Failure of non-selective inhibition of arachidonic acid metabolism to ameliorate hyperoxic lung injury.
We have previously reported that bronchoalveolar lavage fluid cyclo-oxygenase products of arachidonic acid (AA) metabolism increase prior to the development of significant hyperoxic lung injury. To further assess the role of AA metabolites in the development of hyperoxic lung injury, we have utilized this same model of hyperoxic lung injury and administered either indomethacin (an inhibitor of the cyclo-oxygenase pathway of AA metabolism) or dexamethasone (inhibitor of AA release). A total of 46 adult rabbits were exposed to greater than 95% oxygen for 65 hours. Fourteen animals were given either 2 or 3 mg/kg/day indomethacin, 7 served as controls: 18 animals were given either 0.5 or 1.0 mg/kg/day of dexamethasone, 7 served as controls. The surviving animals were sacrificed after 65 hours of hyperoxia and bronchoalveolar lavage of the left lung was done; the right lung was examined by light microscopy. Treatment with indomethacin or dexamethasone failed to ameliorate the hyperoxic lung injury process. However, in both the indomethacin and dexamethasone treatment groups, significant suppression of 6-keto-PGF1 alpha, a PGI2 metabolite, was observed. Some suppression of TXB2 production was observed, but there was no evidence of any decrease in leukotriene production. We postulate that failure to ameliorate hyperoxic lung injury with either indomethacin or dexamethasone therapy was related to significant suppression of PGI2, a potentially protective AA metabolite, and/or to failure to significantly decrease production of potential pathogenic participants, such as TXA2 or LTB4.(ABSTRACT TRUNCATED AT 250 WORDS)
D015121:6-Ketoprostaglandin F1 alpha / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D007213:Indomethacin / Q000494:pharmacology; D008168:Lung / Q000187:drug effects*; D010100:Oxygen / Q000494:pharmacology*; D011817:Rabbits; D013929:Thromboxane B2 / Q000096:biosynthesis
D001095:Arachidonic Acids; D016718:Arachidonic Acid; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D003907:Dexamethasone; D010100:Oxygen; D007213:Indomethacin