Emphysema and Fibrosis Universitätsklinik für Pneumologie Prof. Thomas Geiser Head Div. of Pulmonary Medicine and Laboratory of Lung Research, MU50 thomas.geiser@insel.ch
The healthy lung: The pathway of oxygen Nose, Pharynx: Warming, moistering Trachea, Bronchi: Transportation, Immunology Alveoli Gas exchange Immunology Th. Geiser 2
Lung: O2 Transportation, gas exchange, defense systems Airways, blood vessels Alveoli, Capillaries Alveoli 400 Millions 0.25 mm Th. Geiser 3
Air-Blood barrier in the lung Air-Blood barrier = 2 m Inst. of Anatomy, Bern Th. Geiser 4
Clearance of particles: mucociliary clearance Mucus 2-13 mm/min Cilia 10 0.25 m 22 Hz Inst. of Anatomy, Bern Th. Geiser 5
Clearance of particles: Macrophages (innate immunity) 3 µm Macrophage with spores in the airways Macrophage in the alveoli Inst. of Anatomy, Bern Th. Geiser 6
Inhaled particles in the lung 5 µm 5 µm Glass fibers in the conducting airways Spores in alveoli Courtesy of Inst. of Anatomy, Bern Th. Geiser 7
Chronic obstructive lung disease (COPD) smoking related occupational (farmers) other etiologies (autoimmune disease?) Th. Geiser 8
Proportion der Rate 1965 3.0 3.0 2.5 2.5 2.0 2.0 1.5 1.5 1.0 1.0 Chronic obstructive lung disease (COPD): Increase in mortality Coronary Heart Disease Stroke Other CVD COPD All Other Causes 0.5 0.5 0.00 59% 64% 35% +163% 7% 1965-1998 1965-1998 1965-1998 1965-1998 1965-1998 Th. Geiser 9
COPD airway obstruction not fully reversible Small airways - Inflammation - Remodeling Damage of Parenchyma - Emphysema Partially reversible - Inflammation - Mucus secretion - smooth muscle contraction Irreversible - Less Recoil pressure - destruction of alveolar walls - fibrosis/remodeling Th. Geiser 10
Initiating faktors (smoking, infection) Reduced mucociliary clearance Colonisation Bacterial infections Bacterial products (LPS) Inflammation Epithelial damage Proteases O2-Radikals Emphysema Remodeling with obstruktion COPD Th. Geiser 11
COPD a disease of the airways and the lung parenchyma Th. Geiser 12
Normal lung Smokers lung (emphysema) Th. Geiser 13
COPD pathomechanisms Th. Geiser 14
COPD future therapies Th. Geiser 15
Chronic (lung) injury Fibrosis NORMAL PULMONARY FIBROSIS Th. Geiser 16
Histology of IPF: usual interstitial pneumonia Th. Geiser 17
Old Hypothesis Stimulus New Hypothesis Repeated stimulus Chronic inflammation Injury Sequential lung injury Inflammation Aberrant wound repair Fibrosis Fibrosis Th. Geiser 18
Alveolar epithelium Typ I Typ II Growth factors PDGF, TGF-b Endothelin-1 Coagulation activation Fibrinous matrix Myofibroblasts Proteases Antiproteases Thorax 2007 Thromb Hemost 2005 Th. Geiser 19
Growth factors Fibrinous Matrix Collagen Neoangiogenesis Keratinocyte Growth Factor (KGF) Hepatocyte Growth Factor (HGF) Am J Physiol Lung 2004, 2007 Th. Geiser 20
KGF, HGF Adapted from Selman, Ann Intern Med. 2001;134:136-51. Th. Geiser 21
Growth factors modulate cell differentiation and stem cell recruitment in pulmonary fibrosis Local SC and BMSC recruitment Epithelial mesenchymal transition (EMT) Fibroblast-myofibroblast differentiation Th. Geiser 22
Growth factors relevant in the fibrotic process in the lung Profibrotic antifibrotic Transforming growth factor beta (TGF-b) Hepatocyte growth factor (HGF) Vascular endothelial growth factor (VEGF) Keratinocyte growth factor (KGF) Basic fibroblast growth factor (bfgf-2) Interferon-g1b Platelet derived growth factor (PDGF) Connective tissue growth factor (CTGF) Insulin-like growth factor (IGF) Endothelin-1 Epidermal growth factor (EGF) Chemokine ligand -18 Th. Geiser 23
Tissue injury and remodeling Epithelial or endothelial damage platelets Clot formation TGFβ Cell-matrix interactions Fibrocyte/fibroblast differentiation Apoptosis Mediator release: growth factors, cytokines Neutrophils and monocytes accumulate IL-4, IL-13 T-cells Fibroblast migration and differentiation to myofibroblasts Collagens and fibronectin Th. Geiser 24
Pro- and antiapoptotic balance in fibrosis Alveolar epithelial cells (myo) fibroblasts Th. Geiser 25
Epithelial fibroblast crosstalk Modified from Thannickal, ARM 2004 Th. Geiser 26
Origins of (myo)fibroblasts in fibrosis resident mesenchymal cells epithelial - mesenchymal transition (EMT) fibrocytes Hinz et al, 2007 Th. Geiser 27
Epithelial mesenchymal transition (EMT) Jain et al, AJRCMB 2007 Th. Geiser 28
Fibrocytes, orinating from the bone marrow Fibrocyte markers: CD 45 CD 34 CD 11b CD 18 CD 13 CCR3, CCR5, CCR7, CXCR4 Type I, III collagen vimentin Th. Geiser 29
The alveolar epithelium: Abnormal reepithelialisation in fibrosis Selman, Pardo, 2007 Th. Geiser 30
Lung injury and epithelial repair HGF Lung injury Alveolar repair Restitutio Inflammation Lung fibrosis Th. Geiser 31
Own studies: hepatocyte growth factor has antifibrotic properties (Gazdhar et al, Hum Gen Ther 2013) discovered as a mitogen for hepatocytes mitogenic morphogenic motogenic antiapoptotic organotropic (including lung) Antiinflammatory Induces alveolar epithelial repair in vitro Th. Geiser 32
hhgf transfected stem cells interact with the injured alveolar epithelium in vivo and reduce fibrosis (Gazdhar et al, PLoSOne 2013) Spc Stem cells h HGF Th. Geiser 33