Pulmonary angiotensin-converting enzyme activity in the oxygen-toxic sheep

Area of Science:

• Pulmonary Medicine
• Endothelial Biology
• Acute Lung Injury Research

Background:

• Endothelial metabolic substrates offer potential for early acute lung injury (ALI) detection.
• Lung capillary injury from oxygen toxicity is known in sheep models.
• Pulmonary endothelial metabolic function in ALI models is not well understood.

Purpose of the Study:

• To investigate pulmonary endothelial angiotensin-converting enzyme (ACE) activity in a sheep model of oxygen-induced lung injury.
• To determine if lung capillary injury affects the metabolic function of pulmonary endothelial ACE.

Main Methods:

• Five unanesthetized sheep breathed 100% oxygen for 3 days; four control sheep breathed compressed air.
• Indicator-dilution methods assessed pulmonary metabolism of the ACE substrate [3H]Benzoyl-Phe-Ala-Pro (BPAP).
• Apparent kinetics (KM and Vmax) of ACE activity were measured.

Main Results:

• Oxygen-breathing sheep developed hypoxemia, hypercapnia, and increased alveolar-to-arterial O2 gradient, indicating lung injury.
• Morphological examination confirmed interstitial edema, capillary endothelial damage, and alveolar epithelial damage in oxygen-exposed lungs.
• Pulmonary BPAP metabolism was saturable, inhibited by enalaprilat, and not due to plasma ACE; no differences in metabolism or KM were found between groups. Vmax and Vmax/KM decreased in both groups due to reduced cardiac output.

Conclusions:

• Oxygen toxicity in sheep causes significant lung injury, including pulmonary capillary endothelial damage.
• Despite lung injury, pulmonary endothelial ACE substrate metabolism (BPAP) and its Michaelis constant (KM) remained unchanged.
• Maximal velocity (Vmax) and Vmax/KM for BPAP metabolism decreased in both groups, likely due to hemodynamic changes.