Wound repair in healthy lungs and IPF Slidekit references

Wound repair in healthy lungs references

In healthy lungs, alveolar epithelial cells form part of the alveolar-capillary barrier.1 Alveolar epithelium Interstitial space Strieter RM, et al. Chest. 2009;136:1364-1370. Gordon SB, et al. Br Med Bull. 2002;61:45-61. Clarke DL, et al. Fibrogenesis Tissue Repair. 2013;6:20. references

On the inner surface of the alveolus, macrophages serve as a first-line defence against pathogens.2  Alveolar macrophages Interstitial space Strieter RM, et al. Chest. 2009;136:1364-1370. Gordon SB, et al. Br Med Bull. 2002;61:45-61. Clarke DL, et al. Fibrogenesis Tissue Repair. 2013;6:20. references

Gas exchange takes place across the alveolar-capillary barrier and the blood is oxygenated.1  Gas exchange Strieter RM, et al. Chest. 2009;136:1364-1370. Gordon SB, et al. Br Med Bull. 2002;61:45-61. Clarke DL, et al. Fibrogenesis Tissue Repair. 2013;6:20. references

Local fibroblasts play a central role in maintaining normal tissue structure and function, and mediate the wound healing response.3 Fibroblasts Strieter RM, et al. Chest. 2009;136:1364-1370. Gordon SB, et al. Br Med Bull. 2002;61:45-61. Clarke DL, et al. Fibrogenesis Tissue Repair. 2013;6:20. references

Damage to the alveolar epithelium initiates the coagulation cascade Cytokines Alveolar damage Camelo A, et al. Inflamm Pharmacol. 2014;4:173. Chambers RC. Eur Respir Rev. 2008;17:130-137. references

Activated platelets from the blood stream release pro-fibrotic factors including PDGF and TGF-β1…1 Platelets Camelo A, et al. Inflamm Pharmacol. 2014;4:173. Chambers RC. Eur Respir Rev. 2008;17:130-137. Clarke DL, et al. Fibrogenesis Tissue Repair. 2013;6:20. references

…and form a loose plug, which is stabilised by long strands of fibrin Fibrin network Camelo A, et al. Inflamm Pharmacol. 2014;4:173. Chambers RC. Eur Respir Rev. 2008;17:130-137. Clarke DL, et al. Fibrogenesis Tissue Repair. 2013;6:20. references

Inflammatory cells are recruited to the site of injury.1,3 Alveolar macrophages Neutrophils Camelo A, et al. Inflamm Pharmacol. 2014;4:173. Chambers RC. Eur Respir Rev. 2008;17:130-137. Clarke DL, et al. Fibrogenesis Tissue Repair. 2013;6:20. references

In this repair response, fibroblasts differentiate into myofibroblasts and begin to remodel the extracellular matrix.1-3 Fibroblasts Myofibroblasts Camelo A, et al. Inflamm Pharmacol. 2014;4:173. Chambers RC. Eur Respir Rev. 2008;17:130-137. Clarke DL, et al. Fibrogenesis Tissue Repair. 2013;6:20. references

1. Gardner A., et al. Expert Rev Respir Med. 2010;4:647-660. In the physiologic healing process, these cells normally undergo apoptosis once wound contraction is complete.1 Collagen 1. Gardner A., et al. Expert Rev Respir Med. 2010;4:647-660. references

Reformed alveolar epithelium Mature extracellular matrix The provisional extracellular matrix matures and the alveolar epithelium reforms.1  Reformed alveolar epithelium Mature extracellular matrix 1. Gardner A., et al. Expert Rev Respir Med. 2010;4:647-660. references

IPF Mechanism of Disease references

Although the pathophysiology of IPF is not yet fully understood… Alveolar damage 1. Gardner A., et al. Expert Rev Respir Med. 2010;4:647-660. 2. Chambers RC. Eur Respir Rev. 2008;17:130-137. references

