We will study the nature, mechanisms and consequences of impaired lung metabolic functions and, with such knowledge, develop a reliable means for early detection of acute lung injury. Pulmonary microvascular endothelial cells are metabolically active and synthesize and degrade many circulating vasoactive and other compounds. We found previously that alterated magnitude of these processes can reflect the presence of lung microvascular injury. We also found that the magnitude of change is influenced both by intrinsic endothelial dysfunction and by hemodynamic factors, including blood flow rate and its distribution relative to endothelial surface area. We propose, therefore, to apply a new non-linear analysis of multiple indicator dilution data to estimate the apparent kinetic parameters of selected lung metabolic functions. We believe that Kmapp will reflect endothelial metabolic function and Vmaxapp, indirectly, will be related to endothelial surface area. Kinetic parameters will be determined with isolated perfused lungs where the influence of altered flow, vascular surface area, transpulmonary pressure will be controlled. Kinetic data derived by bolus injection or steady state infusion of Benz-phe-ala-pro (BPAP) or prostaglandins will be compared. Kmapp and Vmaxapp will also be determined in intact, anesthetized or conscious rabbits under control conditions and after injury by hyperoxia, endotoxin, live organisms, embolization, used alone or in combination. This approach will allow us to unravel the complex interaction of endothelial cell damage and accompanying hemodynamic influences. With such knowledge we will then use kinetic measurements to follow (a) the development of injury; (b) the appearance of potential eicosanoid mediators of injury; and (c) the effectiveness of three reportedly specific inhibitors of eicosanoid biosynthesis - nafazatrom, BW775c and U-60257 - in preventing or ameliorating effects of acute lung injury. Finally, we will use photon-emitting isotopes to develop virtually """"""""on-line"""""""" methods for determination of Kmapp and Vmaxapp of lung metabolic events in perfused lung and intact animal.

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