Alveolar Transfer and Metabolism of Eicosanoids in the Rat

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Abstract
Alveolar transfer of eicosanoids was studied in the rat after instillation of [3H]prostaglandin, leukotrienes, and arachidonate into the distal airways. The percentage of originally added label remaining in lung or lavage was determined 2 min after instillation, with the remainder of the label having been transferred out of the lung. Peptidoleukotrienes were found to be largely (> 85%) retained in the lung after 2 min, and even after 15 min, more than 50% of the added radiolabel remained in the lung. In clear contrast, greater than 90% of the radiolabeled prostaglandin (PG) D2 was removed from the lung within 2 min after instillation. PGE2, thromboxane B2, leukotriene (LT) B4, and 5-hydroxyeicosatetraenoic acid (5-HETE) were also quickly removed from the lung, with less than 30% of the added label remaining in the lung after 2 min. Arachidonic acid and 6-keto-PGF1.alpha. were removed more slowly from the lung, with 40 to 70% remaining in the lung 2 min after instillation. The arachidonic acid remaining in the lung was largely esterified into phospholipids, especially phosphatidylcholine. The 5-HETE radiolabel remaining in the lung was also associated in part with phosphatidylcholine. The radioactivity remaining in the lung after [3H]LTB4, 6-keto-PGF1.alpha., PGD2, and thromboxane B2 instillation reflected predominantly unmetabolized eicosanoids. The peptidoleukotrienes underwent a slow metabolism from LTC4 to LTD4 to LTE4. In addition, LTE4 was metabolized to a more polar product with chromatographic properties identical to those of N-acetyl LTE4. Rat lung slices and homogenates also metabolized peptidoleukotrienes via this pathway, although less N-acetyl LTE4 was produced. Thus, rates of efflux and metabolism of mediators need to be taken into account in the assessment of their duration of action in the lung. The differences in alveolar transfer and metabolism of mediators in the airways are important variables to consider when collecting and analyzing lavage samples for eicosanoids.