Hyperoxic lung injury in mice: a possible protective role for prostacyclin.
Arachidonic acid metabolites have biologic properties that can mimic the pulmonary changes produced by hyperoxic exposure, but little information is available regarding their importance in this setting. The role of prostacyclin (PGI2) and thromboxane (Tx) A2 in oxygen-induced lung injury was evaluated by exposing mice to 100% oxygen for up to 4 days and measuring plasma and bronchoalveolar lavage (BAL) fluid concentrations of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), a metabolite of PGI2, and TxB2, a metabolite of TxA2. To determine whether a relationship exists between changes in these arachidonic acid metabolites and the severity of the lung injury, we also measured mortality, BAL protein concentration, BAL angiotensin-converting enzyme (ACE) activity, and plasma lactate dehydrogenase activity, and we examined lung sections by light and electron microscopy. After 3 days of exposure to 100% oxygen, microscopic and biochemical changes consistent with mild lung damage were found, but there was no increase in either plasma or BAL 6-keto-PGF1 alpha concentration. On day 4, severe lung damage was present. and BAL 6-keto-PGF 1 alpha level increased threefold (P less than 0.001). The level of TxB2 in BAL fluid did not change on any day. Twice-daily administration of either a high (5 mg/kg) or a low (1 mg/kg) dose of indomethacin reduced BAL concentrations of 6-keto-PGF1 alpha, and it resulted in increased mortality and higher BAL protein concentration and BAL ACE activity. These data suggest that TxA2 has little if any role in the pathogenesis of oxygen-induced lung injury, whereas prostacyclin may play a protective role.
D015121:6-Ketoprostaglandin F1 alpha / Q000032:analysis; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D011464:Epoprostenol / Q000502:physiology*; D007213:Indomethacin / Q000494:pharmacology; D008168:Lung / Q000032:analysis / Q000187:drug effects*; D008171:Lung Diseases / Q000209:etiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010100:Oxygen / Q000633:toxicity*; D011506:Proteins / Q000032:analysis; D007507:Therapeutic Irrigation; D013929:Thromboxane B2 / Q000032:analysis
D001095:Arachidonic Acids; D011506:Proteins; D016718:Arachidonic Acid; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D011464:Epoprostenol; D010100:Oxygen; D007213:Indomethacin