Glucocorticoids are widely used as anti-inflammatory drugs. These steroids suppress activation of many inflammatory cells, including lymphocytes, leukocytes, macrophages and endothelial cells. This project will test the hypotheses that """"""""Glucocorticoids inhibit prostaglandin released in microvascular endothelium by the elaboration of phospholipase inhibitory proteins (endocortins). These endocortins are release from glucocorticoid treated endothelial cells and will limit the inflammatory activation of cells involved in the immune response"""""""". Glucocorticoids have been widely used in the treatment of cerebral edema and also in the treatment of myocardial infarction. However, the undesirable side effects of these steroids and their long-lasting actions have often limited their use. The actions of glucocorticoids on many cellular elements of the inflammatory system have been studied to varying extents. However, the endothelial cell has recently emerged as an important cellular component in the events leading to inflammation. There are very few (1-2) studies of glucocorticoid action and receptors in endothelial cells, and of particular relevance to this application, no published studies in microvascular endothelium. In this project we propose to demonstrate and define the glucocorticoid receptors of cerebral and coronary microvascular endothelial cells, to elucidate the level at which glucocorticoids inhibit prostaglandin release, and to demonstrate (and partially purify) phospholipase inhibitory proteins(s) (endocortins) which are released by glucocorticoid- treated microvascular endothelial cells, and which in turn modify the activation of various cells (including endothelium) involved in the elicitation of an inflammatory response. The models for these studies are isolated rabbit coronary and cerebral microvessels and cultured coronary and cerebral endothelial cells. Techniques used include cell culture, HPLC, thin layer chromatography, gel electrophoresis, bioassays for chemotaxis, radioimmunoassay. Improved understanding of glucocorticoids action at the level of the microvasculature, and the development of compounds that selectively evoke a defined spectrum of glucocorticoid action are of long term clinical relevance and could lead to new therapeutic advances in disorders of the coronary and cerebral circulation.
| Gerritsen, M E; Rimarachin, J; Perry, C A et al. (1989) Arachidonic acid metabolism by cultured bovine corneal endothelial cells. Invest Ophthalmol Vis Sci 30:698-705 |
| Medow, M S; Intrieri, L; Moatter, T et al. (1989) Dexamethasone effects on microvascular endothelial cell lipid composition. Am J Physiol 257:C512-9 |
