Chapter
1.2 Lung Epithelial Composition
1.3 Epithelial Dysfunction in Lung Disease
1.3.2 Environmental Insults
1.4 Epithelia as a Therapeutic Target
1 Junctional Interplay in Lung Epithelial Barrier Function
1.2 Epithelial Cell Polarity Complex
1.3.2 Scaffold-Cytoskeletal Interactions
1.3.3 Cross-talk With Wnt Signaling
1.4.1 Scaffold Proteins and Positioning in the AJC
1.4.2 Claudins and Paracellular Permeability
1.4.3 MarvelD Proteins and Tricellular Junctions
1.4.4 Junctional Adhesion Molecule A
1.5 Gap Junctions and Pannexin Channels
1.5.1 Connexins in Lung Epithelia
1.5.2 Regulation of Barrier Function
1.6 Processes Regulated by Intercellular Communication
1.6.1 Mucociliary Clearance
1.6.2 Pulmonary Surfactant Secretion
1.6.3 Injury and Inflammation
1.7 Summary and Perspectives
2 Ion Transport and Lung Fluid Balance
2.1.1 Overview of the Structure and Function of the Lung Epithelium
2.1.2 Overview of Transbarrier Ion and Fluid Transport
2.1.3 Bioelectric Properties of the Lung Epithelium
2.1.3.1 Epithelial Sodium Channel
2.1.3.2 Other Sodium Transporters, Na+/K+-ATPase
2.1.3.3 Chloride Channels
2.1.3.4 Potassium Channels
2.2 Lung Fluid Balance in the Airways
2.2.1 Regulation of Lung Fluid Balance in the Airways
2.3 Altered Lung Fluid Balance and Disease of the Airways
2.3.2 Chronic Obstructive Pulmonary Disease
2.4 Lung Fluid Balance in the Alveoli
2.4.1 Regulation of Lung Fluid Balance in the Alveoli
2.5 Altered Lung Fluid Balance and Disease of the Alveolar Capillary Membrane
2.5.1 Acute Respiratory Distress Syndrome
2.5.1.1 Pulmonary Edema in ARDS
3 Glucose Transport and Homeostasis in Lung Epithelia
3.2 Glucose Transport and Epithelial Glucose Homeostasis
3.2.1 Glucose Transporters
3.2.1.1 Facilitative Glucose Transporters (GLUT)
3.2.1.2 Sodium-Coupled Glucose Transporters (SGLT)
3.2.1.3 SemiSweet Facilitative Hexose Transporters (SWEETS)
3.3 Glucose Transporters in the Lung
3.3.1 Glucose Transporter mRNA
3.3.2 Glucose Transporter Proteins
3.3.2.3 SemiSweet Facilitative Hexose Transporter
3.3.4 Lung Epithelial Glucose Homeostasis
3.3.4.1 ASL Glucose Concentrations
3.3.4.2 Processes that Determine ASL Glucose Concentrations
3.3.4.2.1 Transepithelial Glucose Gradient and Glucose Diffusion
3.3.4.2.2 Paracellular Pathways
3.3.4.2.3 Transcellular Pathways
3.3.4.2.4 Glucose Transport and Metabolism
3.3.4.3 Regional Differences in Glucose Homeostasis
3.3.5 Abnormalities in Lung Epithelial Glucose Homeostasis—Insights from Cell Culture, Mouse Models, and Human Studies
3.4 Abnormal Epithelial Glucose Homeostasis and Lung Infection
3.4.1 Abnormal Airway Glucose Homeostasis and Bacterial Growth
3.4.1.1 Staphylococcus aureus
3.4.1.2 Pseudomonas aeruginosa
3.4.2 Abnormal Airway Glucose Homeostasis and Innate Immunity
3.4.2.1 Mucociliary Clearance
3.4.2.2 Antimicrobial Factors
3.4.2.4 Taste Receptor Signaling
3.4.2.5 Collagenated Lectins
3.4.2.6 Immune Cell Function
3.4.3 Implications for Human Health
