Targeting Cellular Signalling Pathways in Lung Diseases

Preface
Acknowledgment
Contents
About the Editors
1: Introduction to Lung Diseases
1.1 Chronic Obstructive Pulmonary Disorder (COPD)
1.1.1 Definition
1.1.2 Epidemiology
1.1.3 Causes
1.1.4 Symptoms (Fig. 1.2)
1.1.5 Pathophysiology
1.1.6 Treatment
1.2 Asthma
1.2.1 Definition
1.2.2 Epidemiology
1.2.3 Causes (Fig. 1.3)
1.2.4 Symptoms (Fig. 1.4)
1.2.5 Pathophysiology
1.2.6 Types of Asthma [40]
1.2.7 Treatment
1.3 Lung Cancer
1.3.1 Classification
1.3.2 Epidemiology
1.3.3 Etiology and Risk Factors [45] (Fig. 1.6)
1.3.4 Sign and Symptoms
1.3.5 Diagnosis
1.3.6 Staging of Lung Cancer
1.3.7 Treatment [54]
1.4 Acute Respiratory Tract Infections
1.4.1 Upper Respiratory Tract Infections
1.4.1.1 Acute Pharyngitis
1.4.1.2 Acute Sinusitis
1.4.1.3 Acute Viral Laryngitis
1.4.2 Lower Respiratory Tract Infection
1.4.2.1 Pneumonia
1.4.2.2 Influenza
1.5 Idiopathic Pulmonary Fibrosis (IPF)
1.5.1 Epidemiology
1.5.2 Causes
1.5.3 Pathophysiology
1.5.4 Symptoms
1.5.5 Diagnosis
1.5.6 Treatment
References
2: Targeting Molecular and Cellular Mechanisms in Asthma
2.1 Introduction
2.1.1 Rationale to the Study
2.1.2 Asthma: A Global Health Burden
2.1.3 Asthma: GINA Definition
2.2 Traditional Understanding and Parallel Non-specific Therapy
2.2.1 Major Types of Asthma
2.2.2 Allergens Are Major Inducers for Atopic Asthma
2.2.3 Pathophysiology
2.2.4 Symptomatic Therapy
2.3 Current Understanding and Steps Towards Pathway-Specific Therapy(Fig. 2.1)
2.3.1 Cells Involved in Asthma Pathogenesis and Respective Targets
2.3.1.1 Airway Epithelium
2.3.1.2 Dendritic Cells
Dendritic Cell Modulator as a Target
2.3.1.3 Lymphocytes
2.3.1.4 T Helper Type 2 (Th2) Cells
Th2 Cytokines as Target
2.3.1.5 B Lymphocytes and IgE
2.3.1.6 Mast Cells
2.3.2 Th2-High Eosinophilic Asthma Versus Th2-Low Neutrophilic Asthma
2.3.2.1 Eosinophilic Asthma/Th2-High Asthma
2.3.2.2 Neutrophilic Asthma
2.3.3 Asthma: A Complex Syndrome with Multiple Endotypes
2.4 Nitro-Oxidative Stress in Asthma Pathogenesis
2.4.1 Oxidative Stress
2.4.2 Mitochondrial Dysfunction in Asthma
2.4.3 Nitric Oxide (NO)
2.5 Airway Remodelling in Asthma: The Knowledge that Will Shape the Future Treatment
2.6 Non-pharmacological Intervention for Asthma: Bronchial Thermoplasty
2.7 Tailoring the Patient Needs Via `Personalised Approach´ in Asthma
2.8 Conclusions and Future Perspectives
References
3: Various Cellular and Molecular Axis Involved in the Pathogenesis of Asthma
3.1 Introduction
3.2 Epidemiology and Risk Factors
3.3 Granulocytes: As Predictors of Asthma
3.3.1 Basophils and Allergic Inflammation
3.3.1.1 Stimuli for Basophil Activation
3.3.1.2 Inflammatory Mediators of Basophils
3.3.1.3 Basophil Adhesion Molecules
3.3.2 Neutrophil Granule Contents
3.3.2.1 Mechanisms in Neutrophil Activation
3.3.2.2 Neutrophil in Airway Inflammation and its Signal Transduction Pathways
3.3.2.3 Neutrophil Apoptosis: The Resolution of Inflammation
3.3.3 Eosinophilic Asthma
3.3.3.1 Eosinophil-Derived Cytokines and Associated Bronchial Hyperresponsiveness
3.4 Fibroblasts and Myofibroblasts
3.4.1 Extracellular Matrix Production in the Airways
3.4.2 Fibroblast to Myofibroblast Transition
3.5 Pathological Signaling Pathways Involved in the Activation of Lung-Resident Macrophages and Dendritic Cells (DCs)
3.5.1 Macrophage Activation Pathways
3.5.1.1 IL-4/IL-13 Signaling Pathway
3.5.1.2 TNF-α Signaling Pathway
3.5.1.3 TGF-β Signaling Pathway
3.5.2 Reactive Oxygen and Nitrogen Species
3.5.3 Antigen Presentation by Dendritic Cells and their Role in the Pathology of Asthma
3.6 Bronchial Epithelial Cells
3.6.1 Mechanisms of Endothelial Cell Activation
3.6.1.1 Cytokine Activation
3.6.1.2 Role of Epithelial Cells in Type 2-Driven and Non-type 2 Allergic Asthma
3.7 Airway Epithelial and Smooth Muscle Cells
3.7.1 Physiological Barrier
3.7.2 Airway Epithelial Cell-Derived Mediators
3.7.2.1 Nitric Oxide (NO)
3.7.2.2 Endothelin
3.7.2.3 Arachidonic Acid Metabolites
3.7.2.4 Inflammatory Cytokines
3.7.2.5 Cell Adhesion Molecules
3.7.2.6 Platelet-Activating Factor (PAF)
3.7.2.7 Tachykinin
3.7.2.8 Histamine
3.7.2.9 Adenosine
3.8 Role of Innate Immunity in Asthma
3.8.1 CD4+ and CD8+ T Cells in Asthma
3.8.2 Cellular Receptors of Innate Immunity in Asthma
3.8.3 Innate-like T Cells and Asthma
3.9 Conclusion
References
4: Targeting Molecular and Cellular Mechanisms in Steroid-Resistant Asthma
4.1 Introduction
4.2 Inducers of Steroid Resistance in Asthma
4.3 Shedding Light on the Cellular Mechanisms Underlying the Glucocorticoid Receptor Signalling Pathway-Mediated Steroid Resis...
