Abstract
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
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