Lipoxin A4 attenuates hyperoxia-induced lung epithelial cell injury via the upregulation of heme oxygenase-1 and inhibition of proinflammatory cytokines

The present study examined whether lipoxin A(4) (LXA(4)) increases the expression of HO-1, and inhibits the production of interleukin 6 (IL-6) and monocyte chemotactic protein 1 (MCP-1) in LXA(4)-induced protection during hyperoxia-induced injury in murine lung epithelial cells (MLE-12) and what signal pathway may participate in the actions of LXA4 inhibiting IL-6 and MCP-1. MLE-12 cells were exposed to air or hyperoxia with or without pretreatment with LXA(4), Zinc protoporphyrin IX (ZnPP-IX), IL-6, anti-IL-6, MCP-1, anti-MCP-1, inhibitors of p38 mitogen-activated protein kinase (p38 MAPK), protein kinase B (Akt) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathways. The cell survival rates, cell viability, apoptosis rates, expression of superoxide dismutase (SOD), heme oxygenase-1 (HO-1), IL-6 and MCP-1, and the activations of p38 MAPK, ERK1/2 and Akt were measured. LXA(4) significantly increased the cell survival rates, cell viability, SOD levels and HO-1 expression, reduced the apoptosis rates, and inhibited the MCP-1 and IL-6 levels induced by hyperoxia in cells. ZnPP-IX, an inhibitor of HO-1, blocked LXA(4)-induced protection on cell viability in cells exposed to hyperoxia. Anti-IL-6 and anti-MCP-1 improved the cell viability of cells exposed to hyperoxia. Inhibition of p38 MAPK and ERK1/2 blocked the expression of MCP-1 and IL-6 induced by hyperoxia. LXA(4) inhibited the activation of p38 MAPK and ERK1/2 induced by hyperoxia, and increased the activation of the Akt signaling pathway, which was inhibited by hyperoxia. Therefore, LXA(4) attenuated hyperoxia-induced injury in MLE-12 cells via the upregulation of HO-1 expression. The protection of LXA(4) in hyperoxia-induced cell injury may be associated with the downregulation IL-6 and MCP-1 levels via the inhibition of the p38 MAPK and ERK1/2 signaling pathways.