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Prostaglandin (PG) E 2  exhibits an anti-fibrotic effect in the lung in response to inflammatory reactions and is a high-affinity substrate of PG transporter (SLCO2A1). The present study aimed to evaluate the pathophysiological relevance of SLCO2A1 to bleomycin (BLM)-induced pulmonary fibrosis in mice. Immunohistochemical analysis indicated that Slco2a1 protein was expressed in airway and alveolar type I (ATI) and II (ATII) epithelial cells, and electron-microscopic immunohistochemistry further demonstrated cell surface expression of Slco2a1 in ATI cells in wild type (WT) C57BL/6 mice. PGE 2  uptake activity was abrogated in ATI-like cells from  Slco2a1 -deficient ( Slco2a1   -/- ) mice, which was clearly observed in the cells from WT mice. Furthermore, the PGE 2  concentrations in lung tissues were lower in  Slco2a1   -/-  than in WT mice. The pathological relevance of SLCO2A1 was further studied in mouse BLM-induced pulmonary fibrosis models. BLM (1 mg/kg) or vehicle (phosphate buffered saline) was intratracheally injected into WT and  Slco2a1   -/-  mice, and BLM-induced fibrosis was evaluated on day 14. BLM induced more severe fibrosis in  Slco2a1   -/-  than in WT mice, as indicated by thickened interstitial connective tissue and enhanced collagen deposition. PGE 2  levels were higher in bronchoalveolar lavage fluid, but lower in lung tissues of  Slco2a1   -/-  mice. Transcriptional upregulation of TGF-β1 was associated with enhanced gene transcriptions of downstream targets including plasminogen activator inhitor-1. Furthermore, Western blot analysis demonstrated a significant activation of protein kinase C (PKC) δ along with a modest activation of Smad3 in lung from  Slco2a1   -/-  mice, suggesting a role of PKCδ associated with TGF-β signaling in aggravated fibrosis in BLM-treated  Slco2a1   -/-  mice. In conclusion, pulmonary PGE 2  disposition is largely regulated by SLCO2A1, demonstrating that SLCO2A1 plays a critical role in protecting the lung from BLM-induced fibrosis.

Prostaglandin Transporter (PGT/SLCO2A1) Protects the Lung from Bleomycin-Induced Fibrosis