Cytokines (e.g. PDGF, TGF-β1) …there is evidence that repetitive alveolar injury causes dysregulated wound healing in susceptible individuals.1,2  Cytokines (e.g. PDGF, TGF-β1) 1. Gardner A., et al. Expert Rev Respir Med. 2010;4:647-660. 2. Chambers RC. Eur Respir Rev. 2008;17:130-137. references

Under the influence of numerous fibrogenic mediators such as PDGF and TGF-β1, myofibroblasts proliferate uncontrolled.1,2 Fibroblasts Myofibroblasts Collagen Chambers RC. Eur Respir Rev. 2008;17:130-137. Hinz B. Proc Am Thorac Soc 2012;9:137-147. references

Excessive deposition of Permanently impaired epithelium extracellular matrix in the interstitium creates fibrotic scar tissue.2 Permanently impaired epithelium Fibrotic tissue Chambers RC. Eur Respir Rev. 2008;17:130-137. Hinz B. Proc Am Thorac Soc 2012;9:137-147. references

Excessive deposition of As a result, the lung tissue stiffens and the gas exchange is impaired.2 Excessive deposition of extracellular matrix in the interstitium creates fibrotic scar tissue.2 Impaired gas exchange Chambers RC. Eur Respir Rev. 2008;17:130-137. Hinz B. Proc Am Thorac Soc 2012;9:137-147. references

References Strieter RM, et al. Chest. 2009;136:1364-1370. 1. Strieter RM., et al. NEw mechanisms of pulmonary fibrosis. Chest 2009;136:1364–1370. Gordon SB., et al. Macrophage defences against respiratory tract infections The immunology of childhood respiratory infections. Br Med Bull 2002;61:45–61. 3. Clarke DL., et al. Matrix regulation of idiopathic pulmonary fibrosis: the role of enzymes. Fibrogenesis Tissue Repair 2013;6:20. 4. Chambers RC. Abnormal wound healing responses in pulmonary fibrosis: focus on coagulation signalling. Eur Respir Rev 2008;17:130–137. Camelo A., et al. The epithelium in idiopathic pulmonary fibrosis: breaking the barrier. Inflamm Pharmacol 2014;4:173. Gardner A., et al. Lung epithelial wound healing in health and disease. Expert Rev Respir Med 2010;4:647–660. 7. Hinz B. Mechanical Aspects of Lung Fibrosis. Proc Am Thorac Soc 2012;9:137–147. 8. Gardner A., et al. Lung epithelial wound healing in health and disease. Expert Rev Respir Med 2010;4:647–660. 9. Wollin L., et al. Antifibrotic and Anti-inflammatory Activity of the Tyrosine Kinase Inhibitor Nintedanib in Experimental Models of Lung Fibrosis. J Pharmacol Exp Ther 2014;349:209–220. Wollin L., et al. Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. Eur Respir J 2015;45:1434–1445. 11. Thannickal VJ., et al. Myofibroblast differentiation by transforming growth factor-beta1 is dependent on cell adhesion and integrin signaling via focal adhesion kinase. J Biol Chem 2003;278:12384–12389. 12. Hostettler KE., et al. Anti-fibrotic effects of nintedanib in lung fibroblasts derived from patients with idiopathic pulmonary fibrosis. Respir Res 2014;15:157. Richeldi L., et al. Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis. N Engl J Med 2014;370:2071–2082. Strieter RM, et al. Chest. 2009;136:1364-1370. Gordon SB, et al. Br Med Bull. 2002;61:45-61. Clarke DL, et al. Fibrogenesis Tissue Repair. 2013;6:20. Chambers RC. Eur Respir Rev. 2008;17:130-137. Camelo A, et al. Inflamm Pharmacol. 2014;4:173. Hinz B. Proc Am Thorac Soc. 2012;9:137-147. Gardner A, et al. Expert Rev Respir Med. 2010;4:647-660. references