Lessons learnt from the guinea pig to rat transplantation model of AAA

Transcription

1 Lessons learnt from the guinea pig to rat transplantation model of AAA M. Gervais-Taurel J. Dai A. Fifre Anne-Marie Guinault S. Ngo Maha David Ibtissam Chabane Surgeons Dr. Losy Dr. Van Laere Dr. Dai Dr. Jousset Dr. Schneider Dr. Saucy Dr. C. Kakon Dr. F. Cochennec Radiologists JF Deux R Blanc Studants Claire Poulet Faiza Mohand Kacy Pr. Eric Allaire Department of Vascular Surgery Henri Mondor Hospital University Paris-Est Créteil, France IMAD6 Liège 2018 )

2 AAA animal models are far from human disease Plate-form of 4 AAA models: each designed to answer a set of questions Microsurgical replacement of rat subrenal aorta >50%diameter increase at day 14 Guinea pig aorta 2 weeks

3 A chimeric injured, dilated aorta SDS-decellularized aortic guinea pig aorta: ECM Ad Ad Lu Lu AAA: gpecm + recipient rat cells and proteins Ad Ad Ad Ad Lu Th Th Th Lu Th Th Lu Th Lu Th Pg elastin V-alpha actin + cells (VSMCs?) Macrophages, Lymphocytes PMNs MMPs, plasmin pathway Adventitial microvessels

4 MMPs activated by fibrinolytic system serum plasminogen PAI-1 X Arterial ECM Inflammatory cells Wall cells PA inactive MMP-3 inactive MMP-9 X plasmin active MMP-3 active MMP-9 TIMP-1 X TIMP-1 E Allaire, JCI, Circulation 1998

5 Luminal fresh thrombus: blood/fibrin interface Ad Th Th Lu

6 Light and shadows humans Genetic / environment trigger xenograft Rejection of xenogeneic ECM injury Response to injury AAA AAA formed AAA stabilization by healing

7 Light and shadows humans Genetic / environment trigger xenograft Rejection of xenogeneic ECM Genetic / environment injury Response to injury AAA AAA formed AAA stabilization by healing

8 Light and shadows humans Genetic / environment trigger xenograft Rejection of xenogeneic ECM Genetic / environment injury Response to injury AAA AAA Genetic / environment formed AAA stabilization by healing

9 Light and shadows humans Genetic / environment trigger xenograft Rejection of xenogeneic ECM Genetic / environment injury Response to injury AAA AAA Genetic / environment formed AAA stabilization by healing

10 Preclinical model to test therapeutic hypotheses Pathophysiology? Th Therapeutic diameter d 2 months d 0 d AAA treatment group AAA expansion treatment effect time start of degeneration endovascular treatment assessment of remodeling % diameter increase = (d 2 months - d 0 ) x 100 / d 0

11 Local endovascular biotherapies artère rénale AAA cathéter artère aortotomie iliaque PCR / construction AdnlsLacZ à j3 thrombus aneurysmal wall

12 1. VSMC enrichment stabilizes expanding AAAs with protease-injured ECM No hemodynamic substraction a-actin Monocyte macrophages VSMC - thrombus thrombus VSMC/ Inflammation containment VSMC + néointima néointima TIMP TGF-b1 Allaire et al., Ann Surg 2004 Losy JVS 2005

13 2. AAA wall reprogrammation Recovered aortic stability and structure unstable stable : VSMC : endothelial cells

14 2. AAA wall reprogrammation Recovered aortic stability and structure unstable stable : VSMC : endothelial cells Concept of endovascular healing induction through reprogrammation diameter 1 shot interventional delivery - cells (VSMCs, MSCs, endothelial cells) - genes (TGF-beta1) - drug (Cyclosporine A)

15 2. AAA wall reprogrammation Recovered aortic stability and structure unstable stable : VSMC : endothelial cells Concept of endovascular healing induction through reprogrammation diameter Cellular reconstruction VSMC, endothelium 1 shot interventional delivery - cells (VSMCs, MSCs, endothelial cells) - genes (TGF-beta1) - drug (Cyclosporine A)

16 TGF-b1 positive cells (10 3 / mm 2 ) human TGF-b1 mrna / 18S rat TGF-b1 mrna / 18S Exogenous TGF-b1 induces endogenou rat TGF-b1 mrna 0,3 thrombus media + adventitia 14 Ad-LacZ 0,2 10 Ad-hTGF-β1 0, J 3 J 14 J 28 0 thrombus media + adventice Protein * NS thrombus Ad-LacZ Ad-sTGF-β1 NS day 3 day 14 day 28 day 3 day 14 day 28 * * * Media/ adventitia

17 2. AAA wall reprogrammation Diameter Adenovirus Exogenous TGF-beta1 1 shot interventional delivery

18 2. AAA wall reprogrammation Endogenous TGF-beta1 Diameter Adenovirus Exogenous TGF-beta1 1 shot interventional delivery

19 2. AAA wall reprogrammation DESTRUCTION VSMCs Endogenous TGF-beta1 RECONSTRUCTION Diameter Adenovirus Exogenous TGF-beta1 1 shot interventional delivery

20 2. AAA wall reprogrammation DESTRUCTION VSMCs Endogenous TGF-beta1 RECONSTRUCTION Diameter Adenovirus Exogenous TGF-beta1 1 shot interventional delivery

21 MMP-9 TGF-beta1 3. AAA wall reprogrammation by inductive pharmacology Ciclosporin A induces TGF-beta1 in human AAA explants * * Ciclosporine ng/ml * *

22 3. AAA wall reprogrammation by inductive pharmacology CsA induces a TGF-beta1-dependant healing process in AAAs Dai J, PLosONE 2011

23 3. AAA wall reprogrammation by inductive pharmacology Study in AAA patients Mo 3 Mo 6 Mo 12 Mo 24 Etude ACA4

24 1. VSMC enrichment stabilizes expanding aorta with proteaseinjured ECM, without hemodynamic substraction 2. AAA wall reprogrammation to gain stability beyond treatment stimulation to avoid systemic side effects 3. Pre-clinical means in formed, expanding experimental AAAs

25 Science describes facts with words that need to be as precise as words in poetry