Inactivation of peptidoleukotrienes in the isolated perfused rat lung

Inactivation of peptidoleukotrienes by alveolar transfer and metabolism was investigated in isolated perfused rat lungs. [3H]Leukotriene (LT)C4 or [3H]LTE4 was instilled into the airways and 25 min later the distribution of tritiated metabolites in bronchoalveolar lavage fluid, lung, and perfusate was determined. Metabolism of LTC4 was found to occur in both the alveolar and vascular space in contrast to metabolism of LTE4, which occurred exclusively on the alveolar side. The alveolar transfer of leukotrienes into the perfusate was slow with only 25-29% transfer occurring during the 25-min perfusion. Only a small percentage of instilled LTC4 was transferred out of the airways unmetabolized, suggesting that this leukotriene is not the major one that is removed from the airways. In contrast, LTE4 either added directly into the airways or produced in the alveolar space from LTC4 metabolism was more readily transferred out of the lung. LTE4 was transported into alveolar cells by a nonenergy requiring, receptor-mediated mechanism inhibited by LTD4/LTE4 receptor antagonists and by probenecid. Cysteine-containing compounds (cysteine, cystine, and N-acetylcysteine) added to the perfusate caused a significant increase in LTE4/N-acetyl-LTE4 transport possibly due to a coupling of cyst(e)ine (in) and LTE4 (out) transport. Metabolism of LTC4 by gamma-glutamyltransferase appears to be the rate limiting step of peptidoleukotriene inactivation in the rat airways, being necessary for both metabolic inactivation and the formation of products which can be eliminated by transfer.