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 effectiveness of PGE1 in preventing endotoxin injury was studied. Eight sheep with chronic lung lymph fistula were given Escherichia coli endotoxin (2 .mu.g/kg) alone and endotoxin plus an immediate infusion of PGI2 (0.1-0.2 .mu.g/kg per min) for a 5 h 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 (.ovrhdot.QL) increasing 3-fold. This was followed in about 3 h by an increase in permeability characterized by an increasing lymph to plasma protein ratio (0.63 to 0.74) and a 3-fold increase in .ovrhdot.QL. In 7 of 8 animals infused with PGI2 the pulmonary hypertension and alteration in .ovrhdot.QL in the early and later phases were significantly decreased. In 4 paired studies, prostaglandins [PG] 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 1 animal not protected by PGI2 had the lowest plasma PGI2 level. PGI2 apparently protected the lung against injury from endotoxin.