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The pathomechanism of lung fibrosis

and sarcoidosis

Manuela Funke-Chambour MD

Pulmonary Department

University Hospital

Inselspital Bern, Schweiz

ERS 2016

Conflict of interest disclosure

I have no, real or perceived, direct or indirect conflicts of interest that relate to this

presentation.

This event is accredited for CME credits by EBAP and speakers are required to disclose their potential conflict of interest going back 3 years prior to this presentation. The intent of this disclosure is not to prevent a speaker with a conflict of interest (any significant financial relationship a speaker has with manufacturers or providers of any commercial products or services relevant to the talk) from making a presentation, but rather to provide listeners with information on which they can make their own judgment. It remains for audience members to determine whether the speaker’s interests or relationships may influence the presentation. Drug or device advertisement is strictly forbidden.

Aims

Aim 1: Understanding the pathomechanism of fibrosis

comparing IPF and sarcoidosis with pulmonary fibrosis

Aim 2: Apprehend the difference of IPF pathogenesis

with impaired wound repair from predominant

inflammation in sarcoidosis with pulmonary fibrosis

Aim 3: Understanding the implications of

pathomechanisms for treatment in pulmonary fibrosis

Overview

1. Impaired Wound healing in pulmonary fibrosis -

example IPF

2. Inflammatory fibrosis- example sarcoidosis

3. Conclusion

Interstitial lung diseases

American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus

Classification of the Idiopathic Interstitial Pneumonias. Am. J. Respir. Crit. Care Med. January 15, 2002

vol. 165 no. 2 277-304

Pulmonary Fibrosis - example IPF

An Official American Thoracic Society/European Respiratory Society Statement: Update of the International

Multidisciplinary Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med Vol 188, Iss. 6,

pp 733–748, Sep 15, 2013.

Idiopathic pulmonary fibrosis

• Fatal lung disease with unpredictable

decline of lung function due to fibrosis1,2

• Prognosis is extremely poor, no cure

available

• Specific histopathologic and radiologic

criteria (usual interstitial pneumonia - UIP)1

• The cause is not known1,2

7


An Official ATS/ERS/JRS/ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidence-based

Guidelines for Diagnosis and Management. Am J Respir Crit Care Med Vol 183. pp 788–824, 2011

Funke M, Geiser T. Idiopathic pulmonary fibrosis: The turning point is now. Swiss Med Wkly. 2015 May 29;145.

An Official ATS/ERS/JRS/ALAT Clinical Practice Guidelines: Treatment of Idiopathic Pulmonary Fibrosis: Executive

Summary An Update of the 2011 Clinical Practice Guideline. Am J Respir Crit Care Med Vol 192. No 2, pp 238-248, 2015

Risk factors

• Smoking

• Environmental pollution

• Viral or bacterial infection

• Genetics


Histopathology

Katzenstein AL, Myers JL. State of the Art: Idiopathic

pulmonary fibrosis: Clinical Relevance of pathological

classification. AJRCCM Vol 157. pp 1301-1315, 1998.


Histopathology

Honey combing

Katzenstein AL, Myers JL. State of the Art: Idiopathic

pulmonary fibrosis: Clinical Relevance of pathological

classification. AJRCCM Vol 157. pp 1301-1315, 1998.

Usual Interstitial Pneumonia- UIP

• Connective tissue disease

• Chronic Hypersensitivity Pneumonitis

• Asbestosis


Fibroblast focus


UIP/IPF – radiological features

Hansell D M et al. Radiology 2008;246:697-722

Zemans RL et al. Conceptual approaches to lung injury

and repair. Ann Am Thorac Soc Vol 12, Supplement 1,

pp S9-S15, Mar 2015.

LUNG INJURY AND NORMAL WOUND HEALING

Epithelial cell-

Apoptosis

- Fibroblast apoptosis

- Collagen reabsorption

- Re-epithelialisation

insult

Coagulation

(Fribrin)

Phase of Resolution

Alveolarepithel Capillary

Extracellular

Matrix

Fibroblasts

Wound healing

Vaskular Leak with

extravascular

Coagulation

Fibroblast Recruitment,

proliferation and matrix

deposition

IPF – model of impaired wound healing

Dysregulation of any of these phases

can contribute to fibrosis


Todd NW et al. Molecular and cellular mechanisms of pulmonary

Fibrosis. Fibrogenesis & Tissue Repair 2012, 5:11

PRO-FIBROTIC MECHANISMS










ALVEOLAR EPITHELIAL CELLS

Damage of alveolar epithelial cells

- apoptosis -

• Type II pneumocytes undergo apoptosis in IPF/UIP Barbas-Filho JV et al. Evidence of type II pneumocyte apoptosis in the

pathogenesis of IPF/UIP. J Clin Pathol 2001;54:132-138.

