The biology of endothelial cells (EC) is central to the laboratory's long-term objectives. Specifically, we wish to demonstrate: 1) that EC are a metabolic as well as an anatomic barrier, 2) mechanisms by which specific vasoactive substances breach the barrier, 3) unique characteristics of microvascular EC, and 4) that EC in culture are valuable experimentally because they respond physiologically to specific stimuli as their counterparts do in vivo. Current proposed aims are to demonstrate nonrespiratory metabolic functions of pulmonary EC (PEC) isolated from canine, bovine and human tissues. The projected studies are based upon the premise that PEC dysfuncton, caused by hypoxia or chemical and mechanical pertubation, results in an abnormal outpouring of fatty acid metabolites and a breakdown of serotonin and norepinephrine clearance. The outcome of this PEC pathophysiologic state is that amine and fatty acid autocoids, because of prolonged secretion by PEC, became vasotoxic and contribute importantly to non-hydrostatic pulmonary edema and decreased cardiac output. The circulating proin-flammatory agents exacerbate existing inflammatory conditions and can initiate new injury in other areas of the traumatized lung and in a non-injured contralateral lung. In other words, focal pulmonary microvascular perturbation can lead to distant inflammatory sequellae because of circulating inflammatory mediators. An hypoxic environment is theorized to stimulate the release of PEC fatty acids, which are shunted abnormally into thromboxane synthesis. The in vitro assays are designed to determine the conditions by which PEC, in response to known prophlogistic agents, produce more of these inflammatory substances. Also, how eicosanoids affect PEC PEC Serotonin and norepinephrine clearance, and how these amines affect eicosanoid synthesis will be tested. The cultured PEC will thus be used as both a substrate for secretion and as a target tissue. The mechanism of action and the prevention of vasotoxic agents mediating increased pulmonary permeability and decreased cardiac output will also be tested with animal models and isolated organ assays.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL033104-03
Application #
3344709
Study Section
(SRC)
Project Start
1984-09-30
Project End
1988-09-29
Budget Start
1986-09-30
Budget End
1987-09-29
Support Year
3
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Boston University
Department
Type
Schools of Arts and Sciences
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
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Mineau-Hanschke, R; Patton, W F; Hechtman, H B et al. (1993) Immunolocalization of cytokeratin 19 in bovine and human pulmonary microvascular endothelial cells in situ. Comp Biochem Physiol Comp Physiol 104:313-9
Wiles, M E; Welbourn, R; Goldman, G et al. (1991) Thromboxane-induced neutrophil adhesion to pulmonary microvascular and aortic endothelium is regulated by CD18. Inflammation 15:181-99
Morel, N M; Petruzzo, P P; Hechtman, H B et al. (1990) Inflammatory agonists that increase microvascular permeability in vivo stimulate cultured pulmonary microvessel endothelial cell contraction. Inflammation 14:571-83
Mineau-Hanschke, R; Wiles, M E; Morel, N et al. (1990) Modulation of cultured pulmonary microvessel and arterial endothelial cell barrier structure and function by serotonin. Microvasc Res 39:140-55
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Kelley, C; D'Amore, P; Hechtman, H B et al. (1987) Microvascular pericyte contractility in vitro: comparison with other cells of the vascular wall. J Cell Biol 104:483-90
Alexander, J S; Hechtman, H B; Shepro, D (1987) Serotonin induced actin polymerization and association with cytoskeletal elements in cultured bovine aortic endothelium. Biochem Biophys Res Commun 143:152-8
Bottaro, D; Shepro, D; Hechtman, H B (1986) Heterogeneity of intimal and microvessel endothelial cell barriers in vitro. Microvasc Res 32:389-98
Welles, S L; Shepro, D; Hechtman, H B (1985) Eicosanoid modulation of stress fibers in cultured bovine aortic endothelial cells. Inflammation 9:439-50