Sorting nexin 10 knockdown: new strategies for alleviating sepsis-associated acute lung injury.

Abstract

Acute lung injury (ALI) is a common complication of sepsis in connection with excessive inflammation and accumulation of oxidative stress. Sorting nexin 10 (SNX10) is a sorting nexin family member involved in inflammatory processes. This study aimed to explore the function of SNX10 in ALI. The cecal ligation and puncture (CLP) model was established to induce ALI in C57BL/6J mice. CLP mice exhibited elevated levels of SNX10 expression in the lung tissues. Mice were intratracheally injected with 50 μL adenovirus (108 PFU) containing short hairpin RNA plasmid targeting SNX10. SNX10 knockdown mice showed remission of CLP-induced pulmonary edema, hemorrhage, inflammatory infiltration, and thickened alveolar septum. SNX10 downregulation reduced reactive oxygen species (ROS) levels, increased superoxide dismutase activity and glutathione content, and decreased malondialdehyde content in the lung tissues. SNX10 knockdown decreased the phosphorylation of NF-κB p65 and its nuclear translocation, thus inhibiting the levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6. Furthermore, SNX10 downregulation inhibited the NLRP3, p20 caspase 1, and ASC protein levels and the levels of IL-18 and IL-1β. A549 cells were treated with lipopolysaccharide (LPS) (10 μg/mL) for 24 h to simulate the inflammatory condition and SNX10 was knocked down using small interfering RNA. SNX10 knockdown cells showed increased viability and less ROS accumulation. Consistent with the in vivo results, the NF-κB/NLRP3 pathway and the secretion of inflammatory cytokines were inhibited after SNX10 knockdown in A549 cells. In summary, SNX10 downregulation mitigated sepsis-induced oxidative stress and pulmonary inflammation by inhibiting the NF-κB/NLRP3 pathway.