Funke M. et al. The Lysophosphatidic acid Receptor LPA1 promotes

epithelial cell apoptosis after lung injury. AJRCMB Mar;46(3):355-64.

WT LPA1 KO

Figure 1

0

WT

LPA1 KO

2

4

TUNEL (+) cells / hpf

p21(+) cells / hpf 0

1

2

3

A B C

D E F

G H

TUNEL

p21

p53

J

WT

LPA1 KO

time after challenge (d)0 1 3 5

time after challenge (d)0 3


0

1

2

ca

sp

ase

3 a

ctivity /

wh

ole

lu

ng

se

t

1

3

5

p53(+) cells / hpf 0

1.6

I

WT

LPA1 KO


0.4

0.8

1.2WT

LPA1 KO

**

**

**

#

D3


Fibroblast

The myofibroblasts

Myofibroblast

αSMA

Fibroblast foci

TGF-β- receptor

Funke M, Geiser T. Idiopathic pulmonary fibrosis: The

turning point is now. Swiss Med Wkly. 2015 May 29;145.

20



Origin of the myofibroblast

1. Resident fibroblasts differentiate into

myofibroblasts

2. Circulating fibrocytes or bone marrow-

derived progenitors are recruited to sites

of injury

3. Epithelial-mesenchymal transition

Bagnato G and Harari S. Cellular interactions in

the pathogenesis of interstitial lung diseases.

Eur Respir Rev 2015;24:102-114.


Hinz B et al. The myofibroblast- one function,

multiple origins. Am J Pathol

2007Jun;170(6):1807-16..


Apoptosis paradox in IPF

Thannikal VJ, Horovitz JC. Evolving concepts of apoptosis in IPF. Proc Am Thorac Soc 2006; 3:350-356.

Epithelial cells undergo apoptosis

Fibroblasts become resistant to apoptosis


Apoptosis paradox in lung fibrosis

- regulatory role for LPA1

Epithelium

Lung Injury

Fibrin Clot

Re-epithelialization

Extracellular

Matrix

Fibroblasts Fibroblast Recruitment

Proliferation and

Matrix Deposition

Vascular leak and

Extravascular Coagulation

Capillary

LPA Fibroblast

Apoptosis

Epithelial Cell

Death

Extracellular matrix

• IPF ECM: cellular Fibronectin (FN-EDA), Collagen I and III,

proteoglycan, hyaluronan

Thannikal VJ et al. Matrix Biology of IPF. A Workshop Report of the National Heart, Lung, and

Blood Institute. Am J Pathol 2014, 184:1643-1651.


Kim DS, et al. Proc Am Thorac Soc 2006; 3:285-92.

Years

Rapidly progressive Acute

exacerbations

slowly progressive

Lu

ng

fu

nc

tio

n/s

ym

pto

ms

0 1 2 3 4

Course of IPF

FIBROSIS PROGRESSION AFTER

PNEUMONIA IN IPF

Pulmonary infections

(Pneumonia)

Pneumonia patient IPF patient

Usually no fibrosis Fibrosis progression

26

Why is the clinical

response different? 1) H&E staining, courtesy of Sabina Berezowska,, Pathology Inselspital Bern

2) Hyzy R et al. Chest, 2007

Fibroblast (normal control) Fibroblasts (IPF)

αSMA

TGF-β- receptor

TLR4 LPS TLR4

TGF-β- receptor

LPS

27 Ebener S, Barnowski S, Wotzkow C, Marti TM, Cretsani B, Blank F, Schmid RA, Geiser T,

Funke-Chambour M. TLR4 activation attenuates pro-fibrotic resposne in control lung fibroblasts

but not in fibroblasts from IPF. in revision 2016

Why does TLR4 activation not induce fibrosis in

healthy lungs?

TOLLIP

2

8

Zhu L et al. Tollip, an intracellular trafficking prortein, is a novel modulator of the transforming

growth factor-β signlaing pathway. JBC Vol 287, No 47, pp39653-39663, Noc 2012.

