The long term objectives of this proposal are to determine some of the mechanisms responsible for hypoxic pulmonary hypertension in man.
The specific aims and experimental approach are based on the hypothesis that the initiating feature in this poorly understood pulmonary vascular response is hypoxic activation of the pulmonary endothelial cells, directly or indirectly, indicated by morphologic changes in the endothelial cell within minutes after onset of hypoxia, with protuberant nuclei, development of spherical structures electron dense bodies in the adluminal endothelial cytoplasm and presence of subcellular edema. In successive apparently cascade steps there are arteriolar wall edema and platelet accumulation at the endothelium, followed by fibroblast recruitment (hours) into the arteriolar wall and transformation of the latter into vascular smooth muscle (days). Since these steps appear successive and cascade they are probably mediator driven and lend themselves to investigation by biochemical, pharmacological and immunological methods including light and electron microscopy. We will initially distinguish between hypoxic vasoconstriction and vasoconstriction and resulting pulmonary hypertension without hypoxia. Tissues and fluid from intact animals and the isolated perfused lung exposed to hypoxia will be studied using complement activated fragments C3a, C4a and C5a in neutropenic and platelet depleted preparations. The """"""""activated endothelial cell"""""""" will be studied for cytoskeletal changes as will the composition of the dense bodies. The cause and mechanisms of the subcellular edema and platelet accumulation will also be examined. Since these events can be appropriate to obtain some understanding of the mechanisms of hypoxic pulmonary hypertension. Full blown pulmonary hypertension is a devastating fulminating disease in infants and adults, often rapid in progression with great morbidity and high mortality. In many, hypoxia is a strongly contributing cause. There is little effective therapy for most individuals. At this time neither the initiating nor perpetuating pathogenic mechanisms are known.
| Sobin, S S; Chen, P C (2000) Ultrastructural changes in the pulmonary arterioles in acute hypoxic pulmonary hypertension in the rat. High Alt Med Biol 1:311-22 |
