Macrolides as Immunomodulatory Agents (Progress in Inflammation Research, 92) (Jan 5, 2024)_(3031428587)_(Springer)

For over 50 years, clinicians have known that macrolide antibiotics have effects on inflammation and the immune system that are not related to their antimicrobial properties. These immunomodulatory properties, best described for treating inflammatory airway diseases, protect the lung and the host and improve clinical status. This book summarizes our current knowledge regarding proposed mechanisms for these properties, established clinical results, and what the future may hold with emphasis on novel clinical applications and the fascinating development of non-antimicrobial macrolides with preserved and enhanced immunomodulatory properties. Preface: A Brief History of the Macrolide Antibiotics References Contents Part I: Mechanisms of Action and Novel Macrolides Macrolides and Diseases Associated with Loss of Epithelial Barrier Integrity 1 Introduction 2 Epithelial Barrier Failure, a Common Pathophysiological Feature of Various Chronic Inflammatory Diseases 2.1 Epithelial Homeostasis, Remodeling, and Barrier Failure 2.1.1 Airway Epithelium 2.1.2 Epidermis 2.1.3 Intestinal and Colon Epithelium 3 In Vitro Models to Study Epithelial Integrity and the Mechanism of Action of Macrolides 4 Macrolides and the Epithelial Barrier 5 Macrolide-Sensitive Inflammatory Diseases 5.1 Distinctions between Macrolide Antibiotics 5.2 Macrolide Antibiotics in COPD and Asthma 5.3 Macrolides in Other Inflammatory Disorders 6 Concluding Remarks References Macrolides and Inflammatory Cells, Signaling, and Mediators 1 Introduction 2 Regulation of Airway Secretion and Inflammatory Cells/Cytokines and Chemokines by Macrolides 3 Intracellular Signaling Mechanisms 4 Conclusion References Part II: Clinical Use for Airway Disease Macrolides as Immunomodulatory Agents 1 Introduction 2 Epidemiology 3 HLA Antigens 4 Pathophysiology 5 Diagnosis 6 Treatment 7 Macrolide-Resistant DPB 8 Conclusion References Macrolides and Cystic Fibrosis 1 Introduction 2 Pathophysiology 2.1 Low Volume Hypothesis 2.2 Primary Inflammation Hypothesis 2.3 Aberrant Mucin Secretion Hypothesis 2.4 Cell Receptor Hypothesis 3 Clinical Features in CF 4 Proposed Mechanisms for Action of Macrolides in CF 4.1 Signalling Pathways and Chemokine Release 4.2 Direct Neutrophil Effect 4.2.1 Endothelial and Airway Adhesion 4.2.2 Migration 4.2.3 Reactive Oxygen Species (ROS) 4.2.4 Apoptosis 4.3 Effect on Pseudomonas aeruginosa 4.3.1 Adherence 4.3.2 Suppression of Bacterial Exoproducts and Mucus Secretion 4.3.3 Non-inflammatory Effects 4.4 Antiviral Effects 4.5 Effects on Ion Transport 4.6 Nitric Oxide (NO) 4.7 Airway Remodelling 4.8 Bioactive Phospholipids 4.9 Antibacterial Effects in CF 4.10 Summary 5 Clinical Evidence in CF 5.1 Efficacy 5.2 Safety 5.3 Macrolide Use in CF: Concerns 6 Conclusions and Future Directions References Non-CF Bronchiectasis 1 Introduction 2 The History of Macrolide Antibiotic Use in Bronchiectasis 3 Mechanism of Action of Macrolide Antibiotics in Bronchiectasis 4 Recommendations for Long-Term Macrolide Therapy in Bronchiectasis 4.1 Paediatric Evidence on Long-Term Macrolides in Bronchiectasis Management 4.2 Adult Evidence on Long-Term Macrolides in Bronchiectasis Management 5 Recommended Macrolide Dosage and Duration in Bronchiectasis 6 Cost-Effectiveness of Azithromycin in Bronchiectasis 7 Safety and Adverse Effects of Long-Term Azithromycin 8 Azithromycin as Acute Management for Acute Respiratory Exacerbations in Bronchiectasis 9 Conclusion and Future Perspectives References Macrolide Use in Chronic Obstructive Pulmonary Disease 1 Introduction and Background 2 Macrolides for the Treatment of Acute Exacerbations of COPD 3 Prophylactic Macrolides for the Prevention of Acute Exacerbations of COPD 4 Adverse Effects 5 Evidence Summary and Future Directions 6 Conclusion References Macrolides and Asthma Therapy 1 Introduction 2 Mechanisms of Action of Macrolides in Asthma 2.1 Anti-inflammatory and Immunomodulatory Effects 2.2 Effects on Airway Secretions 2.3 Antimicrobial Effects 2.4 Effects on Gastrointestinal Motility 3 Evidence