This proposal addresses hemodynamic and cellular mechanisms of impaired angiotensin converting enzyme (ACE) activity and serotonin (5HT) transport/binding in experimental lung injury. Both are properties of endothelial cells (EC) which, in the microvasculature of whole lung, provide a large surface area for interaction with blood. Despite the importance of microvessel EC in the interaction with ACE substrates or 5HT, most mechanistic studies have been with large vessel EC (in culture), often from extra-pulmonary sources. Therefore, we will apply selected drug-induced injury protocols to cultured EC from both large vessel and microvessel origin and the intact lung in order to approach the key question, namely, to what extend can cell culture data be extrapolated to the intact lung and whole animal? Our proposed experiments, with intact lung and EC or large and small vessels, will shown whether, 1) ACE protein synthesis in microvascular EC and whole lung is regulated by glucocorticoid, as proposed for large vessel EC, 2) reduced ACE hydrolytic activity associated with lung-injury reflects inhibition, not of the enzyme, but of the putative glucocorticoid receptor which modulates syntheses of ACE, 3) reduced 5HT transport of drug-induced lung injury reflects a cell action modifying the expression or accessibility of receptor/transporter protein, 4) this effect is functionally linked to edema production in perfused lungs. We will also examine the impact of altered flow, or microvascular EC surface area, on kinetics of endothelial-substrate interaction. For this purpose we will use microcarrier bead-EC columns, superfused at different flow rates in series or parallel networks, which are fixed with respect to both surface area and cell number. Mathematical analysis of these simple initial models will be refined to incorporate data form experiments which will simulate heterogenity of injury by inhibiting ACE in one of two columns perfused in parallel from a common reservoir. This approach will allow us to unravel the complex interaction of endothelial cell damage and accompanying hemodynamic influences.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Schools of Medicine
New Haven
United States
Zip Code
Gillis, C N (1997) Panax ginseng pharmacology: a nitric oxide link? Biochem Pharmacol 54:1-8
Rimar, S; Gillis, C N (1995) Site of pulmonary vasodilation by inhaled nitric oxide in the perfused lung. J Appl Physiol 78:1745-9
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

Showing the most recent 10 out of 37 publications