Kaempferol reduces pyroptosis in acute lung injury by decreasing ADAM10 activity through the NLRP3/GSDMD pathway

Abstract

Sepsis-associated acute lung injury (SA-ALI) is a significant problem in intensive care units worldwide, and no specific treatment is currently available. Therefore, it is crucial to identify new potential therapeutic targets for SA-ALI, in which inflammation and inflammation-activated pyroptosis play an important role. In recent years, a disintegrin and metalloprotease (ADAM)10 and ADAM17, which regulate inflammation and the immune system, have become essential targets. However, the efficacy of ADAM10/17 inhibition on pyroptosis in SA-ALI is unclear. Hence, we aimed to investigate the effects of GW280264X, a selective ADAM10/17 inhibitor, and kaempferol, a natural product frequently consumed by humans, on pyroptosis in lipopolysaccharide (LPS)-induced SA-ALI model in male and female mice. Enzyme-linked immunoassay (ELISA) was used to measure C-reactive protein (CRP), procalcitonin (PCT), interleukin (IL)-1β, IL-10, tumor necrosis factor-α (TNF-α), glucose-regulated protein-78 (GRP78) and vascular adhesion molecule-1 (VCAM-1) levels. Western blotting was used to measure levels of ADAM10, ADAM17, nod-like protein receptor-3 (NLRP3), gasdermin D (GSDMD/GSDMD-N), and caspase-1 (Cas-1). In addition, lung tissue was evaluated histopathologically. In the present study, reduced inflammation (CRP, PCT, IL-1β, VCAM-1), pyroptosis (NLRP3, GSDMD-N, Cas-1), endoplasmic reticulum stress (GRP78), and histopathological damage were found by decreasing ADAM10 levels using kaempferol. These results strongly suggest that kaempferol-mediated ADAM10 inhibition may be a promising therapeutic target against pyroptosis in SA-ALI, offering a potential breakthrough in the treatment of this condition.