Ent-kaur-16-en-19-oic acid protects mice from neutrophilic lung inflammation and sepsis

Abstract

Abstract The roots of Aralia continentalis Kitagawa (Araliaceae), a remedy to treat patients with inflammatory diseases in traditional Asian medicine, contain kaurenoic acid (ent-kaur-16-en-19-oic acid: KA) that activates Nrf2, a key transcription factor that suppresses inflammation. Here, we explored a possible therapeutic usage of KA against acute lung injury (ALI), a neutrophilic inflammatory lung disease. When administered intratracheally (i.t.) to mouse lungs 2 h after intraperitoneal lipopolysaccharide injection that induces lung inflammation, differential amounts of KA (0.3, 3, or 30 μg/kg) significantly suppressed cellular and neutrophil infiltrations and the expression of pro-inflammatory cytokines in mouse lungs. In a mouse model of sepsis, a major cause of ALI, single i.t. KA (3 μg/kg) administered 2 h after the onset of sepsis significantly decreased the mortality of the mice. KA treatment increased Nrf2-dependent gene expression in the lung. However, while KA could not significantly suppress cellular infiltration to the lung of Nrf2 knockout (KO) mice, KA suppressed neutrophil infiltration to the lung of Nrf2 KO mice, suggesting that Nrf2 is not prerequisite for KA to suppress neutrophil infiltration. Together, these results suggest that KA, likely via multiple pathways, exerts a suppressive effect against neutrophilic lung inflammation and sepsis in mice.