Toxicological implication of prostaglandin transporter SLCO2A1 inhibition by cigarette smoke in exacerbation of lung inflammation

Abstract

We reported that bleomycin (BLM)-induced pulmonary fibrosis was exacerbated in the prostaglandin transporter gene (Slco2a1)-deficient mice (Slco2a1(−/−)). Because cigarette smoke (CS) contributes to creating a profibrotic milieu in the respiratory region, the present study aimed to investigate the impact of CS on SLCO2A1-associated pathogenesis in the lungs of BLM-instilled mice. Bronchoalveolar lavage (BAL) fluid cell analysis indicated more severe inflammation in Slco2a1(−/−) on day 5 after BLM intratracheal instillation, and Slco2a1 deletion increased mRNA expression of pro-inflammatory cytokines (Tnf-α and Il-1β) and chemokine (Ccl5) in BAL cells. Male Slco2a1(−/−) exhibited significantly higher amounts of released Il-1β in BAL fluid, compared with female Slco2a1(−/−), male or female Slco2a1(+/+) group. The amount of PGE2 collected in BAL fluid tended to increase in Slco2a1(−/−) compared with Slco2a1(+/+) group, whereas the PGE2 concentrations in lung tissues were comparable between both groups. Besides, PGE2 accumulated more in BAL fluid of male than that of female mice. Therefore, Slco2a1-deficient male mice were found to be more susceptible to BLM-treatment. Moreover, CS extracts (CSE) significantly reduced initial PGE2 uptake by rat type1 alveolar epithelial cell-like (AT1-L) cells and human SLCO2A1-transfected cells. Exposure of AT1-L cells to CSE resulted in decreased mRNA expression of Slco2a1, suggesting that CS modulates SLCO2A1 function. These results indicate that exacerbated lung inflammation is attributed to an increase in Il-1β peptide and PGE2 accumulation in the alveolar space, which exhibits a male predominance. SLCO2A1 inhibition by CSE is considered to be a new rationale for the lung toxicity of CS.