The adverse structural alterations occurring in the chronically hypoxic pulmonary vasculature are clinically significant because they underlie transition from reversible hypoxic pulmonary hypertension to sustained, relatively irreversible hypertensive pulmonary vascular disease. Although the pathophysiologic events characterizing hypoxic pulmonary vascular disease have received considerable attention, only few studies have explored the biochemical mechanism(s) regulating the hyperplastic and hypertrophic responses of the cells affecting the adverse structural remodeling. In this context, research described herein proposes to test key elements of the Working Hypothesis that the polyamines, a family of low molecular weight organic cations with documented regulatory roles in cell growth and differentiation, comprise an obligatory link between exposure to chronic alveolar hypoxia and evolution of hyperplasia and hypertrophy of pulmonary arterial effector cells which underlies development of hypertensive pulmonary vascular disease. Using rats chronically exposed to isobaric hypoxia, studies are proposed to: 1) characterize the time-dependent effects of hypoxic exposure on lung polyamine biosynthesis, 2) determine if inhibition of polyamine biosynthesis forestalls progression of hypoxic pulmonary hypertension, and 3) immunocytochemically identify lung cell types in which chronic hypoxia enhances the content of the initial are rate-limiting polyamine biosynthetic enzyme. Results of these studies will provide fundamental information on the biochemical mechanism(s) which couple chronic hypoxic exposure to the adverse structural remodeling of the pulmonary arteries underlying sustained hypertensive pulmonary vascular disease. In addition, the proposed research may point to definitive pharmacotherapeutic interventions with the potential to arrest progression of this disorder.
