The impacts of SphK1 on inflammatory response and oxidative stress in LPS-induced ALI/ARDS

Abstract

As severe conditions, acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) threaten human health. Inflammation and oxidative stress play a vital role in the pathogenesis of ALI/ARDS. Sphingosine kinase 1 (SphK1) significantly contributes to mediating inflammatory responses. Nevertheless, the impact of SphK1 on lipopolysaccharide (LPS)-triggered ALI/ARDS remains largely undetermined. In our current work, we explored the impact of SphK1 on ALI/ARDS using a mouse model. We studied whether it could reduce LPS-triggered inflammatory response and oxidative stress by suppressing SphK1 in ALI/ARDS. The mice were treated with the inhibitor of SphK1 (N,N-dimethylsphingosine, DMS) before intraperitoneal injection of LPS. Moreover, we assessed the survival rate, and several parameters, such as the lung wet/dry (W/D) ratio, myeloperoxidase (MPO) activity, superoxide dismutase (SOD) activity, malondialdehyde (MDA) content, and the release of inflammatory cytokines. Western blotting analysis was adopted to evaluate the levels of phosphoinositide 3-kinase (PI3K)/serine/threonine kinase (AKT) pathways. We showed that the inhibitor of SphK1 not only ameliorated LPS-stimulated lung histopathological changes and W/D ratio of lung tissue but also elevated the survival rate, the SOD activity and decreased the MDA content, MPO activity, interleukin-6 (IL-6) and tumor necrosis factor-ɑ (TNF-ɑ) production by regulating the PI3K/AKT signaling pathway in lung tissue. Taken together, SphK1 played an essential role in inflammatory responses and oxidative stress. The underlying mechanism might be linked to the activation and up-regulation of the PI3K/AKT signaling pathway in LPS-triggered ALI/ARDS.