Mechanistic study of imipenem-cilastatin sodium modulating RAGE/HMGB1/IL-10 in the treatment of hospital-acquired pneumonia

Pan Lulu; Ren Fayan; Sun Cheng; Fang Huihua; Zhou Hongliang; Liu Shun; Zhu Jing

doi:10.11986/j.issn.1673-873X.2025.08.05

Abstract：Objective To investigate the mechanism by which imipenem-cilastatin sodium regulates the receptor for advanced glycation end products(RAGE)/high-mobility group box 1 in lung tissue(HMGB1)/interleukin-10(IL-10)signaling to treat hospital-acquired pneumonia(HAP).Methods A HAP model was established in 10 mice using Acinetobacter bau-mannii;an efficacy-dose curve was used to determine the optimal concentration of imipenem-cilastatin sodium.The remai-ning 15 mice were then randomly divided into a control group,a model group,and a high-dose treatment group(n=5 per group).The control group received no treatment;the HAP model was established in the model group and the high-dose treatment group;the model group received intraperitoneal injections of an equal volume of saline;the high-dose group re-ceived intraperitoneal imipenem-cilastatin sodium(0.13 mg/kg).Three days after dosing,three mice from each group were sacrificed for histopathological examination of lung tissue,quantification of pulmonary bacterial load,routine blood tests,oxidative stress markers,and lung tissue inflammatory cytokine levels.Western blotting was used to detect expression of RAGE/HMGB1/IL-10/MAPK/PI3K/Akt-related proteins.The remaining mice in each group were observed for survival during the 7 days following drug withdrawal.Results Histopathology of model-group lungs showed abundant inflammatory cell infiltration in alveolar spaces and peribronchial regions,a small amount of focal alveolar wall disruption and fusion with cavitation and inflammatory exudation,increased interstitial thickness,and localized pulmonary fibrosis.Compared with the model group,the high-dose group showed varying degrees of improvement in alveolar wall disruption and reduced inflamma-tory cell infiltration.The model group had significantly lower white blood cell and neutrophil counts and higher bacterial loads than the control group(P＜0.05);the high-dose group had significantly higher white blood cell and neutrophil counts and lower bacterial loads than the model group(P＜0.05).Proinflammatory cytokines IL-1β,tumor necrosis factor(TNF)-α,and TGF-β in the model group were higher and IL-10 was significantly lower versus control(P＜0.05).The high-dose group showed decreases in IL-1β,TNF-α,and TGF-β and an increase in IL-10 versus the model group(P＜0.05).The levels of malondialdehyde(MDA)and myeloperoxidase(MPO)were elevated significantly and glutathione(GSH)and total antioxidant capacity(T-AOC)were decreased significantly in the model group compared with controls(P＜0.05).The levels of MDA and MPO in the high dose group were significantly lower than those in the model group,and the levels of GSH and T-AOC were significantly higher than those in the model group(P＜0.05).The expression levels of RAGE,HMGB1,MAPK,PI3K and Akt protein in the model group were higher than those in the control group,and the expression levels of IL-10 protein were lower than those in the control group,with significant differences(P＜0.05);the expression levels of RAGE,HMGB1,MAPK,PI3K and Akt protein in the high-dose group were lower than those in the model group,and the expression levels of IL-10 protein were higher than those in the model group,with significant differ-ences(P＜0.05).Survival rate during the 7 days post-treatment was 100％(2/2)in the control group,0(0/2)in the mod-el group,and 50％(1/2)in the high-dose group.Conclusion Imipenem-cilastatin sodium exhibits marked antibacterial effects in this HAP model and attenuates lung tissue injury by modulating the RAGE/HMGB1/IL-10 signaling pathway,thereby inhibiting inflammation and oxidative stress.