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The transporter multidrug resistance protein 2 (MRP2) can transport some tobacco carcinogens and plays an important role in the transport of mediators related to pulmonary inflammatory diseases. However, it is not fully understood whether the pulmonary inflammation caused by cigarette smoke extract (CSE) and lipopolysaccharide (LPS) is related to the regulation of MRP2. In this study, CSE and LPS were used alone and in combination as stimuli to induce pulmonary inflammation. In addition, the establishment of a pulmonary inflammation model was verified by animal experiments in vivo. We found that compared with those in the control group, the expression of MRP2 protein was downregulated and the expression of inflammatory cytokines was upregulated in pulmonary inflammation in the CSE group and the CSE combined with LPS group. However, there was almost no change in the expression of MRP2 stimulated by LPS alone. Our results show that CSE and CSE combined with LPS downregulate the expression of MRP2 under inflammatory conditions, while LPS has almost no effect on the expression of MRP2 under inflammatory conditions. The in vivo experimental results of CSE combined with LPS were consistent with the cellular results of CSE combined with LPS, which provides a model and basis for other studies of the role of MRP2 in pulmonary inflammation. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is an inflammatory disease characterized by airway obstruction and abnormal inflammatory responses. Multidrug resistance-related protein 1 (MRP1) can reduce lung inflammation and damage by excreting various toxic exogenous substances and certain pro-inflammatory molecules. We studied whether DJ-1 modulates nuclear factor erythroid 2-related factor 2 (Nrf2) by activating the Wnt3a/β-catenin signalling pathway to further regulate MRP1 expression and pulmonary antioxidant defences in alveolar epithelial (A549) cells treated with smoke extract (CSE) and lipopolysaccharide (LPS). Marker expression was studied by western blot analysis, quantitative real-time PCR and immunofluorescence staining of A549 cells. A549 cells exposed to CSE and LPS showed downregulation of DJ-1, Wnt3a, MRP1 and haem oxygenase-1 (HO-1) and upregulation of inflammatory factors. Additionally, Nrf2 protein levels were significantly decreased, while there was no change in Nrf2 mRNA levels. Overexpression of DJ-1 and Wnt3a activated Nrf2 signalling, increased MRP1 and HO-1 levels and decreased IL-6 protein expression, while knockdown of DJ-1 and Wnt3a had the opposite effects. Furthermore, DJ-1 overexpression and DJ-1 knockdown increased and decreased, respectively, the levels of Wnt3a and β-catenin. Interestingly, Nrf2 and Wnt3a deficiency reduced the protective effects of Wnt3a and DJ-1, respectively, in A549 cells. However, the levels of DJ-1 and Wnt3a were not altered by Wnt3a and Nrf2 deletion, respectively. In A549 cells treated with CSE and LPS, DJ-1 regulates Nrf2-mediated MRP1 expression and antioxidant defences by activating the Wnt3a/β-catenin signalling pathway. These findings may provide potential therapeutic targets for COPD intervention. • DJ-1 modulated Nrf2-mediated MRP1 expression by activating Wnt3a/β-catenin signalling in A549 cells exposed to CSE and LPS. • As the concentration of CSE increased, the expression of DJ-1, Wnt3a, Nrf2 and MRP1 decreased gradually. • The effect of CSE and LPS on the expression of p-Nrf2, Nrf2, MRP1, TNF-α and IL-6 was additive. • This was the first time to explore the combined effects of CSE and LPS on the expression ofDJ-1, Wnt3a, Nrf2 and MRP1. [ABSTRACT FROM AUTHOR]

• Changes in MRP2 expression play an important role in the development of chronic pulmonary inflammation. • CSE combined with LPS induced the downregulation of MRP2 expression in a time-dependent manner. • FXR can regulate the expression of MRP2 in the lung. • Overexpression of FXR can reduce chronic pulmonary inflammation by upregulating MRP2 expression. The transporter multidrug resistance protein 2 (MRP2) plays an important role in chronic pulmonary inflammation by transporting cigarette smoke and other related inflammatory mediators. However, it is not completely clear whether pulmonary inflammation caused by cigarette smoke extract (CSE) and lipopolysaccharide (LPS) is related to MRP2 and its signal factors. In this study, CSE combined with LPS was used to establish an inflammation model in vivo and in vitro. We found that compared with the control group, after CSE combined with LPS treatment, the expression of MRP2 in rat lung tissue in vivo and human alveolar cell line in vitro was down-regulated, while the expression of inflammatory factors was up-regulated. Through silencing and overexpression of FXR, it was found that silent FXR could down-regulate MRP2 and up-regulate the expression of inflammatory factors. On the contrary, overexpression of FXR could up-regulate MRP2 and down-regulate the expression of inflammatory factors. Our results show that CSE combined with LPS can down-regulate the expression of MRP2 under inflammatory conditions, and the down-regulation of MRP2 expression may be achieved partly through the FXR signal pathway. [ABSTRACT FROM AUTHOR]