Phosphatidylinositol 3-kinase-mediated HO-1/CO represses Fis1 levels and alleviates lipopolysaccharide-induced oxidative injury in alveolar macrophages.

Sepsis-related acute respiratory distress syndrome is characterized by marked oxidative stress and mitochondrial dysfunction lacking of specific therapy. Heme oxygenase (HO)-1 followed by endogenous carbon monoxide (CO) exerted a cytoprotective effect against multi-organ damage during sepsis. Additionally, the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway, which serves as an upstream regulator of HO-1, was associated with inflammation and oxidative stress. Therefore, the purpose of the present study was to investigate whether the PI3K/Akt pathway was involved in the effects of HO-1/CO on the expression of mitochondrial fission 1 protein (Fis1). In the present study, CO releasing molecule-2 (CORM2), as the exogenous source of CO, plus LY294002, as a specific PI3K inhibitor, were pre-incubated in lipopolysaccharide (LPS)-simulated rat NR8383 alveolar macrophages. The results demonstrated that CORM2 improved cell viability, inhibited tumor necrosis factor-α levels, malondialdehyde contents, while elevating interleukin-10 levels and superoxide dismutase activities. In addition, pretreatment with CORM2 suppressed the fragmentation of mitochondria, upregulated the expressions of phosphorylated-Akt and HO-1 but downregulated the levels of Fis1 mRNA and protein in LPS-exposed cells. However, pretreatment with LY294002 significantly inhibited the phosphorylation of Akt, decreased HO-1 levels, aggravated mitochondrial fragmentation, increased Fis1 mRNA and protein levels, and reversed the above protective effects of CORM2. Collectively, the results of the present study indicated that the PI3K/Akt pathway mediated the cytoprotective effects of HO-1/CO on the transcription and translational levels of Fis1, and alleviated LPS-induced oxidative injury in alveolar macrophages.