Lung injury produced by endotoxin is characterized by both pulmonary hypertension and increased pulmonary vascular permeability. Prostacyclin (PGI2) has been found to be a vasodilator and a membrane stabilizer. The purpose of this study was to determine the effectiveness of PGI2 in preventing endotoxin injury. Eight sheep with chronic lung lymph fistula were given both Escherichia coli endotoxin (2 microgram/kg) alone and endotoxin plus an immediate infusion of PGI2 (0.1 to 0.2 microgram/kg/min) for a 5-hour period; the studies were performed 4 days apart. The endotoxin injury was characterized by early severe pulmonary hypertension, with pulmonary artery pressure increasing from 18 +/- 0.6 to 40 +/- 3.1 mm Hg and lung lymph flow (QL) increasing threefold. This was followed in about 3 hours by an increase in permeability characterized by an increasing lymph to plasma protein ratio (0.63 to 0.74) and a threefold increase in QL. In seven of eight animals infused with PGI2 the pulmonary hypertension and alteration in QL in the early and later phases were significantly decreased. In four paired studies, prostaglandins PGE, PGF2 alpha, and PGI2 as 6-keto PGF1 alpha were measured in lymph and plasma. PGF2 alpha and PGI2 were significantly increased in lung lymph during the early hypertensive phase immediately after endotoxin injection, but returned to baseline during the later phase. In the PGI2 infusion studies, PGF2 alpha showed the same pattern of response, but PGI2 was increased to much higher levels in lymph and plasma, as compared to values of endotoxin alone. The higher plasma values corresponded with less severe lung injury. The one animal not protected by PGI2 had the lowest plasma PGI2 level. We therefore found PGI2 to protect the lung against injury from endotoxin.