.0305). Importantly, there was no relationship between serum zinc and alveolar macrophage intracellular zinc levels, suggesting that serum measurements are a poor surrogate marker of pulmonary zinc status (Spearman's r = -0.129; p = 0.48). Further, alcoholism was associated with significantly decreased immune function as measured by both phagocytosis and GM-CSF receptor expression. There was a significant correlation between intracellular zinc level and immune function, providing provocative evidence that alcohol-induced immune dysfunction may be the result of zinc deficiency (Spearman's r = 0.68; p < 0.0001). These data provide important validation of animal models of chronic alcohol ingestion and argue that clinical trials be undertaken to further investigate the potential therapeutic value of zinc supplements in this vulnerable population.
Table of Contents
INTRODUCTION 1 BACKGROUND 4 METHODS 9 Characteristics of the study population 9 Bronchoscopy and laboratory procedures 11 Variables 12 Power and sample size considerations 12 Analytic plan 13 RESULTS 14 Subject enrollment 14 Subject characteristics 14 Serum zinc levels 15 Intracellular zinc levels 15 Immune function 15 Relationship between intracellular zinc and immune function 17 Impact of drug abuse 17 DISCUSSION 18 REFERENCES 23 TABLES/GRAPHS 31 Table 1 - Power and sample size considerations 31 Table 2 - Demographic characteristics of the study population 32 Table 3 - Determinants of alveolar macrophage intracellular zinc levels 33 Table 4 - Determinants of alveolar macrophage phagocytosis 34 Table 5 - Determinants of alveolar macrophage GM-CSF receptor expression 35 Table 6 - Impact of drug use on intracellular zinc and immune function 36 Figure 1 - Proposed causal diagram for the effect of alcohol abuse on the lung 37 Figure 2 - Recruitment of study subjects 37 Figure 3 - Distribution of serum zinc measurements 38 Figure 4 - Distribution of alveolar macrophage intracellular zinc levels 38 Figure 5 - Relationship between serum zinc and intracellular zinc levels 39 Figure 6 - Distribution of alveolar macrophage phagocytosis 39 Figure 7 - Distribution of alveolar macrophage GM-CSF receptor expression 40 Figure 8 - Relationship between phagocytosis and GM-CSF receptor expression 40 Figure 9 - Relationship between intracellular zinc levels and immune function 41
About this Master's Thesis
|Committee Chair / Thesis Advisor|
|The Role of Zinc Deficiency in the Alcohol Lung Phenotype ()||2018-08-28||