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AKT Inhibitor MK-2206 Attenuates Sepsis Acute Lung Injury (SALI) by Regulating Macrophage Polarization and Apoptosis
Vol 37, Issue 3, 2023
Abstract
Background: Alveolar macrophages accumulation is the leading cause of sepsis acute lung injury (SALI). AKT (protein kinase B, PKB) signaling pathway is closely related to macrophages apoptosis and polarization. This study aimed to assess AKT inhibitor MK-2206 effect on lipopolysaccharide (LPS)-induced macrophages and on acute lung injury in a septic mice model. Methods: Cell Counting Kit-8 (CCK-8) was used to evaluate the impact of MK-2206 on macrophages proliferation in vitro. AKT-mTOR (mammalian target of rapamycin) pathway proteins expression level and apoptosis-related proteins were measured by western blot (WB). Macrophages phenotypic modulation and cell apoptosis level were assessed by flow cytometry. In vivo, survival rate and lung tissue wet: Dry weight ratio were evaluated to assess MK-2206 influence on SALI in septic mice. Immunohistochemistry (IHC) was used to assess alveolar macrophages infiltration. The level of inflammation-related factors were determined by ELISA in vivo and ex vivo. Results: Ex vivo, MK-2206 critically restrained Raw264.7 cell proliferation in a dose-dependent way. MK-2206 at 100 ng/mL could up-regulate macrophages apoptosis and skew macrophages from M1 towards M2, followed by an increased in IL (interleukin)-10 level and decreased TNF-α (tumor necrosis factor-α) level. In vivo, MK-2206 could significantly mitigate alveolar macrophages aggregation, reduce lung tissue edema, down-regulate IL-6 and TNF-α levels in peripheral blood, and improve survival in sepsis mice. Conclusions: This research revealed that MK-2206 may serve as a promising drug in SALI by regulating macrophage apoptosis and macrophage polarization, which consequently inhibits macrophage pro-inflammatory response by down-regulating AKT signaling pathway.
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Copyright (c) 2023 Zi-Yi Wang, Zhe Guo, Xue-Song Wang, Hai-Yan Liao, Feng Chen, Yu-Xin Liu, Zhong Wang
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Medical Genetics, University of Torino Medical School, Italy

Department of Biomedical, Surgical and Dental Sciences, University of Milan, Italy