Experimental Evidence for Resecretion of PGE 2 across Rat Alveolar Epithelium by OATP2A1/S LCO2A1 -Mediated Transcellular Transport.

Prostaglandin transporter Oatp2a1/ Slco2a1 is expressed at the apical (AP) membranes of type-1 alveolar epithelial (AT1) cells. To investigate the role of OATP2A1 in prostaglandin E ₂ (PGE ₂ ) handling by alveolar epithelium, we studied PGE ₂ transport across and secretion from monolayers of rat AT1-like (AT1-L) cells obtained by trans-differentiation of type-2 alveolar epithelial cells isolated from male Wistar rats. Rat AT1-L cells expressed Oatp2a1/ Slco2a1 , together with smaller amounts of Mrp4/ Abcc4 and Oct1/ Slc22a1 PGE ₂ uptake was saturable with K _m 43.9 ± 21.9 nM. Transcellular transport of PGE ₂ across AT1-L cells grown on permeable filters in the AP-to-basolateral (BL) direction was 5-fold greater than that in the reverse direction and was saturable with K _m 118 ± 26.8 nM; it was significantly inhibited by OATP inhibitors bromosulfophthalein (BSP) and suramin, and an MRP4 inhibitor, Ceefourin 1. We simultaneously monitored the effects of BSP on the distribution of PGE ₂ produced by bradykinin-treated AT1-L cells and PGE ₂ -d ₄ externally added on the AP side of the cells. In the presence of BSP, PGE ₂ increased more rapidly on the AP side, whereas PGE ₂ -d ₄ decreased more slowly on the AP side. The decrease in PGE ₂ -d ₄ from the AP side corresponded well to the increase on the BL side, indicating that intracellular metabolism did not occur. These results suggest that Oatp2a1 and Mrp4 mediate transepithelial transport of PGE ₂ in the AP-to-BL direction. Therefore, OATP2A1 may be an important regulator of PGE ₂ in alveolar epithelium by reducing secretion of PGE ₂ and facilitating "resecretion" of PGE ₂ present in the alveolar lumen to the interstitial space or blood.
(Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)