Protective effects of dihydroartemisinin against sterile inflammation and oxidative stress in alveolar macrophages.

Abstract

BACKGROUND: Pulmonary alveoli are highly vulnerable to oxidative stress due to high oxygen tension, with alveolar macrophages serving as the primary defense. Dihydroartemisinin (dha), an active derivative of Artemisia annua L., possesses potent biological activities. We investigated the efficacy and mechanisms of dha against acute lung injury (ALI). METHODS: Inflammation and oxidative stress were induced in MH-S alveolar macrophages using PMA and TNFα. In vivo, an ALI mouse model was established via intratracheal TNFα administration, followed by oral dha treatment (3 days). We assessed inflammasome activation, reactive oxygen species (ROS) levels, and lung pathology. RESULTS: In MH-S cells, dha significantly inhibited PMA- and TNFα-induced inflammasome activation by downregulating NLRP3, ASC, and cleaved-caspase-1. Dha also reduced total and mitochondrial ROS production, likely through SOD2 upregulation. In mice, oral dha effectively alleviated TNFα-induced immune cell infiltration, cytokine secretion, pulmonary edema, and early-stage fibrotic remodeling. These protective effects were associated with attenuated pulmonary inflammasome activation and IL-1β expression. CONCLUSIONS: Dha exerts robust anti-inflammatory and anti-oxidative effects by modulating the NLRP3/ASC axis and mitochondrial ROS production, thereby mitigating pulmonary structural damage. GENERAL SIGNIFICANCE: These findings highlight dha as a promising therapeutic candidate for acute inflammatory lung diseases, providing a mechanistic basis for its clinical potential.