Lung Inflammation in Health and Disease, Volume I (Advances in Experimental Medicine and Biology, 1303)

Respiratory diseases are leading causes of death and disability globally, with about 65 million people suffering from COPD, and 334 million from asthma, the most common chronic disease. Each year, tens of millions of people develop and can die from from respiratory infections such as pneumonia and TB. Systemic inflammation may induce and exacerbate local inflammatory diseases in the lungs, and local inflammation can in turn cause systemic inflammation. There is increasing evidence of the coexistence of systemic and local inflammation in patients suffering from asthma, COPD, and other lung diseases, and the co-morbidity of two or more local inflammatory diseases often occurs. For example, rheumatoid arthritis frequently occurs together with, and promotes the development of, pulmonary hypertension. This co-morbidity significantly impacts quality of life, and can result in death for those affected. Current treatment options for lung disease are neither effective, nor condition-specific; there is a desperate need for novel therapeutics in the field. Additionally, the molecular and physiological significance of most major lung diseases is not well understood, which further impedes development of new treatments, especially in the case of coexistent lung diseases with other inflammatory diseases. Great progress has been made in recent years in many areas of the field, particularly in understanding the molecular geneses, regulatory mechanisms, signalling pathways, and cellular processes within lung disease, as well as basic and clinical technology, drug discovery, diagnoses, treatment options, and predictive prognoses. This is the first text to aggregate these developments. In two comprehensive volumes, experts from all over the world present state-of-the-art advances in the study of lung inflammation in health and disease. Contributing authors cover well-known as well as emerging topics in basic, translational, and clinicalresearch, with the aim of providing researchers, clinicians, professionals, and students with new perspectives and concepts. The editors hope these books will also help to direct future research in lung disease and other inflammatory diseases, and result in the development of novel therapeutics. Preface Contents Contributors Philip Aaronson School of Immunology and Microbial Sciences, King’s College London, London, UK About the Editor 1: Potential Role of Mast Cells in Regulating Corticosteroid Insensitivity in Severe Asthma 1.1 Introduction 1.2 Increased Airway Infiltration of Mast Cells Is a Key Feature in Asthma Pathogenesis 1.3 Clinical Evidence Suggesting a Role of Mast Cells in Corticosteroid Insensitivity 1.4 Mediators Produced by Mast Cells and Associated Mechanisms Shown to Blunt Corticosteroid Sensitivity 1.4.1 Interleukin 2 and 4 (IL-2/IL-4) 1.4.2 TNFα 1.4.3 TGFβ 1.4.4 Interleukin 17 (IL-17) 1.4.5 Interleukin 13 (IL-13) 1.4.6 Alarmins (TLSP) 1.5 Potential Mast Cell Inhibitors for the Treatment of Allergic Diseases 1.6 Conclusions References 2: Galectin-3 Promotes ROS, Inflammation, and Vascular Fibrosis in Pulmonary Arterial Hypertension 2.1 Pulmonary Arterial Hypertension (PAH) 2.2 Evidence for ROS Signaling in PAH 2.3 Galectin-3 2.4 Galectin-3 Ligands 2.5 Galectin-3 in Inflammation 2.6 The Role of Galectin-3 in Fibrosis 2.7 PAH Is Associated with Increased Levels