3.4.3.1 People With Diabetes Mellitus Without Chronic Lung Disease
3.4.3.2 People With Chronic Lung Disease who also have Diabetes
3.4.4 Drugs that Restore Airway Glucose Homeostasis
3.4.4.2 Glucose Transporters
3.4.4.3 Blood–Glucose Concentrations
3.4.5 Effect of Drugs that Restore Airway Glucose Homeostasis on Respiratory Infection
3.4.6 Glucose Transporters in Lung Cancer
4 Pulmonary Surfactant Trafficking and Homeostasis
4.2.1 Alveolar Type I Epithelial Cells
4.2.2 Alveolar Type II Epithelial Cells
4.2.3 Other Cells of the Alveolus
4.3.1.1 Phosphatidylcholines and Dipalmitoyl Phosphatidylcholine
4.3.1.2 The Acidic Phospholipids: PG and PI
4.3.1.3 Remaining Phospholipids
4.3.1.4 Neutral Lipids and Cholesterol
4.4.1 Hydrophobic Peptides: SP-B and SP-C
4.4.2 Hydrophilic Multimers: SP-A and SP-D
4.5.1 Biogenesis of Lamellar Bodies
4.6 Exocytosis of Lamellar Bodies and Surfactant
4.6.1 Regulated Secretion of Lamellar Bodies
4.7 Endocytosis of Surfactant
4.8 Endocytic Vesicle Trafficking
4.9 Surfactant Catabolism
5 Integrin Regulation of the Lung Epithelium
5.1 Lung Extracellular Matrix in Development, Homeostasis, and Repair
5.1.1 ECM Proteins of the Pulmonary Interstitium
5.1.1.2 Interstitial Collagens
5.1.2 ECM Proteins of the Lung Basement Membrane
5.1.2.3 Other Lung Basement Membrane Proteins
5.2 Integrins are the Principal Receptors for ECM
5.3 Integrins in Lung Development, Alveolar Homeostasis, and Disease
5.4 β1 Integrin—The Central Integrin Subunit
5.5 Laminin-Binding Integrins
5.6 Collagen-Binding Integrins
5.7 RGD-Binding Integrins
5.7.1 RGD-Binding Integrins as ECM Receptors
5.7.2 RGD-Binding Integrins as TGF-β Activators
6 Epithelial Regeneration and Lung Stem Cells
6.1 Lung Epithelial Stem/Progenitor Cells
6.1.1 Stem/Progenitor Cells of the Conducting Airway Epithelium
6.1.1.3 Neuroepithelial Bodies
6.1.2 Stem/Progenitor Cells of the Alveolar Epithelium
6.2 Mechanisms/Pathways of Repair by Airway Progenitors
6.2.2.1 Functions of Purinergic Receptors in Airway Repair
6.2.2.2 Role of Tissue Factor in Airway Epithelial Basal Cell Function
7 The Function of Epithelial Cells in Pulmonary Fibrosis
7.1.1 Apoptosis and Senescence
7.2 Epithelial–Mesenchymal Transition
7.3 Epithelial Gene Mutations and Familial Fibrosis
7.4 Paracrine Functions of Epithelial Cells During Fibrosis
7.4.1 Epithelial Cell Cross-talk with Other Cell Types
7.4.2 Proteins Expressed by the Epithelium Implicated in Fibrogenesis
7.5 Reepithelization versus Progressive Fibrosis
7.5.1 Stem and Progenitor Cells versus Epithelial Cell Plasticity
7.5.2 Pathways of Regeneration
7.5.3 Regeneration of the Damaged Matrix
8 The Role of Epithelial Cell Quality Control in Health and Disease of the Distal Lung
8.2 AT2 Cells and the Biosynthetic Challenge of Surfactant
8.3 A New “Old” Hypothesis: Alveolar Epithelial Dysfunction and Parenchymal Lung Disease
8.4 Cellular Quality Control
8.5 Epithelial Dysfunction is Induced By Surfactant Protein C Mutations
