title: Pulmonary angiotensin-converting enzyme activity in the oxygen-toxic sheep.
abstract: Despite the potential utility of endothelial metabolic substrates for the early clinical detection of acute lung injury, the relationship between lung capillary injury and pulmonary endothelial metabolic function remains incompletely understood. Previous studies have shown that lung capillaries are damaged by oxygen toxicity in the sheep; however, metabolic functions of the pulmonary endothelium have not been examined in this otherwise well-characterized animal model of lung injury. Therefore, we studied the activity of pulmonary endothelial angiotensin-converting enzyme (ACE) in five unanesthetized adult sheep that breathed 100% O2 via tracheostomy for 3 days and in four other sheep that breathed compressed air. In contrast to the sheep that breathed air, the sheep that breathed O2 developed substantial arterial hypoxemia and hypercapnia, an increased alveolar-to-arterial O2 gradient and a slight respiratory acidosis. Morphological examination of lungs from sheep that breathed O2 revealed a multifocal distribution of injury, including interstitial edema, capillary endothelial damage, and alveolar epithelial damage. Indicator-dilution methods were used to assess first-pass pulmonary metabolism of the ACE substrate [3H]Benzoyl-Phe-Ala-Pro (BPAP) and the apparent kinetics (KM and Vmax) of ACE activity. Pulmonary metabolism of BPAP exhibited saturability, was reduced by an ACE inhibitor (enalaprit), and did not result from the activity of circulating plasma ACE. There was no difference between the 2 groups of sheep in the percent metabolism of either 0.1 mumol BPAP/kg or 1.0 mumol BPAP/kg or in the KM of BPAP metabolism. In both groups, the Vmax and Vmax/KM decreased as a result of reductions in cardiac output and volume distribution.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia.
authors.forename: R E
authors.initials: RE
authors.lastname: Howell
authors.forename: J H
authors.initials: JH
authors.lastname: Hansen-Flaschen
authors.forename: E B
authors.initials: EB
authors.lastname: Wheeldon
mesh_terms: D000818:Animals; D001784:Blood Gas Analysis; D002216:Captopril / Q000378:metabolism; D002302:Cardiac Output; D006400:Hematocrit; D008168:Lung / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D008854:Microscopy, Electron; D009842:Oligopeptides / Q000378:metabolism; D010100:Oxygen / Q000506:poisoning*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D012756:Sheep
chemical_list: D009842:Oligopeptides; C029689:benzoylphenylalanyl-alanyl-proline; D002216:Captopril; D007703:Peptidyl-Dipeptidase A; D010100:Oxygen