There is significant evidence that the anti-fibrotic action of PGE2 in the lungs results in the increased sensitivity of fibroblasts to apoptosis. Under normal physiological conditions, PGE2 exists as an organic anion that requires an uptake transporter to be imported into the cell. Previous studies have indicated that OATP2A1 (encoded by SLCO2A1) is a high-affinity prostaglandin uptake transporter that plays a critical role in PGE2 signaling. OATP2A1 is expressed in the lungs, particularly in the endothelial cells of rodents and humans, where it mediates the rapid clearance of PGE2 from the systemic circulation. Indeed OATP2A1 is abundantly expressed in the alveolar lumen of rodents and lung tissue of mice. Although there is some evidence to suggest that OATP2A1 regulates the pulmonary distribution of PGE2 produced by the inflammatory and epithelial cells in the lumen of the alveoli, the role of OATP2A1 in the regulation of PGE2 distributed by alveolar epithelial cells is not fully understood.
Recently scientists at Kanazawa University: Professor Takeo Nakanishi (currently affiliated in Takasaki University of Health and Welfare), Mr. Hiroki Takashima, Ms. Yuka Uetoko, Dr. Hisakazu Komori and Dr. Ikumi Tamai, from the Institute of Medical, Pharmaceutical and Health Sciences demonstrated the role of OATP2A1 in the pulmonary distribution of PGE2 produced by type-1 alveolar epithelial (AT1) cells. The authors conducted cellular uptake and transcellular transport studies of native PGE2 in order to characterize the function of OATP2A1 in monolayers of rat AT1-like (AT1 L) cells. The research work is published in Journal of Pharmacology and Experimental Therapeutics.
The research team observed that the monolayers of rat AT1-like (AT1 L) cells expressed large amounts of Oatp2a1/Slco2a1, and reduced amounts of Mrp4/Abcc4 and Oct1/Slc22a1. They also observed that the transport of PGE2 across the monolayer of AT1-L cells from the alveolar lumen (AP side) to the interstitial space (BL side) was greater than the transport of PGE2 across the monolayer of AT1-L cells from the interstitial space (BL side) to the alveolar lumen (AP side). The transport of PGE2 across the monolayer of AT1-L cells was inhibited by OATP inhibitors (i.e. suramin, and bromosulfophthalein and an MRP4 inhibitor (i.e., ceefourin-1).
There was a rapid increase in the endogenous accumulation of PGE2 in the alveolar lumen (AP side), in the presence of bromosulfophthalein, while PGE2-d4 decreased more slowly in the alveolar lumen (AP side), in the presence of bromosulfophthalein. Contrastingly, the amounts of PGE2 and PGE2-d4 in the interstitial space (BL side) increased in a time-dependent manner while the accumulation of PGE2 in the interstitial space (BL side) was not affected by the presence of bromosulfophthalein.
The findings documented by Dr. Nakanishi and colleagues successfully reported for the first time that OATP2A1 plays a critical role in the transcellular transport of PGE2 across the monolayers of primary-cultured rat AT1-like cells from the alveolar lumen to the interstitial space. These findings suggest that OATP2A1 may mediate the redisposition of secreted PGE2 from the alveolar lumen to the interstitial space, thereby eliminating PGE2 from the alveolar lumen and modulating PGE2 signaling of interstitial cells, where PGE2 is needed. This will advance further studies on the development of new therapeutic solutions to pulmonary fibrosis.
Nakanishi, T., Takashima, H., Uetoko, Y., Komori, H., and Tamai, I. Experimental Evidence for Re-Secretion of PGE2 across Rat Alveolar Epithelium by OATP2A1/SLCO2A1-Mediated Transcellular Transport, Journal of Pharmacology and Experimental Therapeutics 368 (2019) 317-325Go To Journal of Pharmacology and Experimental Therapeutics