Animal Models of IPF
Martin Kolb MD, PhD
Associate Professor, Research Director Animal Models of IPF Proof of Concept in Pharmaceutical Research:
The biggest divide of all is the one between animal and human studies. "In many areas we have relied a bit too much on animal models and fooled ourselves into thinking they tell us exactly what happens“…Now scientists are taking a more skeptical look at their models and trying to find better ways to correlate results in animals to early human findings.
May 2006
Animal Models of IPF –Right or Wrong ?
We have good models of IPF
We have good models of some IPF features
Animal models help to understand the pathogenesis of IPF initiation
Animal models help to understand the pathogenesis of IPF progression
We asses severity and progression of experimental fibrosis correctly Animal models are useful to investigate drug efficacy in a preclinical setting
We use the right animals
Animal Models of Pulmonary Fibrosis
Chua, AJRCMB 2005
FITC induced PF
Gene overexpression/ k.o.
Adoptive cell transfer (UIP fibroblasts)
Dox-inducible TGF-βoverexpression
Lee et al. J. Exp. Med. 2004Moore et al, Am J Physiol 2008
Bleomycin i.t.The AMDCC is an interdisciplinary consortium designed to develop new animal models that closely mimic the human complications of diabetes for the purpose of studying disease pathogenesis, prevention and treatment.
What is “THE”Animal Model of IPF?
IPF is a complex disease!
pathogenesis/ treatment/ modeling …is modeling IPF any easier than diabetes?
Animal Models of IPF –Right or Wrong ? We have good models of IPF
We have good models of some IPF features Animal models help to understand the pathogenesis of IPF initiation Animal models help to understand the pathogenesis of IPF progression
We asses severity and progression of experimental fibrosis correctly Animal models are useful to investigate drug efficacy in a preclinical setting
We use the right animals AdTGF-β1 overexpression/ RAT i.t.AdTGF-β1 overexpression/ MOUSE i.pl.AdTGF-β1 overexpression/ Rhesus Monkey AdIL-1βoverexpression/ RAT i.t.
Human UIP
Animal Models of Pulmonary Fibrosis
Animal Models of IPF –Right or Wrong ?
We have good models of IPF
We have good models of some IPF features
Animal models help to understand the pathogenesis of IPF initiation
Animal models help to understand the pathogenesis of IPF progression
We asses severity and progression of experimental fibrosis correctly
Animal models are useful to investigate drug efficacy in a preclinical setting
We use the right animals
Modeling acute exacerbations of IPF
Kim et al, PATS 2006
Are all our animal models modeling acute exacerbations?
Animal Models of IPF –Right or Wrong ? We have good models of IPF
We have good models of some IPF features
Animal models help to understand the pathogenesis of IPF initiation
Animal models help to understand the pathogenesis of IPF progression
We asses severity and progression of experimental fibrosis correctly
Animal models are useful to investigate drug efficacy in a preclinical setting
We use the right animals Examples for agent classes:?Antioxidants ?ACE Inhibitors ?Angiotensin 2 Rec. Blocker ?Anticoagulants ?Macrolide antibiotics ?Cytokines ?Cytokine antibodies ?Chinese herbs ?Immunosuppressants ?Corticosteroids ?Chelating agents ?Pirfenidone ……and many more ……
almost 200 agents with
antifibrotic effects
~250 published studies
1980 -2006
~90%
”Prevention ”~10%
“Therapy”Antifibrotic Drugs in the Bleomycin Model Moeller et al, Int J Biochem Cell Biol 2008
Drug intervention studies in PF animal models
d 21
d 7 d 14initiation drug Intervention
d 42
d 21d 7 d 14initiation drug Intervention
no drug drug
d 21d 7 d 14initiation drug Intervention
d 28
no drug drug
day 7?
How do we assess a patient with IPF?
symptoms
PFT (FVC/ TLC/ DCO)
exercise (6-min walk)
imaging (CXR/ HRCT)
echo/ RV cath
bronchoscopy How do we assess animals with
experimental PF?
(symptoms) histology/ morphometry
collagen (hydroxyprol/ sircol)
gene expression (ECM genes)
Micro-CT and 3D-
Reconstruction of pulmonary vessels down to microns (Ritman, PATS 2005)Micro ‐CT Bleomycin
Day 7Day 125
Day 27Day 0Day 14Fibrosis in Rat Lungs –3D Imaging
AdTGF-β1
Animal models of IPF: “Clinical Outcome ”Follow same animals over time
-Body condition/weights
-Airway resistance
-Lung function/Lung volumes
-Exercise Test
-Imaging
Quantifiable measurements of lung tissue
-Histology/ Histomorphology -Collagen/ / Elastin
-Hydroxyproline/ Desmosin
-Up/Downregulation of ECM genes/ proteins C linical-P athology-R adiology Score in animals?Induce Pathology Sacrifice
?Treat Animal Models of IPF –Right or Wrong ? We have good models of IPF
We have good models of some IPF features
Animal models help to understand the pathogenesis of IPF initiation Animal models help to understand the pathogenesis of IPF progression
We asses severity and progression of experimental fibrosis correctly Animal models are useful to investigate drug efficacy in a preclinical setting
We use the right animals
Animal Models of IPF –Species
rat mouse
guinea pig
primate
dog
swine
inbred/outbred
rabbit
AGE MATTERS
?Ageing mice develop more fibrosis in response to Bleo,
have more fibrocytes
Xu J. et al. J Gerontol A Biol Sci Med Sci 2009
?MSCs have decreased ability to differentiate
Xu J. et al. J Gerontol A Biol Sci Med Sci 2009
Fibrocytes & Mesenchymal Stem ‐Cells following Bleo Circulating fibrocytes 7 days
after bleomycin injury Migration of bone ‐marrow derived MSC (towards SDF ‐1)
SAMP8 = senescence accelerated mouse prone strain 8
SAMR1 = senescence accelerated mouse resistant strain 1
Animal Models of IPF –Right or Wrong We have a good model of IPF We have good models for some features of IPF Animal models help to understand the pathogenesis of IPF initiation Animal models help to understand the pathogenesis of IPF progression
We asses severity and progression of experimental fibrosis correctly Animal models are useful to investigate drug efficacy in a preclinical setting We use the right animals WRONG
Right
RIGHT WRONG WRONG WRONG WRONG