Risk factors: Genetics

• 10-15% Familial pulmonary fibrosis

• Sporadic IPF

– Associated with:

• SFTPC


Mutations in the Surfactant Protein C Gene Associated With Interstitial Lung Disease ; Hamvas, Whitsett,

Nogee, Dunbar III, Wert, Askin; Chest 2002;121;20S-21S

• TOLLIP

• Telomerase gene

Seibold MA et al. A common MUC5B promoter polymorphism and pulmonary fibrosis.

N Engl J Med 2011 Apr 21;364(16):1503-12.

• MUC5B

TOLLIP IN IPF

• TOLLIP variants are associated with disease susceptibility and

mortality

Noth I et al. Genetic variants associated with idiopathic pulmonary fibrosis susceptibility

and mortality: a genome-wide association study. Lancet Respir Med. 2013 Jun;1(4):309-17.

• TLR-4 polymorphisms are associated with a chronic course of

sarcoidosis

Pabst S et al. Toll-like receptor TLR-4 polymorphisms are associated with a chronic course

of sarcoidosis. Clinical and experimental immunology 2006: 143:420-426.

Oldham JM et al. TOLLIP, MUC5B, and the Response to N-Acetylcysteine among

Individuals with Idiopathic Pulmonary Fibrosis. AJRCCM 2015 Dec 15;192(12):1475-82.

• TOLLIP influences Response to N-Acetylcysteine in IPF

Interstitial lung diseases

American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus

Classification of the Idiopathic Interstitial Pneumonias. Am. J. Respir. Crit. Care Med. January 15, 2002

vol. 165 no. 2 277-304


An Official American Thoracic Society/European Respiratory Society Statement: Update of the International

Multidisciplinary Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med Vol 188, Iss. 6,

pp 733–748, Sep 15, 2013.


Sarcoidosis

• inflammatory disease

• non-caseating granulomata

• affecting multiple organs

• Skin

• Heart

• Eye

• Nervous system

• Bone, joints, muscle

• Endocrine and exocrine dysfunction

• Gastro-, genitourinary involvement

• Hematological, immunological involvement


Risk factors

• Environmental - World trade center collapse Izbicki G et al. World trade center sarcoid like granulomatous pulmonary disease in NYC Fire department rescue

workers. Chest 2007; 131:1414.

• T cells dysfunction (Th1, Th17, Treg)

• Genetic predisposition

• Infectious agents

–Mycobacteria

–Propionibacteria

–Fungals, others

Rotsinger JE et al. Molecular Analysis of Sarcoidosis Granulomas

Reveals Antimicrobial Targets. AJRCCM Jan 25.


Sarcoidosis

Courtesy from Dr. Sabina Berezowska, Pathology Department University of Berne, Switzerland

Noncaseating granulomata

bronchocentric

T cell mediated disease

3

5

A B

C D

Berezowska S, Pöllinger A. Histopathologische und radiologische

Korrelationen. Therapeutische Umschau. (2016), 73 (1), 11-17.

Sarcoidosis - fibrotic pulmonary disease

SARCOIDOSIS

RADIOLOGICAL CLASSIFICATION

Patterson KC et al. Pulmonary Fibrosis in Sarcoidosis. Ann Am

Thorac Soc Vol 10, No 4, pp 362-370.

Sarcoidosis

- fibrotic pulmonary disease

IANNUZZI MC ET AL. SARCOIDOSIS. N ENGL J MED 2007;357:2153-2165.

PATHOGENESIS OF SARCOIDOSIS

ACUTE VS CHRONIC SARCOIDOSIS

J. C. Schupp, B. C. Frye, G. Zissel, J. Müller-Quernheim. Neue pathogenetische Konzepte und

frühe pharmakologische Studien bei der Sarkoidose. Pneumologie 2016; 70(04): 231-240

NECESSITY TO DISTIGUISH ORIGIN OF

FIBROSIS

• If diagnosis can not be determined management is challenging

– diverging treatment approaches for IPF and non-IPF ILD

– PANTHER study with negative effects of immunosuppression in IPF

patients

Skolnik K, Ryerson CJ. Unclassifiable interstitial lung disease: A review. Respirology. 2015 Jun 9.

• Diagnostic consens should be achieved whenever possible

CAUSES OF LUNG FIBROSIS

INFLAMMATION

FIBROSIS

CONCLUSION

• Inflammation can lead to pro-fibrotic stimuli

• In IPF anti-inflammatory drug can be harmful

• If anti-fibrotic drugs are useful in other diseases

than IPF needs to be studied.

• With divergent treatment options,

diagnosis is of utmost importance

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Thank you for viewing this presentation ... - ERS-education · An Official ATS/ERS/JRS/ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidence-based Guidelines for Diagnosis and Management