Madecassic acid attenuates sepsis-associated acute lung injury by regulating the PI3K/AKT/mTOR pathway to mediate anti-inflammatory, antioxidant and anti-apoptotic effects

Abstract: Background: Sepsis-induced acute lung injury (ALI) is a critical illness with a high mortality rate. Madecassic acid (MA), a pentacyclic triterpenoid extracted from Centella asiatica, exhibits multiple biological activities, but its role in sepsis-associated ALI remains poorly elucidated. Objectives: The aim of this study was to investigate the protective effect of MA on lipopolysaccharide (LPS)-induced ALI in mice and to elucidate its potential mechanisms in regulating inflammation, oxidative stress, apoptosis and the PI3K/AKT/mTOR signaling pathway. Methods: An ALI mouse model was established by intraperitoneal LPS injection. The mice were randomly divided into a sham operation group, an MA alone group, an LPS model group and an LPS combined with MA treatment group. The degree of lung injury was assessed via histopathological examination of the lungs and the lung wet/dry weight ratio; the levels of inflammatory factors (TNF-α and IL-6) and oxidative stress markers (MPO, MDA, SOD and GSH-Px) in the bronchoalveolar lavage fluid (BALF) were measured; and the expression of apoptosis-related proteins and PI3K/AKT/mTOR pathway activation in the lung tissues were detected via Western blotting. Results: MA treatment significantly reduced LPS-induced lung tissue injury, edema and inflammatory cell infiltration; decreased the levels of proinflammatory factors (TNF-α and IL-6); improved oxidative stress parameters (decreased MPO and MDA levels and increased SOD and GSH-Px levels); inhibited apoptosis (downregulated Bax and cleaved caspase-3 expression and upregulated Bcl-2 expression); and inhibited the phosphorylation of PI3K, AKT and mTOR. Conclusion: MA attenuates sepsis-associated ALI through anti-inflammatory, antioxidant and anti-apoptotic effects and this mechanism is related to inhibiting the activation of the PI3K/AKT/mTOR signaling pathway. MA has the potential to be a therapeutic agent for sepsis-associated ALI.