4.3.1 Neutrophils
4.3.2 Factors Inducing Airway Neutrophilia
4.3.3 Eosinophils
4.3.4 Group 2 Innate Lymphoid Cells (ILC-2)
4.3.5 T Helper Type 9 Cells (Th9 Cells)
4.3.6 CD8+ T Cells
4.4 Possible Molecular Mechanisms behind Steroid-Resistant (SR) Asthma (Fig. 4.1)
4.4.1 Bioavailability of Glucocorticoid Receptor (GR) and the Underlying Molecular Mechanism
4.4.2 IL-17A High and IFN-γ High Phenotypes
4.4.3 PI3K/HDAC Signalling Pathway
4.4.4 p38 MAPK
4.4.5 NLPR3 Inflammasome
4.4.6 Lack of Autophagy
4.4.7 Other Key Mechanisms
4.5 Tailoring Steroid-Refractory Asthma: The Possible Diagnosis and Therapeutics
4.5.1 Immunosuppressive Drugs
4.5.2 Biologic Therapies
4.5.3 Highly Potent Glucocorticoids
4.5.4 Vitamin D
4.5.5 Sulforaphane
4.6 Conclusions and Future Outlook
References
5: Targeting Molecular and Cellular Mechanisms in Chronic Obstructive Pulmonary Disease
5.1 Introduction
5.2 Pathophysiology of COPD
5.2.1 Inflammatory Mediators and Cells
5.2.1.1 Neutrophils (NPHs)
5.2.1.2 Macrophages (MPs)
5.2.1.3 T-Lymphocyte
Eosinophils (Eos)
5.2.1.4 Dendritic Cells (DCs)
5.2.1.5 Epithelial Cells (EP)
5.2.2 Protease and Antiprotease Imbalance
5.2.3 Oxidative Stress (OS)
5.3 Mediators Involved in COPD
5.3.1 Lipid Mediators
5.3.1.1 Prostaglandin
5.3.1.2 Thromboxane
5.3.1.3 Leukotrienes (LT)
5.3.1.4 Platelet-Activating Factor (PAF)
5.3.2 Peptide Mediators
5.3.2.1 Endothelins (ET)
5.3.2.2 Bradykinin (BK)
5.3.2.3 Tachykinins (TK)
5.3.2.4 Chemokines
5.3.2.5 Interleukin-8 (IL-8)
5.4 Potential Targets and Therapies for COPD
5.4.1 PDE (Phosphodiesterase) Inhibitors
5.4.2 Hypersecretion of Mucus
5.4.3 Bronchodilators
5.4.4 Glucocorticoids (Inhaled Corticosteroids)
5.4.5 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)
5.4.5.1 CXCR2 Inhibitors
5.4.6 Phosphoinositide-3 Kinase Delta (PI3K) Inhibitor
5.4.7 Targeting Inflammatory Markers
5.4.8 Other COPD Treatments
5.5 Conclusion
References
6: Probing the Cellular and Molecular Mechanisms Underlying in the Pathogenesis of Chronic Obstructive Pulmonary Disease
6.1 Introduction
6.2 Subtypes of COPD
6.2.1 Chronic Bronchitis
6.2.2 Emphysema
6.2.3 Small Airway Disease
6.3 Inflammatory Cells Involved in COPD
6.3.1 Epithelial Cells
6.3.2 Macrophages
6.3.3 Neutrophils
6.3.4 Eosinophil
6.3.5 Dendritic Cells
6.3.6 T-Lymphocytes
6.4 Inflammatory Mediators Involved in COPD
6.4.1 Lipid Mediators
6.4.2 Pro-inflammatory Cytokines
6.4.3 Inflammasomes
6.4.4 Role of Reactive Oxygen Species (ROS) and Oxidative Stress in COPD
6.5 Conclusion
References
7: Chronic Obstructive Pulmonary Disease: Molecular Basis of Pathogenesis and Targeted Therapeutic Approaches
7.1 Introduction
7.2 Epidemiology
7.3 Aetiology of Disease Progression
7.3.1 Inflammation
7.3.1.1 Neutrophils
7.3.1.2 Macrophages
7.3.1.3 T Lymphocytes
7.3.1.4 Eosinophils
7.3.1.5 Dendritic Cells
7.3.1.6 Epithelial Cells
7.3.2 Oxidative Stress
7.3.3 Genetic Predisposition
7.3.4 Epigenetics
7.3.5 Activity of Proteases
7.3.5.1 Neutrophil Wlastase
7.3.5.2 Cysteine Proteases
7.3.5.3 Matrix Metalloproteinases
7.4 Current Treatments and Their Drawbacks
7.4.1 Quit Smoking
7.4.2 Vaccination
7.4.3 Physical Activity
7.4.4 Pharmacological Treatment
7.4.5 Emerging Antioxidants for an Alternative Therapeutic Approach
7.4.6 Interventional Treatments
7.4.7 Oxygen and Ventilator Support
7.4.8 Comorbidity Treatment
7.5 Conclusion
References
8: Exploring the `Dormancy Activation Switch´ in the Tumour Microenvironment for Metastatic Lung Cancer: The Possible Role of ...
