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Tissue Factor Is Induced in a Rodent Model of Severe Pulmonary Hypertension Characterized by Neointimal Lesions Typical of Human Disease*

R. James White, MD, FCCP; Irfan I. Galaria, MD; Jennifer Harvey, MD; Burns C. Blaxall, MD; Carlyne D. Cool, MD; Mark B. Taubman, MD
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*From the Division of Pulmonary and Critical Care Medicine, Center for Cellular and Molecular Cardiology, Aab Institute for Biomedical Sciences, University of Rochester School of Medicine, Rochester, NY; and Department of Pathology, University of Colorado Health Science Center, Denver, CO.

Correspondence to: R. James White, MD, FCCP, Division of Pulmonary and Critical Care Medicine, University of Rochester School of Medicine, 601 Elmwood Ave, Rochester, NY 14642; e-mail: jim_white@urmc.rochester.edu



Chest. 2005;128(6_suppl):612S-613S. doi:10.1378/chest.128.6_suppl.612S
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In severe human pulmonary hypertension (PH) of many etiologies, endothelial proliferation and medial hypertrophy ultimately obliterate the vascular lumen. To date, most animal models for PH have not reproduced the disordered angiogenesis that characterizes severe human disease. In particular, neointimal and plexiform lesions have not been consistently identified. A model has been described in which high pulmonary flow (pneumonectomy) and endothelial injury (monocrotaline) combine to produce severe PH. To examine this further, young male Sprague Dawley rats (150 to 200 g) were subjected to left pneumonectomy followed 7 days later by 60 mg/kg of subcutaneous monocrotaline. Sham-operated animals were likewise injected with monocrotaline or vehicle; others were treated with pneumonectomy alone and then administered vehicle. Four weeks after monocrotaline, animals were anesthetized and micropuncture measurements of right-heart pressures were made with a fluid-filled catheter; the animals were then killed and examined. The weight of the right ventricle (RV) plus intraventricular septum (S) was compared to that of the left ventricle (LV). Animals treated with monocrotaline and pneumonectomy had severe RV hypertrophy (RV + S/LV = 1.8 ± 0.6), which was statistically different from that of pneumonectomy alone (RV + S/LV = 0.6 ± 0.1) or monocrotaline alone (1.2 ± 0.3; p < 0.01, one-way analysis of variance with Tukey post hoc testing). Both pulmonary artery mean pressures and RV systolic pressures were elevated in combined pneumonectomy/monocrotaline animals compared with sham/monocrotaline animals (RV systolic pressure, 89 ± 12 mm Hg vs 55 ± 16 mm Hg; mean pulmonary artery pressure, 49 ± 11 mm Hg vs 35 ± 3 mm Hg; for both, p < 0.01 with analysis of variance followed by post hoc testing). Interestingly, the pneumonectomy/vehicle animals were indistinguishable from sham/vehicle animals with respect to hemodynamics and RV weight.

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