TYPE-II ALVEOLAR EPITHELIAL EICOSANOID METABOLISM - PREDOMINANCE OF CYCLOOXYGENASE PATHWAYS AND TRANSCELLULAR LIPOXYGENASE METABOLISM IN COCULTURE WITH NEUTROPHILS

Arachidonic acid (AA) metabolism was studied in freshly isolated type II alveolar epithelial cells of rabbits. Substantial basal secretion of prostanoids with predominance of prostaglandin (PG) I2 was noted. Challenge with the calcium ionophore A23187 resulted in a time- and dose-dependent increase in the generation of all AA cyclooxygenase products to severalfold values following the rank order of 12-heptadecatrienoic acid (12-HHT) > PGI2 > PGE2 greater-than-or-equal-to thromboxane A2 > PGF2-alpha almost-equal-to PGD2. Even larger augmentation of prostanoid generation was evoked by challenge with free exogenous AA. Generation of the different AA cyclooxygenase products was inhibited by acetylsalicylic acid with IC50 in the range between 250 and 500-mu-M. In addition to the prostanoid release, ionophore-challenged type II pneumocytes liberated substantial amounts of AA lipoxygenase products with leukotriene (LT) B4 > 15-hydroxyeicosatetraenoic acid (HETE) > 12-HETE > 5-HETE. Generation of LTs and HETEs was markedly increased upon simultaneous disposal of free exogenous AA. No omega-oxidation of LTB4 was noted, and no evidence for secretion of intact LTA4 was obtained. The epithelial cells displayed avid uptake of exogenously offered LTA4 with subsequent enzymatic conversion to LTB4. Co-stimulation of pneumocytes with neutrophils (PMN) resulted in an amplification of LTB4 generation, paralleled by a decrease in nonenzymatic decay products of PMN-derived LTA4; both phenomena were dose dependent on the pneumocyte-PMN ratio. In conclusion, freshly isolated type II alveolar epithelial cells possess the capability of generating a broad profile of AA cyclooxygenase and lipoxygenase metabolites in large quantities, linked with the optional capacity to cooperate in transcellular AA metabolism with amplification of product generation. These findings may be relevant for vasoregulatory, inflammatory, and immune processes in lung parenchyma.