8.1 Lung Cancer
8.2 Metastatic Niche in Different Sites
8.3 Lymph Node Metastasis
8.3.1 MAPK Signalling in Lymph Node Metastasis of Lung Cancer
8.4 Pleura Metastasis
8.4.1 CXCR4/CXCL12 Signalling and Pleura Metastasis in Lung Cancer
8.5 Liver Metastasis
8.5.1 ALK and Liver Metastasis in Lung Cancer
8.6 Brain Metastasis
8.6.1 Rho/ROCK Signalling and Brain Metastasis in Lung Cancer
8.6.2 PI3K/AKT Signalling and Brain Metastasis in Lung Cancer
8.7 Bone Metastasis
8.7.1 RANK/RANKL Signalling and Bone Metastasis in Lung Cancer
8.8 Controversial Role miRNA in Lung Cancer Metastasis
8.9 Concluding Remarks
References
9: Therapeutic Strategies Targeting Signaling Pathways in Lung Cancer
9.1 Introduction
9.2 Epidemiology of Lung Cancers
9.2.1 Mortality
9.2.2 Survival
9.3 Lung Cancer
9.4 Signaling Pathways Involved in Lung Cancers
9.4.1 Epidermal Growth Factor Receptor (EGFR)
9.4.2 Mutations in Other EGFR Signaling Pathway Genes
9.4.3 PI3K
9.4.4 p53 Gene
9.5 Therapeutic Strategies
9.5.1 Immunotherapy
9.5.2 Anti PD-1 and anti-PD-L1
9.5.3 Nivolumab
9.6 Epidermal Growth Factor (EGFR) as a Therapeutic Target
9.6.1 PK13-Akt Pathway
9.6.2 Vaccine Therapy
9.7 Conclusions and Future Challenges
References
10: Modulation of Signaling Pathways by Immunotherapeutics in Lung Cancer
10.1 Introduction
10.2 Immune Checkpoint Blockade in NSCLC
10.2.1 CTLA-4
10.2.2 PD-1/PD-1L
10.2.3 TIM3
10.2.4 LAG3
10.2.5 KIRs
10.2.6 Immune-Related Adverse Effects (irAEs)
10.2.7 Early Detection and Prevention of irAEs by Imaging
10.2.8 ICIs on Elderly People Having NSCLC
10.2.9 Influence of Prognostic Factors
10.2.10 Influence of Probiotics on ICIs in NSCLC
10.3 Vaccination Strategies in NSCLC
10.3.1 Types of Vaccines and Their Mechanisms of Action
10.3.1.1 Whole-Cell Vaccines
10.3.1.2 Protein- and Peptide-Based Vaccines
10.3.1.3 mRNA Vaccines
10.4 Immunotherapy in SCLC
10.4.1 Immune Checkpoint Inhibitors in SCLC
10.4.1.1 CTLA-4
10.4.1.2 PD-L1/PD-1
10.4.1.3 CD 47
10.4.2 Ongoing Clinical Trials
10.4.2.1 IMpower 133
10.4.2.2 CheckMate 331 and CheckMate 451
10.4.2.3 Keynote 028 and Keynote 158
10.5 Combination of Radiotherapy and Immunotherapy in Lung Cancer
10.5.1 Combined Therapy Trials
10.5.1.1 Keynote 001
10.5.1.2 Pacific Trial
10.5.1.3 Bevacizumab
10.5.1.4 Caspian
10.5.1.5 Meru
10.6 Conclusion
References
11: Underpinning the Cellular and Molecular Mechanisms with Nanotheranostics for Lung Cancer
11.1 Introduction
11.2 Types of Lung Cancer
11.3 Waging a War on Cancer by Redox
11.4 Reactive Oxygen Species (ROS)
11.5 Reactive Oxygen Species (RNS) and Reactive Oxygen Species (ROS)
11.5.1 ROS as Signalling Molecules
11.5.1.1 H2O2-Mediated Oxidation of Cysteine
11.5.1.2 H2O2-Mediated Signal Transduction
11.5.2 ROS Promotes Pro-tumourigenic Signalling
11.5.3 ROS Promote Anti-tumourigenic Signalling
11.6 ROS as Targets for Effective Cancer Therapy
11.6.1 Cellular Pathways
11.6.1.1 Apoptosis (Type 1 Programmed Cell Death)
11.6.1.2 Necrosis
11.6.1.3 Necroptosis (Type 3 Programmed Cell Death)
11.6.1.4 Autophagy (Type 2 Programmed Cell Death)
11.6.2 Molecular Pathway
11.6.2.1 MAPK
11.6.2.2 FOXO Transcription Factors
11.6.2.3 Keap1-Nrf2 System
11.7 Exploiting ROS for Lung Cancer Nanotherapeutics
11.7.1 Nanotheranostics for Lung Cancer
11.7.1.1 Lipid-Based Nanoparticles (Liposomes)
11.7.1.2 Polymeric Nanoparticles
11.7.1.3 Metal Nanoparticles
11.7.1.4 Bio-nanoparticles
11.7.1.5 Viral Nanoparticles
11.7.2 Modulation of Redox Homeostasis by Nanoparticles
11.8 Emerging Anticancer Redox Nanotherapeutics Targeting the Pathways
11.8.1 Receptor-Mediated Therapy
11.8.2 Gene-Mediated Therapy
11.8.3 Stimuli Responsive Chemotherapy
11.8.4 Naturally Derived Product Therapy
11.9 Conclusion
References
12: Targeting Molecular and Cellular Mechanisms in Idiopathic Pulmonary Fibrosis
12.1 Introduction
12.1.1 IPF Subclassification
12.2 Pathogenesis of IPF
12.2.1 Modifications of Genetic and Epigenetic Factors in IPF Development
12.2.2 Role of Pro-inflammatory Mediators in IPF
12.2.3 Recruitment of Leukocytes and Fibroblast by Chemokine
