emphysema and fibrosis - pki.unibe.ch · th. geiser 3 immunological lung diseases lung: o2...

Immunological Lung Diseases

Emphysema and Fibrosis

Prof. Thomas Geiser

Head Div. of Pulmonary Medicine

and Laboratory of Lung Research,

MU50

[email protected]

Universitätsklinik für Pneumologie

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The healthy lung:

The pathway of oxygen

Nose, Pharynx:

Warming, moistering

Trachea, Bronchi:

Transportation,

Immunology

Alveoli

Gas exchange

Immunology

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Lung:

O2 Transportation, gas exchange, defense systems

Airways, blood vessels

Alveoli 400 Millions 0.25 mm

Alveoli, Capillaries

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Air-Blood barrier in the lung

Air-Blood barrier = 2 m

Inst. of Anatomy, Bern

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Clearance of particles: mucociliary clearance

Mucus

2-13 mm/Min

Cilia

10 0.25 m 22 Hz


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Clearance of particles: Macrophages (innate

immunity)

3 µm

Macrophage in the alveoli Macrophage with spores in the airways


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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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Chronic obstructive lung disease (COPD)

• smoking related

• occupational (farmers)

• other etiologies

(autoimmune disease?)

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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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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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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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COPD – a disease of the airways and the lung

parenchyma

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Normal lung

Smokers lung

(emphysema)

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COPD – pathomechanisms

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COPD – future therapies

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NORMAL PULMONARY FIBROSIS

Chronic (lung) injury ⇉ Fibrosis

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Histology of IPF:

usual interstitial pneumonia

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Fibrosis

Old Hypothesis

Stimulus

Chronic

inflammation

Injury Aberrant wound repair

Sequential lung injury

Fibrosis

New Hypothesis

Repeated stimulus

Inflammation

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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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Fibrinous

Matrix

Growth factors

Collagen

Keratinocyte Growth Factor (KGF)

Hepatocyte Growth Factor (HGF)

Neoangiogenesis

Am J Physiol

Lung 2004, 2007

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Adapted from Selman, Ann Intern Med. 2001;134:136-51.

KGF, HGF

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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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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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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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Pro- and antiapoptotic balance in fibrosis

Alveolar epithelial cells

(myo) fibroblasts

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2

6

Modified from Thannickal, ARM 2004

Epithelial – fibroblast crosstalk

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• resident mesenchymal

cells

• epithelial - mesenchymal

transition (EMT)

• fibrocytes

Hinz et al, 2007

Origins of (myo)fibroblasts in fibrosis

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Epithelial – mesenchymal transition (EMT)

Jain et al, AJRCMB 2007

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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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The alveolar epithelium:

Abnormal reepithelialisation in fibrosis

Selman, Pardo, 2007

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Lung injury and epithelial repair

Lung injury

Inflammation

Lung fibrosis Restitutio

HGF

Alveolar

repair

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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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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

emphysema and fibrosis - pki.unibe.ch · th. geiser 3 immunological lung diseases lung: o2...

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