Immunological Lung Diseases
Emphysema and Fibrosis
Prof. Thomas Geiser
Head Div. of Pulmonary Medicine
and Laboratory of Lung Research,
MU50
Universitätsklinik für Pneumologie
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
Th. Geiser 3
Immunological Lung Diseases
Lung:
O2 Transportation, gas exchange, defense systems
Airways, blood vessels
Alveoli 400 Millions 0.25 mm
Alveoli, Capillaries
Th. Geiser 4
Immunological Lung Diseases
Air-Blood barrier in the lung
Air-Blood barrier = 2 m
Inst. of Anatomy, Bern
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
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
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
Th. Geiser 8
Immunological Lung Diseases
Chronic obstructive lung disease (COPD)
• smoking related
• occupational (farmers)
• other etiologies
(autoimmune disease?)
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
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
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
Th. Geiser 12
Immunological Lung Diseases
COPD – a disease of the airways and the lung
parenchyma
Th. Geiser 13
Immunological Lung Diseases
Normal lung
Smokers lung
(emphysema)
Th. Geiser 14
Immunological Lung Diseases
COPD – pathomechanisms
Th. Geiser 15
Immunological Lung Diseases
COPD – future therapies
Th. Geiser 16
Immunological Lung Diseases
NORMAL PULMONARY FIBROSIS
Chronic (lung) injury ⇉ Fibrosis
Th. Geiser 17
Immunological Lung Diseases
Histology of IPF:
usual interstitial pneumonia
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
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
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
Th. Geiser 21
Immunological Lung Diseases
Adapted from Selman, Ann Intern Med. 2001;134:136-51.
KGF, HGF
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
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
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
Th. Geiser 25
Immunological Lung Diseases
Pro- and antiapoptotic balance in fibrosis
Alveolar epithelial cells
(myo) fibroblasts
Th. Geiser 26
Immunological Lung Diseases
2
6
Modified from Thannickal, ARM 2004
Epithelial – fibroblast crosstalk
Th. Geiser 27
Immunological Lung Diseases
• resident mesenchymal
cells
• epithelial - mesenchymal
transition (EMT)
• fibrocytes
Hinz et al, 2007
Origins of (myo)fibroblasts in fibrosis
Th. Geiser 28
Immunological Lung Diseases
Epithelial – mesenchymal transition (EMT)
Jain et al, AJRCMB 2007
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
Th. Geiser 30
Immunological Lung Diseases
The alveolar epithelium:
Abnormal reepithelialisation in fibrosis
Selman, Pardo, 2007
Th. Geiser 31
Immunological Lung Diseases
Lung injury and epithelial repair
Lung injury
Inflammation
Lung fibrosis Restitutio
HGF
Alveolar
repair
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
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