12.3 Comorbidities Associated with IPF
12.4 Cellular and Molecular Mechanism Underlying IPF Progression
12.4.1 Cellular Players
12.4.1.1 Fibroblast Activation via Mesenchymal Phenotype Transformation
12.4.1.2 Cellular Mechanism Pertaining to Various Targets for Therapeutic Intervention
Cellular Senescence and Deregulated Metabolism in IPF
Activation of Alveolar Epithelial Type 2 Cells (AEC2 or AT2)
Modified AEC2-Fibroblast Signaling Mechanisms in IPF
12.4.2 Molecular Players as Therapeutic Targets and Their Mechanism in IPF
12.4.2.1 TGF-β-Integrin αvβ6
12.4.2.2 Matrix Metalloproteinase-19 (MMP-19)
12.4.2.3 Caveolin-1
12.4.2.4 Semaphorin 7A
12.4.2.5 Calcium-Activated Potassium Channel (KCa3.1)
12.4.2.6 Micro RNA-26a (miR-26a) and Micro-RNA let-7d (miR let-7d)
12.4.2.7 Transglutaminase 2 (TG2)
12.5 Current Clinical Implications of IPF
12.6 Impediments in IPF Basic Research
12.7 Conclusion
References
13: A Refined Approach to Target the Molecular and Cellular Mechanisms in Pulmonary Fibrosis
13.1 Introduction
13.1.1 Pulmonary Fibrosis: A Global Challenge
13.1.2 Historical Perspective of Pulmonary Fibrosis
13.1.3 Types of Pulmonary Fibrosis Based on the Known Cause
13.1.4 Idiopathic Pulmonary Fibrosis (IPF): The Expert´s Conundrum
13.1.5 The Nexus Between Pulmonary Fibrosis and COVID-19
13.2 Genetic Factors Involved in the Development of Pulmonary Fibrosis
13.2.1 MUC5B Gene Polymorphism
13.2.2 Surfactant Protein Mutations
13.2.3 Mutations in Other Genes
13.3 Various Inducers for the Development of Pulmonary Fibrosis
13.3.1 Silica
13.3.2 Asbestos
13.3.3 Iatrogenic
13.3.4 Paraquat
13.3.5 Polyhexamethylene Guanidine (PHMG)
13.3.6 Carbon Nanotubes (CNTs)
13.3.7 Lung Fibrosis as a Part of Other Diseases
13.4 Lung Injury: A Predominant Inducer for Pulmonary Fibrosis
13.4.1 Mechanical Stretch
13.4.2 Exposure to High Doses of Radiation
13.4.3 Lung Fibrosis as a Post-SARS Sequel
13.4.4 Link with Gastroesophageal Reflux
13.5 Alveolar Epithelial Dysfunction as a Converging Point for the Development of Pulmonary Fibrosis
13.6 Role of Inflammatory Cells and Mediators in Pulmonary Fibrosis
13.7 Role of Oxidative Stress in Pulmonary Fibrosis
13.8 Role of MMPs in the Development of Pulmonary Fibrosis
13.9 Disturbance in Balance of Pro-fibrotic and Anti-fibrotic Molecules
13.10 Therapeutic Targets in Pulmonary Fibrosis
13.10.1 Leukotriene Receptor Antagonists
13.10.2 Targeting B Lymphocyte
13.10.3 Protein Kinase Inhibitors
13.10.4 Phosphoinositide 3-Kinase/Protein Kinase B/Mammalian Target of Rapamycin (PI3K/Akt/mTOR) Pathway Inhibitors
13.10.5 Anti-Integrin Antibodies
13.10.6 Anti-Connective Tissue Growth Factor
13.10.7 Inhibitors of Autotaxin-Lysophosphatidic Acid
13.10.8 Pentraxin-2 (PTX-2) Analogues
13.10.9 Targeting the Respiratory Microbiota
13.11 Pirfenidone and Nintedanib: Success in Pulmonary Fibrosis
13.12 Conclusion
13.13 Future Perspectives
References
14: Targeting Molecular and Cellular Mechanisms in Tuberculosis
14.1 Introduction
14.2 Aetiology and Symptoms/Clinical Features
14.3 Transmission Cycle [6]
14.4 Mechanisms of Drug Resistance
14.5 Treatment of Tuberculosis
14.6 Conclusion
References
15: Cellular and Molecular Mechanisms of Repurposed Antidiabetic Drug as an Adjunctive Treatment for Tuberculosis
15.1 Introduction
15.2 Relationship of Tuberculosis and Diabetes
15.2.1 Diabetes Causes TB
15.2.2 TB as a Diabetes Risk Factor
15.2.3 The Fundamental Pathophysiological Role
15.2.4 Treatment of Comorbid Diabetes and TB
15.2.5 Pharmacological Considerations in the Co-treatment of Diabetes Mellitus and Tuberculosis
15.3 The Requirement for Adjunctive Host-Targeted Therapy
15.4 Repurposing of Adjuvant Antitubercular Drug: Novel Approach to Fight Drug-Resistant TB
15.5 Synergistic Effects of Repurposed Adjuvant Drug with Other Antitubercular Drugs
15.6 Cellular and Molecular Mechanism
15.7 Conclusion and Future Perspective
References
16: Targeting Host and Bacterial Signaling Pathways in Tuberculosis: An Effective Strategy for the Development of Novel Anti-t...
