Necrostatin-1 attenuates lipopolysaccharide-induced acute lung injury in mice

Receptor-interacting protein (RIP) kinase family members are involved in several biological processes. However, their role in acute lung injury (ALI) is still unclear. In the present study, we aim to determine the expression and function of RIP kinase family in ALI.

In the present study, ALI was induced in BALB/c male mice by intravenously injecting lipopolysaccharide (LPS). The expression levels of the RIP kinase family in ALI mice were determined using western blotting and immunohistochemical staining. The specific RIP-1 inhibitor, necrostatin-1, was used to treat LPS-induced ALI mice, followed by survival time recording, as well as histopathological and immunohistochemical staining of lung tissues, western blotting, myeloperoxidase (MPO) assay and enzyme-linked immunosorbent assay (ELISA) of related cytokines and downstream target expression.

We found that RIP-1 expression was upregulated in the lung of ALI mice and inhibition of RIP-1 by necrostatin-1 significantly prolonged the survival time of mice, which was accompanied by less serve lung injury. Furthermore, lower expression of pro-inflammatory cytokines (interleukin [IL]-6, tumor necrosis factor [TNF]-α, IL-8, cyclooxygenase [COX]-2, monocyte chemoattractant protein [MCP]-1, and IL-1β), MPO and nuclear factor (NF)-κB activation were found in bronchoalveolar lavage fluid (BALF) and lung tissues of necrostatin-1-treated ALI mice. Necrostatin-1 also attenuated LPS-induced pro-inflammatory cytokine expression and NF-κB activation in RAW 264.7 cells.

In summary, necrostatin-1 protected against LPS-induced ALI in mice by inhibiting inflammation and pulmonary NF-κB activation. Thus, necrostatin-1 could be a novel therapeutic strategy for ALI.