of Galectin-3 2.8 Galectin-3 Induces the Functional Development of PAH 2.9 Galectin-3 Promotes PAH Through Numerous Mechanisms 2.10 Summary and Clinical Perspectives References 3: Anti-inflammatory Effects of Statins in Lung Vascular Pathology: From Basic Science to Clinical Trials 3.1 Introduction 3.2 Part I. Mechanisms of Statin Modulation on Vasculature 3.2.1 Pulmonary Vascular Remodeling Effects 3.2.1.1 Decreased Muscularization of Small Vessels 3.2.1.2 Attenuation of Vascular Proliferation 3.2.2 Epigenetic Modification Effects 3.2.3 Immune Modulation Effects 3.2.4 Effects on GTPase Isoprenylation Signaling 3.2.5 Transcription Factor Effects 3.2.6 Endothelial Barrier Protection 3.2.6.1 Integrin β4 3.2.6.2 PAK4-Cdc42 Pathway 3.2.7 Attenuation of Oxidative Stress 3.2.7.1 Effects on Endothelial Senescence 3.2.7.2 Inhibition of RhoA-Rho Kinase Signaling 3.2.7.3 Effects on Vasoconstrictive and Vasodilatory Balance 3.3 Part II. Statins and Lung Disease: The Landscape of Clinical Data in Endothelial Dysfunction 3.3.1 Heterogeneity of ARDS: Failure of Statins or Trial Design? 3.3.2 Statins: Lone Wolf or Class Effect? 3.3.3 Nanomedicine-Based Drug Delivery Systems: The Solution to the Statin Problem? 3.4 Part II. Conclusions References 4: Evolving Schema for Employing Network Biology Approaches to Understand Pulmonary Hypertension 4.1 Introduction 4.2 In Silico Network Theory 4.2.1 MicroRNA Regulatory Networks in PH 4.2.2 Long Non-coding RNA Regulatory Networks 4.3 Network Pharmacology 4.4 Intersection Between PH and Other Diseases 4.5 Use of Electronic Medical Records to Build Disease-Specific Networks for PH 4.6 Conclusion References 5: Pulmonary Inflammation and KRAS Mutation in Lung Cancer 5.1 Lung Cancer Overview 5.2 Pathogenesis of Lung Cancer 5.3 KRAS Mutations in Lung Tumors 5.4 KRAS Mutation Type and Status in the Prognosis of Lung Cancer 5.5 Mutant KRAS Signaling in Lung Tumorigenesis 5.6 Extrinsic Inflammation Promotes Mutant KRAS-Initiated Lung Tumorigenesis 5.7 Bacteria-Induced Airway Inflammation and Lung Tumorigenesis 5.8 Persistent Inflammation Induces KRAS Mutation with Various Genotypes 5.9 Conclusion References 6: MicroRNA Targets for Asthma Therapy 6.1 Introduction 6.2 Lung Inflammation in Asthma 6.2.1 Asthma Endotypes 6.2.2 Asthma Therapy 6.2.3 Biologics for Targeted Therapy of Lung Inflammation 6.3 Experimental Asthma Models 6.3.1 Ovalbumin Models 6.3.2 House Dust Mite Models of Mild/Moderate Asthma 6.3.3 Mouse Models of Severe Asthma 6.4 MicroRNAs 6.4.1 MicroRNAs in Lung Diseases 6.4.2 MicroRNAs in Asthma 6.5 MicroRNA-Targeted Therapy for Asthma 6.5.1 Lung Delivery of Oligonucleotide Drugs 6.5.2 Inhalational Toxicity 6.5.3 Preclinical Efficacy Studies of MicroRNAs in Asthma Therapy 6.6 Future Directions References 7: Roles of Genetic Predisposition in the Sex Bias of Pulmonary Pathophysiology, as a Function of Estrogens 7.1 Introduction 7.2 PAH 7.2.1 PAH Prognosis 7.2.2 PAH Incidence 7.2.2.1 BMPR2 7.2.2.2 CYP1B1 7.2.2.3 Soluble Epoxide Hydrolase (sEH) 7.3 COPD 7.4 Asthma 7.5 COVID-19 7.6 Perspectives and Conclusions References 8: Hypercapnic Respiratory Failure-Driven Skeletal Muscle Dysfunction: It Is Time for Animal Model-Based Mechanistic Research 8.1 Introduction 8.2 General Principles of Locomotor Skeletal Muscle Dysfunction in Pulmonary Diseases 8.3 Reductionist Models to Investigate a Complex Comorbidity 8.4 Animal Models of COPD to Investigate Muscle Dysfunction 8.5 