16.1 Introduction
16.2 Existing Tuberculosis Treatment and Need for New Drug Targets
16.3 Drugs Involved In DOTS Therapy
16.3.1 Isoniazid
16.3.2 Rifampicin
16.3.3 Pyrazinamide
16.4 Elimination of M. tuberculosis by Targeting of Bacterial Signaling Pathways
16.5 PE_PGRS in TB Pathogenesis
16.5.1 Tyrosine Phosphatases
16.5.2 Tyrosine Kinase
16.6 Serine/Threonine Protein Phosphatase
16.7 Serine/Threonine Protein Kinases (STPKs)
16.8 Lipid Phosphatase
16.9 By Targeting Bacterial Protein Secretion System and Proteosomal System
16.10 Adenylate Cyclase/cAMP Pathway
16.11 Elimination of M. tuberculosis by Targeting of Host Signaling Pathways
16.11.1 Blocking Survival Within Macrophages by Targeting the Host Factors Which Prevent Phagolysosomal Fusion
16.11.1.1 Coronin 1/Calcineurin Pathway
16.11.1.2 Voltage-Gated Channels
16.11.1.3 Immunity-Related GTPase Family M Proteins
16.11.1.4 Blocking the Persistence of the Bacteria Within the Host
16.12 Conclusions and Future Prospects
References
17: Targeting Molecular and Cellular Mechanisms in Pulmonary Hypertension
17.1 Introduction
17.2 Consequences and Complications of Hypertension
17.2.1 Treatment of Hypertension
17.3 Pulmonary Hypertension (PH)
17.3.1 Pulmonary Arterial Hypertension (PAH)
17.3.2 Clinical Classification of Pulmonary Hypertension
17.3.2.1 Group 1: Pulmonary Arterial Hypertension (PAH)
17.3.2.2 Group 2: PH Due to Left-Heart Disease (PH-LHD)
17.3.2.3 Group 3: PH Due to Lung Diseases and/or Hypoxia
17.3.2.4 Group 4: Chronic Thromboembolic PH (CTEPH)
17.3.2.5 Group 5: PH with Unclear Multifactorial Mechanisms
17.4 Pathophysiology of Pulmonary Hypertension
17.4.1 Genetics and Genomics of PAH
17.4.1.1 Transcript Mapping and Positional Cloning of the Gene Underlying PAH
17.4.2 Role of Inflammation in PH
17.4.3 Caveolin-1 Mutation in PH
17.5 Metabolism Alterations in Pulmonary Hypertension
17.5.1 Energetic Metabolism in PH
17.6 Conclusion
References
18: Targeting Molecular and Cellular Mechanisms of Pulmonary Arterial Hypertension
18.1 Introduction
18.2 Targeting TGFβ/BMP Signaling Activity
18.3 Targeting DNA Methylation and Histone Posttranslational Modifications
18.3.1 Targeting DNA Methylation
18.3.2 Targeting Histone Modifications
18.4 Targeting DNA Damage and DNA Repair Responses
18.5 Targeting Noncoding RNAs
18.6 Targeting Metabolic Regulation
18.7 Targeting Growth Factors and Proliferation
18.8 Targeting Inflammation and Immunomodulation
18.9 Targeting EndMT
18.10 Conclusions
References
19: Potential Cellular Targets Associated with the Signaling of the Pulmonary Hypertension
19.1 Introduction
19.2 Pathophysiological Phenomenon Associated with PAH
19.3 Potential Cellular Targets Associated with the Signaling of the Pulmonary Hypertension
19.3.1 TGF-beta Signaling in Pulmonary Hypertension
19.3.2 Involvement of RhoA/ROCK Pathway in Pulmonary Hypertension Signaling
19.3.3 CypA (Cyclophilin A) and Bsg Signaling in Pulmonary Hypertension
19.3.4 AMPK Signaling in Pulmonary Hypertension
19.3.5 Alteration in Metabolic Pathways in PAH
19.3.6 Thrombin-Activatable Fibrinolytic Inhibitor (TAFI) in CTEPH
19.4 Conclusion
References
20: Targeting Molecular and Cellular Mechanism of Influenza A Virus
20.1 Introduction
20.2 A Glance on IAV and Its Replication
20.2.1 Biology of Influenza A Virus
20.2.2 Life Cycle of Influenza A Virus
20.2.2.1 Viral Entry
20.2.2.2 Endocytosis and Fusion
20.2.2.3 Viral Replication, Transcription, and Translation
20.2.2.4 Export of vRNPs, Assembly, and Budding
20.3 Molecular Pathogenesis of Influenza Virus Infection
20.3.1 Host Cell Immune Response Upon IAV Infection
20.3.1.1 Innate Immune Response Against IAV Infection
20.3.1.2 Adaptive Immune Response Against IAV Infection
20.3.2 Cellular and Molecular Mechanism of IAV Infection
20.3.2.1 Host Cell Protein Synthesis
20.3.2.2 Production of Cytokines and Activation of Transcription Factors in IAV Infection
20.3.2.3 Apoptosis in IAV Infection
Intrinsic Pathway
Extrinsic Pathway
20.3.2.4 Autophagy
20.4 Pharmacological Management of IAV Infection
20.5 Conclusion
References
21: Understanding the Biology of Non-typeable Haemophilus influenzae in Chronic Obstructive Pulmonary Disease Through the Lens...
21.1 Introduction to Haemophilus and Human Colonisation
21.2 Non-typeable Haemophilus influenzae and Human Disease
21.3 Current Techniques for the Genotyping of NTHi
21.4 Differential Genomic Content of NTHi Strains Associated with COPD
21.5 Future Applications of Genomics in NTHi Diagnostics and Treatment
21.6 Conclusions
References
22: Targeting Molecular and Cellular Mechanism in Rhinovirus Infection
22.1 Introduction
22.2 Structure of Rhinovirus (Picornavirus)
22.3 Pathogenesis of Rhinovirus
22.3.1 Pathogenesis of Rhinovirus in the Respiratory Tract (Upper and Lower)
22.3.2 Pathogenic Influences of Rhinovirus on the Epithelium
22.4 Immune Response to Rhinovirus
22.5 Therapeutic Approaches against Rhinovirus
22.5.1 Strategies to Targeting Virus
22.5.2 Strategies to Targeting Host Protein
22.6 Summary
References
23: Targeting Molecular and Cellular Mechanisms in Respiratory Syncytial Virus (RSV) Infection
23.1 Introduction
23.1.1 Etiology
23.1.2 Symptoms of RSV Infection
23.1.3 Diagnosis
23.1.4 Structure of RSV
23.2 Pathogenesis of RSV Infection
23.2.1 Incubation Period
23.3 Immune Response to RSV
23.3.1 Systemic Response to RSV
23.3.1.1 Neutrophils
23.3.1.2 Natural Killer (NK) Cells
23.3.1.3 Dendritic Cells
23.3.1.4 Monocytes and Macrophages
23.3.1.5 T Lymphocytes
23.3.2 Cellular Response in Term and Preterm Infants
23.4 Current Therapies for RSV Infection
23.4.1 Treatments in Clinical Trials
23.5 Molecular and Cellular Targets to Prevent RSV Infection
23.5.1 G Protein
23.5.1.1 Targeting of G Protein with Monoclonal Antibodies (mAb)
23.5.2 F Protein
23.5.3 SH Protein
23.5.4 N Protein
23.6 Future Prospective
References
24: Targeting Molecular and Cellular Mechanisms in SARS-CoV-2 Novel Coronavirus Disease 2019 (COVID-19)
24.1 Introduction
24.2 Transmission Cycle
24.3 Structure of SARS-CoV-2
24.4 Pharmacological Treatment
24.5 Conclusion
References
25: Underpinning the Rudimentary/Underlying Mechanisms Involved in the Pathogenesis of SARS-CoV-2 (COVID-19) in Human Lung Cel...
