Hydnocarpin D attenuates lipopolysaccharide-induced acute lung injury via MAPK/NF-κB and Keap1/Nrf2/HO-1 pathway.

Background: Acute lung injury (ALI) is a complex pulmonary destructive disease with limited therapeutic approaches. Hydnocarpin D (HD) is a flavonolignan isolated from Hydnocarpus wightiana which possesses antioxidant and anti-inflammatory properties. However, whether HD has beneficial effects on ALI as well as its underlying mechanism remains to be elucidated.

Purpose: This study evaluated the protective effect of HD in ALI and the underlying molecular mechanisms.

Methods: In vivo, the role of HD on lipopolysaccharide (LPS)-induced ALI in mice was tested by determination of neutrophil infiltration, levels of inflammatory cytokines, lung histology and edema, vascular and alveolar barrier disruption. In vitro, murine macrophage RAW 264.7 cells were used to investigate the molecular mechanisms RESULTS: Administration of HD protected mice against LPS-induced ALI, including ameliorating the histological alterations in the lung tissues, and decreasing lung edema, protein content of bronchoalveolar lavage fluid, infiltration of inflammatory cell and secretion of cytokines. Moreover, HD blocked the phosphorylation of TLR-4, NF-κB, and ERK in LPS-induced lung injury. In vitro, HD inhibited LPS-induced oxidative stress and inflammation in RAW 264.7 cells, which largely depend upon the upregulation of antioxidant defensive Nrf2 pathway, thereby suppressing LPS-activated proinflammatory mediator secretion, NLRP3 inflammasome, and MAPK/NF-κB signaling pathway.

Conclusion: HD attenuates oxidative stress and inflammation against LPS-induced ALI via MAPK/NF-κB and Keap1/Nrf2/HO-1 pathway, and is a promising novel therapeutic candidate for ALI.