8.5.1 Aberrant Cellular Responses to Other Surfactant Component Substrates
8.5.2 AT2 Quality Control Responses to Surfactant Component Mutants
8.6 Linking Epithelial Dysfunction in vitro to Fibrotic Remodeling in vivo
8.7 Quality Control Issues in Other Parenchymal Lung Diseases
8.8 Unanswered Questions, New Approaches, and Opportunities
9 The Respiratory Epithelium in COPD
9.4 Epithelial Dysfunction in COPD
9.4.1 Physical Barrier Dysfunction
9.4.2 Mucociliary Dysfunction
9.4.3 Airway Repair Dysfunction
9.4.4 Alteration of the Immune Barrier
9.5 The Role of the Epithelium in the Development of Emphysema
9.6 The Epithelium as Therapeutic Target
10 Acute Respiratory Distress Syndrome
10.2.1 Opening of Tight Junctions
10.2.2 Epithelial Cell Loss
10.2.3 Direct Epithelial Injury
10.2.4 Inflammatory Epithelial Injury
10.2.4.1.2 Matrix Metalloproteinases
10.2.4.1.5 Neutrophil Extracellular Traps
10.2.4.4 Additional Mediators
10.3 Role of Epithelium in Host Defense & Inflammation
10.4.2 Resolution of Inflammation
10.4.3 Reabsorption of Edema Fluid
11 Epithelial Barrier Dysfunction in Asthma
11.1 Evidence for Barrier Dysfunction in Asthma
11.2 Causes of Epithelial Barrier Dysfunction in Asthma
11.3 Implications of Epithelial Barrier Dysfunction for Asthma Immunology and Therapy
12 Cystic Fibrosis: An Overview of the Past, Present, and the Future
12.1 Introduction to Cystic Fibrosis
12.1.1 Historical Context of Cystic Fibrosis
12.1.2 Epidemiological Impact of Cystic Fibrosis
12.1.3 Clinical Manifestations of Cystic Fibrosis
12.1.4 CFTR Gene and Protein Defects
12.2 Models of Cystic Fibrosis Disease
12.2.1 In Vivo Models of Cystic Fibrosis Disease
12.2.2 In Vitro Models of Cystic Fibrosis Disease
12.3 Epithelial Contributions to Innate Immunity in Cystic Fibrosis
12.3.1 Compositional Changes in Airway Surface Liquid
12.3.2 Changes in Airway Surface Liquid pH
12.3.3 Neutrophil Interactions
12.3.4 Nutrient Availability in the Airways
12.4 Cystic Fibrosis-Related Diabetes and the Airway Epithelium
12.4.1 Cystic Fibrosis-Related Diabetes Lung Pathology
12.4.2 CFTR, Insulin, and Glucose in Cystic Fibrosis-Related Diabetes
12.5 Therapeutic Interventions for Cystic Fibrosis Disease
12.5.1 Airway Surface Liquid Restoration
12.5.1.1 Hypertonic Saline
12.5.2 Breaking Up the Mucous with Mucolytics
12.5.2.2 N-Acetyl-Cysteine
12.5.3 Antiinflammatory Agents in Cystic Fibrosis
12.5.4 Inhaled Antibiotics
12.5.5 Modulators of CFTR Protein Trafficking and Channel Function
12.5.5.2 Ivacaftor/Lumacaftor
12.6 Future Directions of Therapies for Cystic Fibrosis
12.6.1 Future Therapies for Airway Surface Liquid Restoration
12.6.2 Future Therapies for Modulating Mucus
12.6.3 Immunomodulation of the Airway Epithelium
12.6.4 CFTR Modulators in Development
12.6.4.3 Other Modulators
12.6.6 Personalized Medicines
12.6.7 Concluding Remarks
Lung Epithelial Biology in the Pathogenesis of Pulmonary Disease
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