The Effect of Ethanol Consumption on Pulmonary Macrophage Maturation and Function Pubblico

Abstract

Abstract
The Effect of Ethanol Consumption on Pulmonary Macrophage Maturation and Function
By
Sheena Denise Brown

Alcohol addiction is a complex multifactorial disease that affects more than 70 million people and contributes to 1 in 25 deaths worldwide. Alcoholics have twice the incidence of intensive care unit-related morbidity and mortality, commonly caused by acute respiratory distress syndrome. This increased risk of respiratory infections is due, in part, to the detrimental effects of alcohol on alveolar macrophage maturation and function. Previous studies have shown that chronic ethanol ingestion leads to increased oxidant stress, increased TGF-β1 production, increased fibronectin production, and decreased phagocytosis in alveolar macrophages. Alternative activation of alveolar macrophages also leads to similar alterations, as well as increased arginase production and activity, events that promote fibroblast proliferation and collagen production in the lung, leading to fibrosis. Our aim was to determine if the altered phenotype of the alveolar macrophage after alcohol abuse is related to alternative activation. Therefore, we hypothesized that chronic oxidant stress induced by chronic ethanol consumption leads to impaired maturation and alternative activation of alveolar macrophages. We also sought to examine the role of TGF-β1, a key player in ethanol-induced lung dysfunction and IL-13 mediated fibrosis. To address this hypothesis, cell culture and rodent models of chronic alcoholism along with alveolar macrophages from otherwise healthy alcoholic subjects were used to examine the potential link between chronic alcohol-induced alterations of alveolar macrophage function and alternative activation. Collectively, these studies demonstrated that chronic ethanol ingestion leads to pulmonary macrophage dysfunction by delaying terminal maturation, impairing phagocytic function, inducing an alternative activation phenotype, increasing endogenous production of reactive oxygen species, and increasing production of TGF-β1. Other studies demonstrated that TGF-β1 was required for IL-13 induced alternative activation and deficits in phagocytic function. Supplementation with the antioxidant glutathione or its precursors prevented or reversed ethanol induced macrophage dysfunction, thereby suggesting ethanol-induced alveolar macrophage dysfunction was modulated by oxidant stress and antioxidant depletion.

Table of Contents

TABLE OF CONTENTS
CHAPTER 1: INTRODUCTION AND BACKGROUND

Chronic Alcoholism...2

Alcoholism: A Major Public Health Concern...2
Defining Alcohol Abuse and Dependence...3
Screening Methods for Diagnosing Alcohol Abuse...5
Chronic Alcoholism and Disease Progression...12

Alcohol Abuse and the Lung...17

Pulmonary Macrophage Dysfunction...21
Alveolar Macrophage Phagocytosis...22
Alveolar Macrophage Activation...23
Alcohol-Induced Alveolar Macrophage Dysfunction...27

Oxidative Stress and Antioxidant Defenses...27

Defining Reactive Oxygen Species and Oxidant Stress...27
Antioxidant Defenses...29

Role of Glutathione in Cellular Homeostasis and Disease Progression...33

Glutathione Synthesis, Transport, and Compartmentalization...33
Role of GSH in Cellular Homoeostasis...37
Diseases Associated With Altered GSH Homeostasis...38

GSH and the Lung...40
Specific Aims...44

CHAPTER 2: CHRONIC ALCOHOL INGESTION IMPAIRS MATURATION AND FUNCTION OF ALVEOLAR MACROPHAGES

Abstract...47
Introduction...48

Materials and Methods...50
Results...54

Discussion...69

CHAPTER 3: REDOX REGULATION OF ALCOHOL-INDUCED ALTERNATIVE ACTIVATION OF ALVEOLAR MACROPHAGES

Abstract...79

Introduction...80

Materials and Methods...82
Results...90
Discussion...116

CHAPTER 4: ROLE OF TGF-Β IN ALTERNATIVE ACTIVATION

Abstract...123
Introduction...124
Materials and Methods...125
Results...130
Discussion...149

CHAPTER 5: CONCLUSIONS, POSSIBLE MECHANISM, AND STUDY LIMITATIONS

Conclusions...153

Study Limitations...158
Genetics and Epidemiology of Alcohol Abuse...158
Alcohol Metabolism: Liver vs. the Lung...159
Liber-Decarli Model of Alcohol Abuse...160
SB-431542 Mediated Inhibition of TGF-β1...161
Proposed Mechanism...164

CHAPTER 6: REFERENCES

About this Dissertation

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School	Laney Graduate School
Department	Clinical Research Curriculum Program
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Health Sciences, Pharmacology Health Sciences, Toxicology
Parola chiave	Macropahge Lung Dysfunction Alcohol Alveolar Glutathione
Committee Chair / Thesis Advisor	Brown, Lou Ann, Emory University
Committee Members	Sutliff, Roy, Emory University Morgan, Edward T, Emory University Taylor, Kathy, Emory University Hansen, Jason, Emory University

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