Cyclooxygenase inhibition prevents PMA-induced increases in lung vascular permeability

The effect of cyclooxygenase inhibition in phorbol myristate acetate (PMA)-induced acute lung injury was studied in isolated constant-flow blood-perfused rabbit lungs. PMA caused a 51% increase in pulmonary arterial pressure (localized in the arterial and middle segments as measured by vascular occlusion pressures), a 71% increase in microvascular permeability (measured by the microvascular fluid filtration coefficient, K(f)), and a nearly threefold increase in perfusate thromboxane (Tx) B₂ levels. Cyclooxygenase inhibition with three chemically dissimilar inhibitors, indomethacin (10^-7 and 10^-6 M), meclofenamate (10^-6 M), and ibuprofen (10^-5 M), prevented the K(f) increase without affecting the pulmonary arterial pressure increase or resistance distribution changes after PMA administration. The specific role of TxA₂ was investigated by pretreatment with OKY-046, a specific Tx synthase inhibitor, or infusion of SQ 29548, a TxA₂ receptor antagonist; both compounds failed to protect against either the PMA-induced permeability or the vascular resistance increase. These results indicate that cyclooxygenase-mediated products of arachidonic acid other than TxA₂ mediate the PMA-induced permeability increase but not the hypertension.