Value of animal models as predictors of response to PAH treatments 英文 医学资料.pptx

Value of animal models as predictors of response to PAH treatments ;To identify new drug targets To validate new drug targets To explore efficacy To explore the safety profile of new medications ;Abnormal pulmonary vasoconstriction Pulmonary vascular remodelling Right ventricular hypertrophy ;80 μm;Animal models of Pulmonary Hypertension ;;;;Hypoxia-induced pulmonary vasoconstriction;Hypoxia-induced pulmonary vascular remodelling and right ventricular hypertrophy ;Chronic dosing with sildenafil attenuates hypoxia- induced pulmonary hypertension in rats;Chronic dosing with sildenafil attenuates hypoxia- induced pulmonary hypertension in rats;Pulmonary artery pressure;;Simvastatin reduces hypoxia-induced PH in rat;Imatinib reduces hypoxia-induced PH in mouse;Genetic variation in response to hypoxia;Strengths True pathological stimulus Common to many mammalian species Useful for dissecting out factors influencing susceptibility Useful for examining vasoreactive molecules Weaknesses Lacks inflammation Remodelling component mild ;Monocrotaline: proposed mechanism;MCT rat pulmonary hypertension model;Schermuly et al. 2005;sGC activation on pulmonary vascular remodeling in MCT-rats;Monocrotaline-induced PH - survival studies ;Monocrotaline-induced PH - plus pneumonectomy;Neointima formation in pneumonectomized rats injected with monocrotaline;Simvastatin reverses monocrotalline-induced PH in rat;Strengths Challenging animal model Enables survival studies Weaknesses Based on a non-specific toxin – tissue damage not specific to pulmonary vasculature Requires metabolic conversion in liver ;Ivy, D. D. et al. Circulation 2005;FASEB J. 2001;Models of acquired PH - Large animal studies;Shunt model of PAH associated with congenital heart disease;Strengths Circulation more representative of humans Easier to collect haemodynamic information Weaknesses Expensive Technically challenging;Pathology of human disease;Genetic models - manipulation of BMPR2 function;;Unbiased comp