of Macrolide Treatment Effectiveness 3.1 Acute Asthma 3.2 Chronic Asthma 4 Conclusions References Macrolides and Interstitial Lung Diseases 1 Introduction 2 Possible Mechanisms for Macrolide Action in ILD 2.1 Promotion of Autophagy Capacity and Regulation of Surfactant Homeostasis 2.2 Eliminating Senescent Alveolar Epithelial Cells 2.3 Modulation of Microbiota 2.4 Macrophage Polarization 2.5 Reducing MUC5B in the Distal Airway 3 Clinical Evidence of Macrolide Efficacy in Patients with ILD (Table 1) 3.1 IPF 3.1.1 Inhibition of IPF Progression 3.1.2 Treatment of AE (Including Other ILDs) 3.2 Cryptogenic Organizing Pneumonia 4 Conclusion 5 Ethical Approval References Macrolides in Acute Respiratory Distress Syndrome and Acute Lung Injury 1 Introduction 2 ARDS 2.1 Overview of ARDS 2.2 Pathophysiology of ARDS 2.3 Possible Mechanisms of Action of Macrolides in ARDS 3 Possible Mechanisms of Action of Macrolides in ARDS-related conditions 3.1 Ventilator-Associated Lung Injury (VALI) 3.2 Ventilator-Associated Pneumonia (VAP) 3.3 Pulmonary Fibrosis after ARDS 4 Current Evidence for Macrolides in ALI and ARDS from Human Data 4.1 Effects of Macrolides in Patients with ARDS 4.2 Severe Pneumonia 4.2.1 Severe Community-Acquired Pneumonia 4.2.2 Viral Pneumonia 4.3 Acute Exacerbation of Pulmonary Fibrosis 5 Summary of the Use of Macrolides in ARDS and ALI 6 Future Research Perspectives 6.1 The Impact of ARDS Phenotypes on Therapeutic Response 7 Conclusion References Azithromycin for Other Lung Diseases: Lung Transplantation and Sarcoidosis 1 Role of Azithromycin in Lung Transplantation 1.1 Short-Term Treatment Effects in Patients with Bronchiolitis Obliterans Syndrome (BOS) 1.2 Long-Term Effects of Add-on Azithromycin in Patients with BOS 1.3 Azithromycin Treatment as Prevention for the Development of BOS 1.4 Other Possible Indications for Azithromycin Treatment after Lung Transplantation 2 Azithromycin in the Treatment of Sarcoidosis 3 Conclusion References Macrolides for Rhinosinusitis and Nasal Polyps 1 Introduction 2 Progress in Macrolide Therapy for CRS 3 The Therapeutic Mechanism of Macrolides on CRS 4 Macrolide Therapy in Children 5 Conclusion References Part III: Clinical Use for Other Diseases Macrolides for Cancer 1 Introduction 2 Carcinogenic Mechanisms and Macrolide Effects on Them 2.1 Infection 2.1.1 Helicobacter pylori (H. pylori) Infection 2.2 Sustaining Proliferative Signaling 2.2.1 Raf to Mitogen-Activated Protein (MAP)-Kinase Pathway 2.2.2 Phosphatidylinositol-3 Kinase (PI3K)/Akt/mTOR Signal Pathway 2.2.3 Wnt/β-Catenin Signal Pathway 2.2.4 Hippo Signaling Pathway 2.3 Evading Growth Suppressors 2.3.1 Corruption of the Transforming Growth Factor (TGF)-β Pathway Promotes Malignancy 2.4 Resisting Cell Death 2.4.1 Apoptosis 2.4.2 Autophagy 2.4.3 Pyroptosis 2.5 Inducing Angiogenesis 2.6 Activating Invasion and Metastasis 2.6.1 Epithelial-Mesenchymal Transition 2.7 Deregulating Cellular Energetics 2.8 Cancer Stem Cells (CSCs) 2.9 Drug Resistance/Synergistic Effect with Other Drugs 3 Clinical Data 3.1 Clarithromycin (Table 1) 3.2 Azithromycin 3.3 Rapamycin (Everolimus (Table 2), Temsirolimus (Table 3), Ridaforolimus (Table 4)) 4 Future Outlook and Conclusion References Macrolides in Chronic Skin Disorders 1 Introduction 2 Rosacea 3 Palmoplantar Pustulosis and SAPHO Syndrome 4 Psoriasis 5 Adult-Onset Still ́s Disease (AOSD) 6 Chronic Urticaria 7 Pityriasis Rosea 8 Pityriasis Lichenoides Chronica 9 Bullous Pemphigoid 10 Idiopathic Thrombocytopenic Purpura 11 Alopecia Areata 12 Targeted Therapy and Chemotherapy Associated Skin Toxicities 13 Itch and Atopic Dermatitis 14 Conclusion References Macrolide Use in Preschool-Aged Children with Acute or Recurrent Respiratory Tract Illnesses with Wheezing 1 Epidemiology of Lower Respiratory Tract Illnesses with Wheezing (WLRI) 2 Etiology of WLRI 3 Biological Effects of Macrolides Relevant to WLRI 4 Use of Macrolides during Acute Wheezing Illnesses 5 Azithromycin for Respiratory Syncytial Virus (RSV) Bronchiolitis to Prevent Future Wheezing Illnesses 6 Risks of Macrolide Use 7 Conclusion References Macrolides and Immunomodulation: Today and the Future References