Inhibition of eicosanoids does not prevent neutrophil injury from phorbol in isolated rabbit lung

Abstract

Studies suggest that pulmonary and neutrophil cyclooxygenase and lipoxygenase products (i.e., eicosanoids) play a role in oxidant lung injury. We tested the hypothesis that such eicosanoids contribute to lung injury from activation of rabbit neutrophils by phorbol myristate acetate (PMA) in the pulmonary circulation of salt-perfused isolated rabbit lung preparations. We measured lung injury from PMA-activated neutrophils under zone 2 pulmonary vascular conditions with transvascular albumin flux by 125I-labeled albumin. We found that this flux was increased; catalase prevented the increase, confirming that the increase was from oxidant injury. However, results were inconsistent: about one-half of the preparations showed a marked increase and about one-half were not elevated. In preparations with a > 40-mmHg increase in pulmonary arterial pressure (Ppa), albumin flux increased, and in those with Ppa < 40 mmHg it did not. In those with Ppa > 40 mmHg, vascular volume, and presumably vascular surface area, was markedly reduced. We next studied PMA-activated neutrophils under zone 3 pulmonary vascular conditions in preparations with Ppa that increased < 40 mmHg. Albumin flux or filtration coefficient (Kf,c) was used to measure injury. Both were elevated. As with albumin flux, catalase prevented increases in Kf,c. BW-755C (a dual lipoxygenase and cyclooxygenase inhibitor) prevented increases in cyclooxygenase products and leukotriene B4 (a lipoxygenase product) but did not prevent increases in Kf,c. We conclude that a marked decrease in vascular volume can occur in zone 2 preparations and may mask the presence of injury as measured by transvascular albumin flux. A zone 3 vascular condition overcomes the vasoconstrictor-induced decrease in surface area and unmasks injury. Finally, oxidant injury from PMA-stimulated rabbit neutrophils in isolated rabbit lungs cannot be readily attributed to formation of eicosanoids.