Kaempferol alleviates sepsis related acute lung injury by inhibiting the activation of alveolar macrophages mediated by extracellular vesicles from alveolar epithelial cells

Abstract

Acute lung injury (ALI) is the most serious complication of sepsis, but there is currently a lack of effective treatment methods. Therefore, finding drugs to treat sepsis induced acute lung injury (SALI) is an urgent clinical problem that needs to be solved. Kaempferol has been proven to have therapeutic effects on various lung diseases. We used cecal ligation puncture (CLP) method to create a mouse model of sepsis. Mouse plasma exosomes and exosomes secreted by alveolar epithelial cells were injected into mice via tail vein, western blotting, PCR, flow cytometry, and other techniques were used to detect lung injury and macrophage activation in mice. Our research shows that the therapeutic effect of kaempferol in alleviating SALI partially depends on the extracellular vesicle mechanism. Compared with the Control group, the CLP group mice showed an increase in plasma exosome content, and these plasma exosomes gathered more in the lungs and promoted overactivation of alveolar macrophages. However, treatment with kaempferol reduced the levels of plasma exosomes in CLP mice and inhibited the harmful effects of exosomes on alveolar macrophages and lung tissue. Through biological information analysis and in vitro and in vivo experiments, we further discovered that the plasma exosomes affected by kaempferol exert their effects by inhibiting the MAPK signaling pathway, and these effects were amplified by MAPK inhibitors. And we found that the plasma exosomes affected by kaempferol come from alveolar epithelial cells. This study suggests that kaempferol can alleviate SALI by reducing the MAPK signaling pathway mediated by extracellular vesicles in alveolar epithelial cells and inhibiting macrophage activation.

Keywords: Exosomes; Kaempferol; MAPK; Macrophage; sepsis induced acute lung injury.