This project has focused on prostaglandin (PG) production by the cells from the pulmonary artery and by fibroblasts from the lung. The ultimate goal is to determine the mechanisms (intracellular and extracellular) which regulate PG production in these cells and to relate this production of PGs to their physiologic function. The working hypothesis is that prostaglandin synthesis is regulated by both the availability of arachidonate and the activity of the enzyme systems which convert arachidonate to PG's and that the regulation of these enzyme systems by the cells is accomplished through: 1) the existance of distinct pools of endoperoxide synthetase which by means of proximity to the sites of arachidonate release are differentially active, 2) the physiological state of the cell which may result in (a) differential turnover of these pools (b) differential turnover of the enzyme systems converting the endoperoxides to PGs (c) differential production of compounds such as hydroperoxy fatty acids from the lipoxygenase pathway which regulate the activity of these enzymes and 3) the production of effectors by certain cell types which regulate PG synthesis in neighboring cell types. The above hypothesis will be tested under cellular conditions of growth and function of cells from the pulmonary artery (smooth muscle, endothelal and fibroblast). These cellular conditions affect PG synthesis, especially prostacyclin (PGI2) synthesis. PGI2 is believed to be important in the function of the lung and the circulatory system. Experiments to be done are: 1) Smooth muscle cells from the pulmonary artery will be cultured under various conditions (growing- nongrowing, contractile-modulated). The other two cell types will also be placed into growing-nongrowing states. 2) PGI2 and synthesis of other PG's will be determined in response to vasoactive agents (bradykinin, angiotensins). 3) The turnover of endoperoxide synthetase pools will be examined under the above cellular conditions. A vasoactive agent responsive vs. unresponsive pool will be looked for. The effect of hydroperoxy compounds, particularly hydroperoxy fatty acids, on enzyme activity will be determined. 4) An inhibitor of endothelial cell PG synthesis extruded by smooth muscle cells and fibroblasts will be fully characterized. 5) The function of the smooth muscle contractile system will be examined with respect to PGI2 production and the effect of vasoactive agents (angiotensin, bradykinin). Hypertension and artherosclerosis are associated with smooth muscle proliferation and decreased PGI2 synthesis.
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