Alveolar Macrophage Oxidative Stress and Metabolic Dysfunction During Chronic Alcohol Use Open Access

Abstract

Nearly 11% of the adult population in the United States have an alcohol use disorder (AUD), characterized by an inability to resist alcohol use despite adverse effects. Chronic alcohol consumption is injurious across multiple tissues and the causes of cellular injury due to chronic alcohol exposure are multifactorial. Alcohol misuse severely impairs many aspects of immune regulation and immune cell function, which predisposes people with AUDs to acute or chronic diseases. Alveolar macrophages are the first line of defense against pathogens in the lower respiratory tract, but alcohol misuse decreases alveolar macrophage function, leading to increased risk of pneumonia and acute respiratory distress syndrome in people with AUDs. Mechanisms of decreased alveolar macrophage function due to alcohol misuse include diminished phagocytic capacity and cellular and mitochondrial oxidative stress. These studies use alveolar macrophages isolated from humans with AUDs and various models of chronic alcohol exposure in combination with agents meant to either decrease oxidative stress or reverse metabolic bioenergetics dysfunction. The extent of metabolic impairment due to chronic alcohol exposure was characterized and included alcohol-induced alterations in glycolysis, hexosamine biosynthesis, and oxidation of pyruvate, glutamine, or long chain fatty acids that are preferred for cellular energy generation. Impaired alveolar macrophage phagocytosis was reversed through improved bioenergetic phenotype using the peroxisome-proliferator activated receptor gamma ligand, pioglitazone. These studies have demonstrated that targeting AM metabolic or bioenergetic dysfunction is a viable strategy to improve AM phagocytosis during chronic alcohol misuse. This work in alcohol misuse expands on the knowledge of alveolar macrophage oxidative stress pathways and mitochondrial biology, since alcohol misuse impairs mitochondrial metabolism pathways necessary for bioenergetics. These approaches can be applied to other pathological conditions characterized by mitochondrial dysfunction, resulting in dysregulation of lung immunity.

Table of Contents

Table of Contents

List of Figures & Tables. 1

List of Abbreviations. 7

Chapter 1: Introduction. 15

1.1 A Critical Review of Recent Knowledge Gained on Alcohol’s Effects on the Immunological Response in Different Tissues. 18

Abstract 20

Introduction. 21

Alcohol-Associated Neuroinflammation. 22

Alcohol Misuse and Advanced Age. 24

Alcohol-Induced Lung Dysfunction. 26

Alcohol-Mediated Liver Inflammation and Disease. 30

Alcohol’s Effects on the Gut and Organ Crosstalk. 33

Conclusion. 38

Chapter 2: Clinical Evaluation of Oral Zinc, S-adenosylmethionine (SAMe), or Combination Supplementation to Improve Alveolar Macrophage Function in People with Alcohol Use Disorders. 41

2.1 Evaluation of Oral Zinc, S-Adenosylmethionine, or Combination Therapy to Decrease Alveolar Macrophage Oxidative Stress in Participants with Alcohol Use Disorders: Blinded and Randomized Clinical Trial 43

Abstract 44

Introduction. 46

Materials & Methods. 48

Results. 53

Discussion. 56

Tables & Figures. 60

2.2 Conclusions. 76

Chapter 3: Application of Pioglitazone to Improve Alcohol-Induced Alveolar Macrophage Metabolic and Phagocytic Dysfunction​ 77

3.1 Alcohol-Induced Glycolytic Shift in Alveolar Macrophages Is Mediated by Hypoxia-Inducible Factor-1 Alpha. 79

Abstract 80

Introduction. 82

Materials & Methods. 84

Results. 92

Discussion. 97

Figures. 104

Supplementary Material 125

3.2 Pioglitazone Reverses Alcohol-Induced Alterations in Alveolar Macrophage Mitochondrial Phenotype. 128

Abstract 130

Introduction. 132

Materials & Methods. 135

Results. 143

Discussion. 148

Tables & Figures. 156

Supplemental Figures. 174

3.3 Conclusions. 178

Chapter 4: Other Alterations in Pulmonary Cell Function due to Changes in Metabolism.. 180

4.1 Hyaluronic Acid Dynamics Affect Alveolar Macrophage Mitochondrial and Phagocytic Function. 184

4.1.1 Excerpt from: New Insights into the Mechanism of Alcohol-Mediated Organ Damage via its Impact on Immunity, Metabolism, and Repair Pathways: A Summary of the 2021 Alcohol and Immunology Research Interest Group (AIRIG) Meeting. 185

4.1.2 Excerpt from: Alcohol and Immunology: Mechanisms of Multi-Organ Damage. Summary of the 2022 Alcohol and Immunology Research Interest Group (AIRIG) Meeting. 193

4.2 Preliminary Data: Chronic Alcohol Exposure Increases Lung Hyaluronic Acid. 201

Abstract 202

Introduction. 204

Methods & Materials. 207

Results. 213

Discussion. 217

Tables & Figures. 219

Supplemental Figures. 227

4.3 Hyaladherins May be Implicated in Alcohol-Induced Susceptibility to Bacterial Pneumonia. 230

Abstract 231

Introduction. 232

Extracellular Matrix in the Lung. 232

Hyaluronic Acid Signaling: Hyaladherins and Hyaluronic Acid-Protein Interactions. 233

Discussion. 241

Controversies in the Hyaluronic Acid Field. 242

Therapeutic Potential 244

Figures. 247

4.4 Application of Hyaluronic Acid in Pulmonary Hypertension. 248

4.4. Conclusions. 251

Chapter 5: Perspectives & Contributions Toward Other Fields. 253

5.1 Perspectives. 253

5.2 Collaborations & Contributions to Other Fields. 256

5.2.1 Regulator of G protein Signaling 14 Affects Mitochondrial Function in Human Embryonic Kidney 293T Cells. 257

5.2.2 Activation of ATP-Dependent Clp protease (ClpXP) Affects Mitochondrial Function in Human Aortic Smooth Muscle Cells. 262

5.3 Conclusions. 266

Chapter 6: Discussion & Future Directions. 267

6.1 Discussion. 267

6.2 Future Directions. 274

References. 278

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Molecular & Systems Pharmacology
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Cell Health Sciences, Immunology Health Sciences, Pharmacology
Keyword	Alcohol use disorder Immunometabolism Oxidative stress Immunity Pneumonia Mitochondria Lung Energy metabolism Alveolar macrophage
Committee Chair / Thesis Advisor	Samantha M. Yeligar, Emory University
Committee Members	Roy Sutliff, National Heart, Lung, and Blood Institute, National Institutes of Health Eric Ortlund, Emory University Kathy Griendling, Emory University

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