25.1 Background
25.2 Classification and Origin of SARS-CoV-2
25.3 Structural Organization of the Virus
25.4 Human Transmission of SARS-CoV-2
25.5 The Temporal Spread of SARS-CoV-2 Subtypes
25.6 Phases of Viral Life Cycle
25.6.1 Cleavage of S Protein
25.6.2 Binding of the Activated S Protein with ACE2 Receptor
25.6.3 Fusion of the Virus and Host Cell Membranes
25.6.4 Replication of the Viral Genome
25.6.5 Assembly and Release of the Progeny Virus Particles
25.7 Pathogenicity of SARS-CoV-2 in Host
25.7.1 Downregulation of ACE2
25.7.2 Impairment of the Immune System
25.7.2.1 Cytokine Storm
25.7.2.2 Activation of the Complement System
25.7.2.3 Lymphocyte Dysfunction
25.8 Role of Host Genetics in Viral Pathogenesis
25.9 Therapeutics Developments for Management of COVID-19
25.9.1 Agents Targeting Viral Replication
25.9.1.1 Remdesivir (GS-5734)
25.9.1.2 Favipiravir
25.9.1.3 Ivermectin
25.9.1.4 Ribavirin
25.9.2 Agents Blocking the Virus-Host Cell Membrane Fusion
25.9.2.1 Recombinant Human Angiotensin-Converting Enzyme 2 (APN01)
25.9.2.2 Hydroxychloroquine
25.9.2.3 Arbidol Hydrochloride (Umifenovir)
25.9.3 Immunomodulatory Medications
25.9.3.1 Tocilizumab
25.9.3.2 Sarilumab and Emapalumab
25.9.3.3 Bevacizumab
25.10 Conclusion
References
26: Targeting Molecular and Cellular Mechanisms in SARS-CoV-2 Novel Corona (COVID-19) Virus Infection
26.1 Introduction
26.2 Phylogeny and Molecular Mechanism of Infectivity of SARS-CoV-2
26.3 The Signaling Pathways and Key Molecules Tangled with SARS-CoV-2 Infections in the Lung
26.4 Role of Angiotensin-Converting Enzyme 2 (ACE2) and Proteases Toward SARS-CoV-2 Infection
26.5 Toll-Like Receptors (TLRs) and Activation of NF-κB and Interferon Regulatory Factor in the Lung
26.6 Association of Interferons in COVID-19
26.7 Involvement of Il-6 and JAK/STAT Signaling During CoV Infection
26.8 NF-κBeta Signaling Pathway: A Major Signaling Pathway in SARS-CoV Infection
26.9 NLPR3 Inflammasomes
26.10 p38-MAP Kinase Pathway
26.11 Targeting Potential Molecules for Treatment of COVID-19
26.12 Conclusion
References
27: Special Features of Human Lung ACE2 Sensitivity to SARS-CoV-2 Spike Glycoprotein
27.1 Introduction
27.2 Angiotensin and Its Physiological Functions
27.3 Role of Angiotensin-Metabolizing Proteins
27.4 Functions of ACE2 and Its Role in Lung Functions
27.5 ACE2 Polymorphism and Its Physiological Implications
27.6 Evolutionary Basis of ACE2 and SARS Spike Glycoprotein Binding
27.7 Clinical Feature of ACE2 and Spike Binding
27.8 Differential Global Binding Pattern of ACE2 and Spike Protein
27.9 Therapeutic Strategies Against SARS-CoV-2 Via ACE2
27.10 Conclusion
References
28: Implications of Phosphoinositide 3-Kinase (PI3K) Signalling in Cellular and Molecular Mechanisms of Respiratory Diseases
28.1 Introduction
28.2 Historical Overview of PI3 Kinase
28.3 Classification and Overview of PI3K Signalling Cascades
28.3.1 Classification
28.3.2 Downstream Signal Transduction Pathways of PI3 Kinase
28.3.2.1 Class I PI3K
28.3.2.2 Class II PI3K
28.3.2.3 Class III PI3K
28.4 Molecular Mechanism of Different Respiratory Diseases Involving PI3K Pathway
28.4.1 Asthma
28.4.2 Chronic Obstructive Pulmonary Disease (COPD)
28.4.3 Cystic Fibrosis (CF)
28.4.4 Activated PI3K Delta Syndrome (APDS)
28.4.5 Idiopathic Pulmonary Fibrosis (IPF)
28.4.6 Lung Cancer
28.5 Role of PI3K Inhibitors in the Prevention of Respiratory Diseases
28.6 Implications of PI3Kinase Signalling in COVID Infection
28.7 Conclusion
References
29: The Role of the Cholinergic System in Lung Diseases
29.1 Introduction
29.2 Components of the Cholinergic System
29.2.1 Acetylcholine
29.2.2 Enzymes of the Cholinergic System
29.2.3 ACh Receptors
29.2.3.1 The Muscarinic Acetylcholine Receptors
29.2.3.2 The Nicotinic Acetylcholine Receptors
29.2.4 Vesicular Acetylcholine Transporter
29.3 Pulmonary Cholinergic System
29.4 Cholinergic System and Lung Cancer
29.5 The Cholinergic System in Asthma and Chronic Obstructive Pulmonary Disease
29.5.1 Treatment of Asthma and COPD with Anticholinergics
29.5.2 Short-Acting Muscarinic Anticholinergics (SAMA)
