emphysema and fibrosis - pki.unibe.ch · th. geiser 3 immunological lung diseases lung: o2...
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Immunological Lung Diseases
Emphysema and Fibrosis
Prof. Thomas Geiser
Head Div. of Pulmonary Medicine
and Laboratory of Lung Research,
MU50
Universitätsklinik für Pneumologie
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Th. Geiser 2
Immunological Lung Diseases
The healthy lung:
The pathway of oxygen
Nose, Pharynx:
Warming, moistering
Trachea, Bronchi:
Transportation,
Immunology
Alveoli
Gas exchange
Immunology
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Th. Geiser 3
Immunological Lung Diseases
Lung:
O2 Transportation, gas exchange, defense systems
Airways, blood vessels
Alveoli 400 Millions 0.25 mm
Alveoli, Capillaries
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Th. Geiser 4
Immunological Lung Diseases
Air-Blood barrier in the lung
Air-Blood barrier = 2 m
Inst. of Anatomy, Bern
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Th. Geiser 5
Immunological Lung Diseases
Clearance of particles: mucociliary clearance
Mucus
2-13 mm/Min
Cilia
10 0.25 m 22 Hz
Inst. of Anatomy, Bern
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Th. Geiser 6
Immunological Lung Diseases
Clearance of particles: Macrophages (innate
immunity)
3 µm
Macrophage in the alveoli Macrophage with spores in the airways
Inst. of Anatomy, Bern
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Th. Geiser 7
Immunological Lung Diseases
Inhaled particles in the lung
Spores in alveoli Glass fibers in the conducting airways
5 µm 5 µm
Courtesy of Inst. of Anatomy, Bern
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Th. Geiser 8
Immunological Lung Diseases
Chronic obstructive lung disease (COPD)
• smoking related
• occupational (farmers)
• other etiologies
(autoimmune disease?)
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Th. Geiser 9
Immunological Lung Diseases
0
0.5
1.0
1.5
2.0
2.5
3.0
Proportion der Rate 1965
0.0
0.5
1.0
1.5
2.0
2.5
3.0
1965 - 1998 1965 - 1998 1965 - 1998 1965 - 1998 1965 - 1998
–59% –64% –35% +163% –7%
Coronary Heart
Disease
Stroke Other CVD COPD All Other Causes
Chronic obstructive lung disease (COPD):
Increase in mortality
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Th. Geiser 10
Immunological Lung Diseases
Small airways
- Inflammation
- Remodeling
Damage of
Parenchyma
- Emphysema
COPD – airway obstruction not fully reversible
Partially reversible - Inflammation
- Mucus secretion
- smooth muscle contraction
Irreversible - Less „Recoil“ pressure
- destruction of alveolar
walls
- fibrosis/remodeling
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Th. Geiser 11
Immunological Lung Diseases
Initiating faktors (smoking, infection)
Colonisation
Reduced mucociliary
clearance
Bacterial products (LPS) Bacterial infections
COPD
Emphysema Remodeling with obstruktion
Epithelial damage
Inflammation
Proteases
O2-Radikals
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Th. Geiser 12
Immunological Lung Diseases
COPD – a disease of the airways and the lung
parenchyma
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Th. Geiser 13
Immunological Lung Diseases
Normal lung
Smokers lung
(emphysema)
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Th. Geiser 14
Immunological Lung Diseases
COPD – pathomechanisms
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Th. Geiser 15
Immunological Lung Diseases
COPD – future therapies
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Th. Geiser 16
Immunological Lung Diseases
NORMAL PULMONARY FIBROSIS
Chronic (lung) injury ⇉ Fibrosis
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Th. Geiser 17
Immunological Lung Diseases
Histology of IPF:
usual interstitial pneumonia
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Th. Geiser 18
Immunological Lung Diseases
Fibrosis
Old Hypothesis
Stimulus
Chronic
inflammation
Injury Aberrant wound repair
Sequential lung injury
Fibrosis
New Hypothesis
Repeated stimulus
Inflammation
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Th. Geiser 19
Immunological Lung Diseases
Alveolar epithelium Typ I
Typ II
Fibrinous
matrix
Coagulation
activation Growth factors
PDGF, TGF-b
Endothelin-1
Proteases
Antiproteases
Myofibroblasts Thorax 2007 Thromb Hemost 2005
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Th. Geiser 20
Immunological Lung Diseases
Fibrinous
Matrix
Growth factors
Collagen
Keratinocyte Growth Factor (KGF)
Hepatocyte Growth Factor (HGF)
Neoangiogenesis
Am J Physiol
Lung 2004, 2007
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Th. Geiser 21
Immunological Lung Diseases
Adapted from Selman, Ann Intern Med. 2001;134:136-51.
KGF, HGF
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Th. Geiser 22
Immunological Lung Diseases
Growth factors modulate cell differentiation
and stem cell recruitment in pulmonary fibrosis
Local SC and BMSC
recruitment
Epithelial mesenchymal
transition (EMT)
Fibroblast-myofibroblast
differentiation
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Th. Geiser 23
Immunological Lung Diseases
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
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Th. Geiser 24
Immunological Lung Diseases
Tissue injury and remodeling
TGFβ
platelets
Clot formation
Neutrophils and monocytes
accumulate
Epithelial or endothelial
damage
Cell-matrix interactions
Fibrocyte/fibroblast
differentiation
Apoptosis
Mediator release: growth
factors, cytokines
Fibroblast migration and
differentiation
to myofibroblasts
Collagens and fibronectin
IL-4, IL-13
T-cells
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Th. Geiser 25
Immunological Lung Diseases
Pro- and antiapoptotic balance in fibrosis
Alveolar epithelial cells
(myo) fibroblasts
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Th. Geiser 26
Immunological Lung Diseases
2
6
Modified from Thannickal, ARM 2004
Epithelial – fibroblast crosstalk
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Th. Geiser 27
Immunological Lung Diseases
• resident mesenchymal
cells
• epithelial - mesenchymal
transition (EMT)
• fibrocytes
Hinz et al, 2007
Origins of (myo)fibroblasts in fibrosis
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Th. Geiser 28
Immunological Lung Diseases
Epithelial – mesenchymal transition (EMT)
Jain et al, AJRCMB 2007
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Th. Geiser 29
Immunological Lung Diseases
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
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Th. Geiser 30
Immunological Lung Diseases
The alveolar epithelium:
Abnormal reepithelialisation in fibrosis
Selman, Pardo, 2007
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Th. Geiser 31
Immunological Lung Diseases
Lung injury and epithelial repair
Lung injury
Inflammation
Lung fibrosis Restitutio
HGF
Alveolar
repair
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Th. Geiser 32
Immunological Lung Diseases
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
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Th. Geiser 33
Immunological Lung Diseases
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