Current Platforms to Perform Mechanistic Research in Disease-Focused Animal Models 8.6 Future Avenues to Produce Innovative Research in the Field 8.7 Conclusion References 9: Role of Airway Smooth Muscle in Inflammation Related to Asthma and COPD 9.1 Introduction 9.2 Mechanical Characteristics of Airway Smooth Muscle 9.2.1 General 9.2.2 Ca2+ Dynamics 9.2.2.1 Membrane Potential–Independent Ca2+ Dynamics 9.2.2.2 Membrane Potential–Dependent Ca2+ Dynamics 9.2.3 Ca2+ Sensitization 9.2.3.1 Characteristics of RhoA/Rho-Kinase 9.2.3.2 Role of RhoA/Rho-Kinase on Tension 9.2.4 Role of Ca2+ Signaling on β2-Adrenergic Action 9.3 Large-Conductance Ca2+-Activated K+ Channels 9.3.1 General 9.3.2 Structure 9.3.3 Electrical Characteristics 9.3.4 Effects on Ca2+ Signaling 9.3.5 Effects on β2-Adrenergic Action 9.3.5.1 Protein Kinase A 9.3.5.2 Stimulatory G Protein of Adenylyl Cyclase 9.3.6 Effects on Muscarinic Action 9.3.6.1 Inhibitory G Protein of Adenylyl Cyclase 9.3.6.2 Muscarinic M2 Receptors 9.3.7 Dual Regulation by G Proteins 9.3.8 Regulation by Other Factors 9.3.8.1 NO, cGMP 9.3.8.2 Reactive Oxygen Species 9.3.8.3 Arachidonic Acid 9.4 Characteristic Action of Bronchodilators on Airway Smooth Muscle 9.4.1 General 9.4.2 Intrinsic Efficacy 9.4.3 Allosteric Effects 9.4.4 Synergistic Effects of Bronchodilators 9.5 Role of Airway Smooth Muscle on Inflammation (Phenotype Plasticity) 9.5.1 General 9.5.2 Contractile Phenotype 9.5.3 Synthetic and Proliferative Phenotypes 9.5.4 Hyper-Contractile Phenotype 9.5.5 Ca2+ Handling 9.5.6 Regulation of Phenotype Switching 9.5.7 Modulation of Cell Phenotype by Cell Culture 9.5.8 Interaction Between Airway Smooth Muscle and Inflammatory Cells 9.6 Role of Airway Smooth Muscle in the Pathophysiology of Asthma and COPD 9.6.1 General 9.6.2 Airflow Limitation (Bronchoconstriction) 9.6.3 Airway Hyperresponsiveness 9.6.4 Desensitization of β2-Adrenergic Receptors 9.6.4.1 Effects of Ca2+ Dynamics 9.6.4.2 Effects of Ca2+ Sensitization 9.6.5 Airway Remodeling 9.6.5.1 Cell Proliferation 9.6.5.2 Cell Migration 9.7 Bronchodilators on Airway Inflammation 9.8 Conclusions References 10: Systemic Sclerosis and Pulmonary Disease 10.1 Introduction 10.2 Multisystem Disease 10.3 Associated Antibodies 10.4 Ethnicity Impact 10.5 Pulmonary Disease 10.5.1 Pulmonary Arterial Hypertension 10.5.2 Interstitial Lung Disease 10.6 Summary References 11: Innate Lymphoid Cells in Airway Inflammation 11.1 Introduction 11.2 Biology and Development of Innate Lymphoid Cells 11.3 Activation and Cytokines Production by ILC2s 11.4 Cellular Interactions and Upregulation of ILC2 11.5 Asthma Heterogeneity and Phenotypes 11.6 Role of ILC2 in Type 2 Inflammation 11.6.1 Allergen and ILC2 Interaction (Murine Model) 11.6.2 Role of ILC2 in Human Airway Disease (Asthma) 11.7 Therapeutic Target 11.8 Conclusion References 12: Sjogren’s Syndrome and Pulmonary Disease 12.1 Introduction 12.2 Pulmonary Manifestations 12.2.1 Nose, Mouth, and Upper Airway Disease 12.2.2 Clinical Evaluation of Airway Disease 12.2.2.1 Lower Airway Disease Bronchiolitis Bronchiectasis 12.2.3 Parenchymal Lung Disease 12.2.3.1 Nonspecific Interstitial Pneumonia (NSIP) 12.2.3.2 Usual Interstitial Pneumonia (UIP) 12.2.3.3 Lymphocytic Interstitial Pneumonia (LIP) 12.2.3.4 Organizing Pneumonia (OP) 12.2.3.5 Pulmonary Lymphoma 12.2.3.6 Pulmonary Amyloidosis 12.2.4 Pulmonary Hypertension 12.2.5 Thromboembolic Disease 12.3 Conclusions References 13: Redox