Synergistic anti-oxidative/anti-inflammatory treatment for LPS-induced ALI with Epigallocatechin gallate-Magnesium nanoparticles through modulating AMPK/Nrf2/HO-1 axis

Acute lung injury (ALI) is one of the serious complications of sepsis, and its incidence and mortality are rising, which greatly threatens human life. The clinical manifestations of ALI are persistent inflammation and severe respiratory disturbances. At present, there is a lack of effective treatment for ALI. To solve this problem, we developed an inhalable nanoparticle composed of epigallocatechin gallate (EGCG) and magnesium.The preparation is administered through nebulization, which greatly increases the rate of lung deposition of the drug. And compared with EGCG alone, nanoparticles significantly improve the treatment efficiency of EGCG. In vitro studies have shown that EGCG-Mg nanoparticles (EM NPs) have significant anti-inflammatory and antioxidant activity. In addition, in the lipopolysaccharides(LPS) induced ALI mouse model, EM NPs attenuated pulmonary edema, reduced levels of pro-inflammatory cytokines in serum and bronchoalveolar lavage fluid, and enhanced the antioxidant effect in lung tissue. Mechanistic studies showed that EM NPs were taken up by human umbilical vein endothelial cells(HUVECs) .Then EM NPs activated AMPK, promoted the expression of key transcription factors on the Nrf2/HO-1 signaling pathway, and enhanced the expression of antioxidant-related enzymes in cells. This cascade reduces intracellular ROS accumulation and inhibits NF-κB phosphorylation and inflammatory response. In addition, EM NPs show excellent biocompatibility. Collectively, these findings illustrate that EM NPs are a promising strategy for inhaled ALI nanotherapeutics with considerable clinical translational potential.