Pulmonary release of thromboxanes and prostaglandins occurs during the first hour after endotoxin infusion in sheep concomitant with transient, severe pulmonary hypertension (phase I) and followed by a prolonged period of increased lung vascular permeability (phase II) characterized by moderately elevated pulmonary artery pressure and high flow of protein-rich lung lymph. Indomethacin and meclofenamate both inhibited phase I pulmonary hypertension but did not prevent later increases in pulmonary artery pressure and lung lymph flow to levels seen with endotoxin alone in the same sheep. Indomethacin significantly exaggerated phase II lung lymph flow (endotoxin = 19 +/- ml/hr; indomethacin + endotoxin = 24 +/- 4 ml/hr, p less than 0.05), and meclofenamate enhanced phase II lymph protein clearance (endotoxin = 12.9 +/- 1.5 ml/hr; meclofenamate + endotoxin = 17.1 +/- 2.5 ml/hr, p less than 0.05). Hypoxemia seen with endotoxin alone was inhibited by meclofenamate. These data indicate that during endotoxemia cyclooxygenase products mediate phase I pulmonary hypertension. Inhibitors of cyclooxygenase prevent ventilation perfusion imbalance that results in endotoxin induced hypoxemia. Exaggeration of phase II lymph responses by cyclooxygenase inhibitors suggests that prostaglandin synthesis moderates phase II or that lipoxygenation products contribute to the phase II increased permeability response.