29.5.3 Long-Acting Muscarinic Anticholinergics
29.6 Future Perspective
References
30: The Keap1-Nrf2 Signaling Pathway in Lung Cancer
30.1 Introduction
30.2 Keap1-Nrf2 Signaling Pathway
30.3 Regulation and Dysregulation of Nrf-Keap1 Signaling Pathway in Lung Cancer
30.4 Mutations in Keap1 and Nrf2 in Lung Cancer
30.5 MicroRNAs Associated with the Keap1-Nrf2 Signaling Pathway in Lung Cancer
30.6 Smoking and Nrf2 Activation in Lung Cancer
30.7 Nrf2-Keap1 Signaling Pathway as a Therapeutic Target in Lung Cancer
30.8 Inhibitors of Nrf2 in Lung Cancer
30.9 Conclusion
References
31: Role of Toll-Like Receptors in Molecular and Cellular Mechanisms of Respiratory Diseases
31.1 Introduction
31.2 Types and Functions of TLR
31.3 Activation and Signaling of TLR
31.4 Implications of TLR in Respiratory Diseases
31.4.1 TLR in Asthma
31.4.2 TLR in Lung Cancer
31.4.3 TLR in COPD
31.4.4 TLR in Pulmonary Infection
31.5 Targeting of TLR Signaling
31.6 Conclusion
References
32: Biomarkers of Oxidative Stress
32.1 Single Oxidation or Antioxidant
32.2 Total Oxidant Status and Total Antioxidant Status
32.2.1 Measurement of Total Antioxidant Status
32.2.1.1 Detection Principle
32.2.1.2 Reagent Composition
32.2.1.3 Instrument Setting
32.2.2 Measurement of Total Oxidant Status
32.2.2.1 Detection Principle
32.2.2.2 Reagent Composition
32.2.2.3 Instrument Setting
32.3 Calculation of Oxidant Stress Index
32.4 End Products of Lipid Hydroperoxide
32.5 Measurement of Malondialdehyde
32.5.1 Detection Principle
32.5.2 Reagent Composition
32.5.3 Manipulation Steps
32.6 Conclusions
References
33: Targeting Chronic Lung Diseases Using Advanced Drug Delivery Systems
33.1 Introduction
33.2 Targeting of Various Chronic Lung Diseases Using Advanced Drug Delivery Systems
33.2.1 Asthma
33.2.2 Chronic Obstructive Pulmonary Disease
33.2.3 Lung Cancer
33.2.4 Idiopathic Pulmonary Fibrosis
33.2.5 Pulmonary Arterial Hypertension
33.2.6 Pulmonary Tuberculosis
33.3 Future Perspectives
33.4 Conclusion
References
34: Plant-Based Chemical Moieties for Targeting Chronic Respiratory Diseases
34.1 Introduction
34.2 Plant-Based Chemical Moieties in the Management of Chronic Respiratory Diseases: From Bench to Bedside
34.2.1 Asthma
34.2.1.1 Overview of Asthma
34.2.1.2 Evidence of Plant-Based Chemical Moieties in the Management of Asthma
34.2.2 Chronic Obstructive Pulmonary Disease
34.2.2.1 Overview of Chronic Obstructive Pulmonary Disease
34.2.2.2 Evidence of Plant-Based Chemical Moieties in the Management of Chronic Obstructive Pulmonary Disease
34.2.3 Lung Cancer
34.2.3.1 Overview of Lung Cancer
34.2.3.2 Evidence of Plant-Based Chemical Moieties in the Management of Lung Cancer
34.3 Conclusion and Future Directions
References
35: Role of Phytoconstituents in Targeting Cytokines for Managing Pathophysiology of Lung Diseases
35.1 Introduction
35.2 Cytokines and Type of Cytokines
35.2.1 Etiology and Therapeutics of COPD
35.3 Effect of Various Phytoconstituents in Chronic Lung Disease and Cytokines
35.3.1 Alkaloids
35.3.1.1 Iso-steroid Alkaloids
35.3.1.2 Indole and Quinolone Alkaloids
35.3.1.3 Quinazoline Alkaloids
35.3.1.4 Bisbenzylisoquinoline
35.3.1.5 Benzophenanthridine
35.3.1.6 Acridone Quinolone Alkaloids
35.3.2 Flavonoids
35.3.2.1 Quercetin
35.3.2.2 Eriodictyol
35.3.2.3 Kaempferol
35.3.2.4 Luteolin
35.3.2.5 Sakuranetin
35.3.2.6 Naringin
35.3.3 Terpenes
35.3.3.1 Limonene
35.3.3.2 Carvacrol
35.3.3.3 Thymol
35.3.3.4 Thymoquinone
35.3.3.5 Farnesol
35.3.4 Miscellaneous
35.3.4.1 Sulforaphane
35.3.4.2 Curcumin
35.3.4.3 Caffeic Acid
35.4 Conclusion
References
36: Targeting Cellular Signaling Pathways in Lung Cancer and Role of Phytochemicals as Novel Therapeutic Approach
36.1 Introduction
36.2 Causes of Lung Cancer
36.3 Signaling Pathways in Lung Cancer
36.3.1 Epidermal Growth Factor Receptor Pathway
36.3.2 Estrogen Receptor Pathway
36.3.3 Insulin-Like Growth Factor Pathway
36.3.4 Hedgehog Signaling Pathway
36.3.5 Vesicular Endothelial Growth Factor Pathway (VEGF)
36.4 Limitations of Ongoing Cancer Therapy
36.5 Phytochemicals as Novel Therapeutic Approach
