Several lung endothelial functions, including 5-hydroxytryptamine removal and hydrolysis of substrates for angiotensin converting enzyme, are impaired by acute lung injury. It was thought that such changes, by signaling altered functional integrity of the endothelium, would allow early detection of acute lung injury. However, lung injury may concurrently diminish the perfused vascular surface area and thus directly reduce removal. It has proven difficult it distinguish between these two determinants of lung removal, primarily because the endothelial function underlying removal is common to both normal and damaged endothelium. We suggest that a qualitative difference between injured and normal endothelium in vivo would be a better basis to distinguish, unequivocally, between them. Such qualitative distinction seems possible, given recent evidence for the induction of specific membrane (receptor) proteins on endothelial cells in culture during inflammatory and immunological reactions. Detection of these membrane proteins in vivo would provide a highly sensitive and specific method of assessing endothelial integrity. Therefore, recognizing that injured endothelium, at least in cell culture systems, expresses a qualitatively different spectrum of membrane-accessible proteins, we will a) continue development of a method for lactoperoxidase-glucose oxidase radioiodination of surface proteins of endothelial cells in the intact lung. Subsequent homogenization, gel electrophoretic and lectin affinity separation will define the """"""""normal"""""""" spectrum of endothelial membane proteins; b) compare the normal spectrum with that of lungs from animals pretreated with bleamycin or phorbol myristate acetate (PMA) to induce novel proteins in the vascular endothelium; c) develop labelled antibody probes to unique, injury-associated antigens; d) use such probes in vivo to explore the presence (or absence) of these proteins in injured lungs and e) compare endothelial responses to injury, so defined, in vivo and in vitro (cells in culture).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL040863-03
Application #
3358140
Study Section
Pathology A Study Section (PTHA)
Project Start
1988-09-30
Project End
1992-01-31
Budget Start
1990-08-01
Budget End
1992-01-31
Support Year
3
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Gillis, C N (1997) Panax ginseng pharmacology: a nitric oxide link? Biochem Pharmacol 54:1-8
Chen, X; Gillis, C N (1993) Methylene blue enhanced photorelaxation in aorta, pulmonary artery and corpus cavernosum. Biochem Biophys Res Commun 190:559-63
Rimar, S; Gillis, C N (1993) Selective pulmonary vasodilation by inhaled nitric oxide is due to hemoglobin inactivation. Circulation 88:2884-7
Kim, H; Chen, X; Gillis, C N (1992) Ginsenosides protect pulmonary vascular endothelium against free radical-induced injury. Biochem Biophys Res Commun 189:670-6
Rimar, S; Gillis, C N (1992) Pulmonary vasodilation by inhaled nitric oxide after endothelial injury. J Appl Physiol 73:2179-83
Rimar, S; Gillis, C N (1992) Rapid reversal of angiotensin converting enzyme inhibition by lisinopril in the perfused rabbit lung. Pulm Pharmacol 5:103-9
Rimar, S; Gillis, C N (1992) Differential uptake of endothelin-1 by the coronary and pulmonary circulations. J Appl Physiol 73:557-62
Chen, X; Gillis, C N (1992) Enhanced photorelaxation in aorta, pulmonary artery and corpus cavernosum produced by BAY K 8644 or N-nitro-L-arginine. Biochem Biophys Res Commun 186:1522-7
Gillis, C N; Chen, X; Merker, M M (1992) Lisinopril and ramiprilat protection of the vascular endothelium against free radical-induced functional injury. J Pharmacol Exp Ther 262:212-6
Chen, X; Gillis, C N (1991) Effect of free radicals on pulmonary vascular response to acetylcholine. J Appl Physiol 71:821-5

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