Anemonin suppresses sepsis-induced acute lung injury by inactivation of nuclear factor-kappa B and activation of nuclear factor erythroid 2-related factor-2/heme oxygenase-1 pathway

Abstract

Sepsis-induced acute lung injury (ALI) is a common acute and severe reason of death in the intensive care unit. Although the pathogenesis is complicated and multifactorial, elevated inflammation and oxidative stress are considered as fundamental mechanisms for the progression of ALI. Anemonin is a natural compound with diverse biological properties including anti-inflammatory and anti-oxidative effects. To identify whether anemonin has protective effects on sepsis-induced ALI, a mouse sepsis-induced ALI model and cellular models using the mouse alveolar macrophage MH-S cells and mouse lung epithelial MLE-12 cells were established. Our results showed that anemonin reduced lipopolysaccharide (LPS)-induced mortality, and improved sepsis-induced ALI in the mouse model, as shown by improved histopathological changes, decreased lung wet/dry weight ratio, and myeloperoxidase activity. Anemonin alleviated LPS-induced secretion of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in bronchoalveolar lavage fluid samples, as well as reversed the LPS-caused increase in malondialdehyde (MDA) content and decrease in activities of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) in lung tissues. In the cellular model, anemonin inhibited the LPS-induced inflammatory responses and oxidative stress in MH-S and MLE-12 cells. In addition, anemonin inhibited LPS-induced nuclear factor-kappa B (NF-κB) pathway, while enhancing the activation of nuclear factor erythroid 2-related factor-2 (Nrf2) in lung tissues, MH-S, and MLE-12 cells. NF-κB inhibition enhanced the anti-inflammatory and anti-oxidative effects of anemonin, while Nrf2 knockdown attenuated these effects of anemonin, implying the critical roles of NF-κB and Nrf2. These results indicated that anemonin suppressed sepsis-induced acute lung injury by inhibition of NF-κB and activation of Nrf2/heme oxygenase-1 pathway, suggesting that anemonin might be developed as a new therapeutic agent for the treatment of sepsis-induced ALI.