36.5.1 Vinca Alkaloids
36.5.2 Cephalotaxus
36.5.3 Derivatives of Camptothecin
36.5.4 Celastrol
36.5.5 Resveratrol
36.5.6 Fisetin
36.6 Conclusion
References
37: Natural Compounds Targeting Major Signaling Pathways in Lung Cancer
37.1 Introduction
37.2 Signaling Pathways in Lung Cancer
37.2.1 Receptor Tyrosine Kinase (RTK) Pathway
37.2.2 Epidermal Growth Factor Receptor (EGFR)
37.2.3 ALK Fusion Proteins
37.3 RAS Pathway
37.4 BRAF/MAPK Pathway
37.5 PI3K Pathway
37.6 LKB1/AMPK Pathway
37.7 TP53 Pathway
37.8 RB1 Pathway
37.9 MYC Pathway
37.10 Developmental Pathways
37.11 Natural Compounds as Anticancer Agent in Lung Cancer
37.11.1 Curcumin
37.11.2 Wortmannin and Roscovitine
37.11.3 Gigantol
37.11.4 Chrysotoxine
37.11.5 Vanillin
37.11.6 Silibinin
37.11.7 Parthenolide
37.11.8 Renieramycin M
37.11.9 Salinomycin
37.11.10 Cordyceps militaris
37.11.11 Resveratrol
37.11.12 Myricetin
37.11.13 Berberine
37.11.14 Antroquinonol
37.11.15 Honokiol
37.11.16 Emodin
37.11.17 Dioscin
37.11.18 Piperine
37.11.19 Plumbagin
37.11.20 Epigallocatechin-3-gallate (EGCG)
37.11.21 Picropodophyllin
37.11.22 Alantolactone
37.11.23 Costunolide
37.11.24 Catechins
37.11.25 Wentilactone A
37.11.26 Evodiamine
37.12 Conclusion
References
38: Drug Delivery in Respiratory Diseases: Current Opportunities, Molecular and Cellular Mechanism, and Future Challenges
38.1 Introduction
38.1.1 Anatomy
38.1.2 Functioning of the Lung in the Human Body
38.1.2.1 Respiratory Functions
38.1.2.2 Non-respiratory Functions of the Lungs
38.2 Effect of Particle Size on Pulmonary Administration of Drug
38.3 Barriers to Drug Delivery at the Respiratory Tract
38.4 Respiratory Barriers to Drug Administration
38.5 Pathophysiology of Respiratory Diseases
38.5.1 Pneumonia
38.5.1.1 Pathophysiology and Cellular Mechanism
38.5.1.2 Treatment Strategies
38.5.1.3 Novel Drug Delivery Strategies
38.5.2 Tuberculosis
38.5.2.1 Treatment Strategies
38.5.2.2 Novel Drug Delivery Strategies
38.5.3 Emphysema
38.5.3.1 Cellular Mechanism
38.5.3.2 Treatment Strategies
38.5.3.3 Novel Drug Delivery Systems for Emphysema
38.5.4 Pulmonary Oedema
38.5.4.1 Pathophysiology
38.5.4.2 Treatment Strategies
38.5.5 Lung Cancer
38.5.5.1 Pathogenesis
38.5.5.2 Treatment Strategies
Treatment of NSCLC
Treatment of Small Cell Lung Cancer (SCLC)
38.5.5.3 Delivery Systems
38.5.6 Asthma
38.5.6.1 Pathogenesis
38.5.6.2 Treatment Strategies
38.5.6.3 Novel Drug Delivery Systems
38.5.7 Cystic Fibrosis
38.5.7.1 Treatment Strategies
38.5.7.2 Novel Drug Delivery Systems
38.5.8 COPD (Chronic Obstructive Pulmonary Disease)
38.5.8.1 Pathophysiology
38.5.8.2 Treatment of Strategies
38.5.8.3 Delivery Systems
38.6 Mechanisms of Particle Internalization into Cell
38.6.1 Phagocytosis
38.6.2 Clathrin-Mediated Endocytosis (CME)
38.6.3 Caveolae-Dependent Endocytosis (CDE)
38.6.4 Clathrin/Caveolae-Independent Endocytosis
38.7 Delivery Device
38.7.1 Dry Powder Inhaler (DPI)
38.7.2 Nebulizers
38.7.3 Soft Mist Inhaler (SMI)
38.7.4 Pressurized Metered Dose Inhalers (pMDI)
38.7.5 Metered Dose Inhaler (MDI) with Spacer
38.7.5.1 Breath-Actuated Metered Dose Inhaler (baMDI)
38.8 Future Challenges
References
39: Future Prospects and Challenges in Targeting Cellular and Molecular Mechanisms in Respiratory Diseases
39.1 Introduction
39.2 Genomic and Molecular Characterization of Lung Disease
39.3 Mechanisms of Respiratory Diseases
39.3.1 Lung Injury Mechanism
39.3.1.1 Inflammatory Mechanism
39.3.1.2 The Role of Nitric Oxide in Lung Injury
39.3.1.3 Apoptosis in Lung Injury
39.3.2 Lung Repair Mechanism
39.3.2.1 The Role of Antioxidant Enzymes
39.3.2.2 Cellular and Molecular Determinants of Lung Repair Following Injury
39.4 Challenges in Targeting Molecular Mechanisms in Respiratory Diseases
39.5 Translational Lung Medicine
39.5.1 Lung Microbiome
39.6 Genetic Consideration in Treatment of Lung Diseases
39.6.1 Gene Therapy for Acute and Acquired Lung Disease
39.6.1.1 Lung Injury
Lung Cancer
39.6.2 Gene Therapy for Chronic Lung Disease
39.7 Cutting-Edge Technologies in Treatment of Lung Diseases
39.8 Future Prospective
39.9 Conclusion
References