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Animal Models of Human Severe PAH

Ivan McMurty

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Conference: 2008 International PHA Conference and Scientific Sessions

Release Date: 06.22.2008

Presentation Type: Slide Shows

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A recent meta-analysis of clinical trials of prostacyclin analogs, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors in severe PAH shows that although the pharmacological agents moderately improve symptoms and hemodynamic parameters, none significantly reduces mortality. These disappointing results are not predicted by animal model studies, which show these classes of drugs largely prevent, and in some cases reverse, chronic hypoxia- and monocrotaline-induced pulmonary hypertension in rats. The limitations of using chronically hypoxic or monocrotaline-injected rats as models of human PAH have been previously noted. It is apparent that preventing or reversing sustained constriction and increased muscularization of pulmonary arteries in these rodent models is not equivalent to “dissolving” obstructive neointimal and other complex vascular lesions that seemingly account for the high pulmonary vascular resistance in human severe PAH. Investigators evaluating new therapies for PAH should consider using more recent rodent models of neointimal lesion-associated pulmonary hypertension, rather than the classic chronically hypoxic and monocrotaline-injected models. At least six different rodent models of distal pulmonary artery neointimal lesion formation have been described. These include: left pneumonectomized plus monocrotaline-injected rats, VEGF receptor blocker (Sugen 5416)-injected plus chronic hypoxia exposed rats, Sugen 5416-injected athymic nude rats, chronically hypoxic athymic nude rats, monocrotaline injected endothelin B receptor-deficient rats and S100A4/Mts1 protein overexpressing mice infected with M1-gamma herpes virus 68. These models develop pulmonary hypertension accompanied by formation of obstructive cellular lesions in the lumen of small pulmonary arteries and arterioles, in addition to increased muscularization of pulmonary arteries. The proliferative neointimal lesions are variously reported to comprise phenotypically abnormal smooth muscle cells, endothelial cells, or cells expressing both endothelial and smooth muscle cell markers. In some of the models, the lesions are considered to resemble the plexogenic arteriopathy of human PAH. Although it is not yet clear how closely any of these neointimal models mimic the cellular and molecular pathobiology of human PAH, it is likely they will provide insights into pathological molecular signaling pathways and potentially efficacious therapies that would not be revealed or rigorously tested in the classic chronically hypoxic and monocrotaline-injected models.