Humans, livestock and rat monocrotaline (MCT) pneumotoxicity is associated with a spectrum of pulmonary vascular lesions reminiscent of idiopathic pulmonary hypertension in humans. A feature common to all forms of pulmonary hypertension si that the initial insult leads to progressive vascular remodeling, which underlies sustained, irreversible increases in pulmonary arterial pressure. Although extensive studies from our laboratories have substantiated essential roles for the polyamines in MCT- caused pathogenic vascular structural remodeling, the intercellular signals (stimuli) which enhance lung artery polyamine contents and thus drive the understood. The proposed research will test the working hypothesis that transforming growth factor-beta (TGF-beta) initiates and/or modulates lung vascular cell processes critical to the development of MCT pneumotoxicity in rats.
Specific aim 1 will determine if TGF-beta production is enhanced in the lungs of rats with MCT-induced pneumotoxicity. Platelets, alveolar macrophages (AMs), isolated pulmonary arteries (IPA), lung, and pulmonary artery smooth muscle cells (SMC) and fibroblast cells (FC) from MCT-treated rats will be assayed for TGF-beta protein content & heterogeneity, TGF-beta mRNA and receptor populations and compared to controls. The biological activity of the secreted TGF-beta protein will be examined in bovine pulmonary arterial SMC, endothelial cell (EC) and FC, and native rat IPA bioassay systems. In situ hybridization and immunocytochemistry will localize TGF-beta mRNA and protein in discrete lung cell types. These responses will be correlated as a function of time and pathophysiological events.
Specific aim 2 will determine if MCT-caused generation of TGF-beta is polyamine dependent by first blocking polyamine biosynthesis; and than restoring polyamine content.
Specific aim 3 will determine if chronically administered TGF-beta can mimic MCT-induced pneumotoxicity in intact rats and also in IPAs and cultured SMC, EC & FCs; and if these effects of TGF- beta are polyamine dependent.
Specific aim 4 will determine if continuous infusion of exogenous anti-TGF-beta antibody will suppress MCT-induced pneumotoxicity. These studies will provide a rigorous examination of the role of TGF-beta in MCT pneumotoxicity and determine the impact of exogenous TGF-beta on rat pulmonary circulation.
| Arcot, S S; Fagerland, J A; Lipke, D W et al. (1995) Basic fibroblast growth factor alterations during development of monocrotaline-induced pulmonary hypertension in rats. Growth Factors 12:121-30 |
| Soltis, E E; Newman, P S; Olson, J W (1994) Eflornithine treatment in SHR: potential role of vascular polyamines and ornithine decarboxylase in hypertension. Clin Exp Hypertens 16:595-610 |
