SPAK-p38 MAPK signal pathway modulates claudin-18 and barrier function of alveolar epithelium after hyperoxic exposure.

BACKGROUND:Hyperoxia downregulates the tight junction (TJ) proteins of the alveolar epithelium and leads to barrier dysfunction. Previous study has showed that STE20/SPS1-related proline/alanine-rich kinase interferes with the intestinal barrier function in mice. The aim of the present study is to explore the association between and barrier function in the alveolar epithelium after hyperoxic exposure. METHODS:Hyperoxic acute lung injury (HALI) was induced by exposing mice to > 99% oxygen for 64 h. The mice were randomly allotted into four groups comprising two control groups and two hyperoxic groups with and without duanyu1842K knockout. Mouse alveolar MLE-12 cells were cultured in control and hyperoxic conditions with or without duanyu1842K knockdown. Transepithelial electric resistance and transwell monolayer permeability were measured for each group. In-cell western assay was used to screen the possible mechanism of being induced by hyperoxia. RESULTS:Compared with the control group, duanyu1842K knockout mice had a lower protein level in the bronchoalveolar lavage fluid in HALI, which was correlated with a lower extent of TJ disruption according to transmission electron microscopy. Hyperoxia down-regulated claudin-18 in the alveolar epithelium, which was alleviated in duanyu1842K knockout mice. In MLE-12 cells, hyperoxia up-regulated by reactive oxygen species which was inhibited by indomethacin. Compared with the control group, duanyu1842K knockdown MLE-12 cells had higher transepithelial electrical resistance and lower transwell monolayer permeability after hyperoxic exposure. The expression of claudin-18 was suppressed by hyperoxia, and down-regulation of duanyu1842K restored the expression of claudin-18. The process of duanyu1842K suppressing the expression of claudin-18 and impairing the barrier function was mediated by p38 mitogen-activated protein kinase (MAPK). CONCLUSIONS:Hyperoxia up-regulates the MAPK signal pathway by which disrupts the TJ of the alveolar epithelium by suppressing the expression of claudin-18. The down-regulation of duanyu1842K attenuates this process and protects the alveolar epithelium against the barrier dysfunction induced by hyperoxia.

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