Regulation, Oxidative Stress, and Inflammation in Group 3 Pulmonary Hypertension 13.1 Introduction 13.2 Clinical Picture for Group 3 PH 13.3 Cellular Pathological Changes in PH Due to Hypoxia 13.4 Oxidant Production and Redox Signaling in PH 13.4.1 Regulation of Pulmonary Vasotone by Oxidants during Acute Hypoxia 13.4.2 Deleterious Role of Oxidants in PH 13.4.3 Protective Role of Oxidants in PH 13.5 Inflammation in Animal Models and Patients with Group 3 PH 13.5.1 Cytokine Production in Group 3 PH 13.5.2 Evidence for Upregulation of pro-Inflammatory Pathways in Group 3 PH 13.5.2.1 Overview of NF-κB 13.5.2.2 Role of NF-κB in PH 13.5.2.3 Overview of TLR4 and HMGB1 13.5.2.4 Role of TLR4 and HMGB1 in PH 13.6 Oxidative Post-translational Protein Modifications Within Inflammatory Pathways 13.6.1 Redox Regulation of NF-κB 13.6.2 Redox Regulation of TLR4 13.6.3 Redox Regulation of HMGB1 13.7 Concluding Remarks References 14: Sex-Steroid Signaling in Lung Diseases and Inflammation 14.1 Introduction 14.2 Sex-Steroids and Their Biology 14.2.1 Estrogen 14.2.2 Progesterone 14.2.3 Testosterone 14.2.4 Crosstalk Between Sex-Steroids 14.3 Role of Sex Steroid Signaling in Lung Diseases 14.3.1 Asthma 14.3.2 COPD 14.3.3 Pulmonary Fibrosis 14.3.4 Role of Sex-Steroids in the Pathophysiology of Rare Lung Diseases 14.3.4.1 Pulmonary Lymphangioleiomyomatosis 14.3.4.2 Alpha1-Antitrypsin Deficiency 14.3.4.3 Lung Sarcoidosis 14.4 Role of Sex-Steroids Signaling in Influencing Immune Responses in the Lungs 14.4.1 Role of Sex-Steroids in Immune Cells 14.4.1.1 Dendritic Cells 14.4.1.2 Macrophages 14.4.1.3 Neutrophils 14.4.1.4 Eosinophils 14.4.1.5 Lymphocytes 14.5 Conclusion and Future Scope References 15: Cytokines, Chemokines, and Inflammation in Pulmonary Arterial Hypertension 15.1 Introduction 15.2 Evidence of Inflammation in PAH 15.2.1 Clinical Classification of PAH 15.2.1.1 Group 1.1/1.2: Idiopathic and Heritable PAH 15.2.1.2 Group 1.3: Drug- and Toxin-Induced Pulmonary Hypertension 15.2.1.3 Group 1.4 Associated with Systemic Conditions 15.2.2 Clinical Evidence of Inflammation in PAH 15.2.2.1 Histological and Cytological Evidence in PAH 15.2.2.2 Inflammatory Mediators and Biomarkers in PAH 15.2.2.3 Inflammatory Conditions Associated with PAH 15.3 Inflammatory Cytokines and Chemokines in PAH 15.3.1 Cytokines 15.3.1.1 IL-1 Family 15.3.1.2 IL-6 15.3.1.3 IL-13 15.3.1.4 TNF-α 15.3.1.5 MIF 15.3.1.6 GDF-15 15.3.2 Chemokines 15.3.2.1 CCL2/MCP-1 15.3.2.2 CCL5/RANTES 15.3.2.3 CXCL12/SDF-1 15.3.2.4 CX3CL1/Fractalkine 15.4 Inflammatory Cells in PAH 15.4.1 T-Lymphocytes 15.4.2 B-Lymphocytes 15.4.3 Dendritic Cells 15.4.4 Macrophages 15.4.5 Mast Cells 15.5 Role of Autoantibodies in PAH 15.5.1 Antifibroblast Antibodies 15.5.2 Antiendothelial Cell Antibodies 15.5.3 Anti-Inflammatory and Immunosuppressive Agents in PAH 15.5.3.1 Anti-Inflammatory Agents 15.5.3.2 Immunosuppressive Agents 15.6 Inflammation in Other Groups of PH 15.7 Summary References 16: Interactive Roles of CaMKII/Ryanodine Receptor Signaling and Inflammation in Lung Diseases 16.1 Introduction 16.2 Structure and Activity of CaMKII 16.3 Structure and Activity of RyRs 16.4 Redox Signaling and CaMKII/RyRs 16.4.1 Ca2+-Dependent Activation of CaMKII 16.4.2 ROS-Dependent Activation of CaMKII 16.5 Oxidative Modification of RyRs 16.6 The Relationship Between CaMKII and Ryanodine Receptors 16.6.1 Regulation of Ryanodine Receptors by CaMKII 16.6.2 Regulation of CaMKII by Ryanodine Receptors 16.7 Oxidative Stress and Redox Regulation of Lung Inflammation 16.8 Inflammatory Cellular Responses and CaMKII/RyR2 Signaling in the Lung 16.8.1 Inflammation and CaMKII 16.8.2 Inflammation and RyR2 16.9 Role of CaMKII/RyR2 in Lung Diseases 16.9.1 Pulmonary Artery Hypertension (PAH) 16.9.1.1 CaMKII in PAH 16.9.1.2 RyR2 in PAH 16.9.2 Asthma 16.9.2.1 CaMKII in Asthma 16.9.2.2 RyR2 in Asthma 16.9.3 Lung Cancer 16.9.3.1 CaMKII in Lung Cancer 16.9.3.2 RyRs in Lung Cancer 16.10 Summary, Open Questions, and Future Research Directions References 17: Reciprocal Correlations of Inflammatory and Calcium Signaling in Asthma Pathogenesis 17.1 Introduction 17.2 Ca2+ Homeostasis and Function in ASM 17.2.1 Smooth Muscle Contraction 17.2.2 Ryanodine Receptors 17.2.3 Sarco/Endoplasmic Ca2+-ATPase 17.2.4 Na+/Ca2+ Exchanger and the Plasma Membrane Ca2+-ATPase 17.2.5 Ca2+-Activated Potassium/Chloride Channels 17.3 Ca2+ Dysregulations in the Asthmatic Airway 17.3.1 MLCK and MLCP Dysregulations 17.3.2 SERCA Activity Downregulation 17.3.3 NCX1 Overexpression 17.3.4 Effect of Inflammation on Ryanodine Receptors 17.4 Genetic Causes of Ca2+ Dysregulations in Asthma 17.5 Asthma Therapies 17.5.1 Current Treatments 17.5.2 Potential Future Therapies 17.6 Summary References 18: Crosstalk Between Lung and Extrapulmonary Organs in Infection and Inflammation 18.1 Introduction 18.2 Microbiome in the Lung 18.3 Brain–Lung Crosstalk 18.3.1 Pneumonia Occurring after Traumatic Brain Injury 18.3.2 Stroke-Associated Pneumonia (SAP) 18.3.3 Neuroinvasive Potential of Coronaviruses 18.4 Gut–Lung Axis 18.4.1 Asthma 18.4.2 COPD 18.4.3 Respiratory Infections 18.5 Other Organ–Lung Interactions 18.5.1 Cardio–Pulmonary Interactions 18.5.2 Liver–Lung Interactions 18.5.3 Lung–Kidney Inter-relationship 18.6 Conclusions and Future Directions References 19: Inflammation in Pulmonary Arterial Hypertension 19.1 Introduction 19.2 T Cells 19.3 Treg Cells 19.4 TH17 Cells 19.5 Th2 Cells 19.6 T Cytotoxic Cells 19.7 Neutrophils 19.8 Macrophages 19.9 Dendritic Cells 19.10 Mast Cells 19.11 Cytokines 19.12 IL-6 19.13 IL-1b 19.14 Other Secreted Factors 19.15 Other Cell Types 19.16 Lymphatics 19.17 Endothelial Cells 19.18 Pericytes 19.19 Other Vascular Mural Cells 19.20 Conclusions References 20: Lysophospholipids in Lung Inflammatory Diseases 20.1 Introduction 20.2 Metabolism of LPA and S1P 20.2.1 Biosynthesis of LPA 20.2.2 Catabolism of LPA 20.2.3 Synthesis of S1P 20.2.4 Catabolism of S1P 20.3 LPA- and S1P-Mediated Signaling Pathways 20.3.1 LPA and S1P Receptors in Lungs 20.3.2 LPA and S1P Receptor-Mediated Signaling 20.4 LPA and S1P in Acute Respiratory Distress Syndrome (ARDS) 20.4.1 Pathogenesis of ARDS 20.4.2 Pro- and Anti-inflammatory Roles of ATX-LPA-LPA Receptor Axis in Experimental Acute Lung Injury 20.4.3 Role of ATX-LPA-LPA Receptor Axis in Biological Functions in Acute Lung Injury-Related Lung Cells 20.4.4 Protective Role of S1P in Experimental Acute Lung Injury 20.4.5 S1P Regulates Biological Functions in Acute Lung Injury-Related Lung Cells 20.5 LPA and S1P in Asthma 20.5.1 Pathophysiology of Asthma 20.5.2 Role of LPA in Asthma 20.5.3 Molecular Mechanisms by which LPA/LPA Receptors Contribute to the Pathogenesis of Allergic Asthma 20.5.4 Role of S1P in Asthma 20.6 LPA and S1P in COPD 20.6.1 Pathogenesis of COPD 20.6.2 Role of LPA in COPD 20.6.3 Role of S1P in COPD 20.7 LPA and S1P in other Lung Diseases 20.8 Perspective References Index