Cryptotanshinone attenuates LPS-induced acute lung injury by regulating metabolic reprogramming of macrophage

Zesen Ye; Panxia Wang; Guodong Feng; Quan Wang; Cui Liu; Jing Lu; Jianwen Chen; Peiqing Liu

doi:10.3389/fmed.2022.1075465

Cryptotanshinone attenuates LPS-induced acute lung injury by regulating metabolic reprogramming of macrophage

Front Med (Lausanne). 2023 Jan 13:9:1075465. doi: 10.3389/fmed.2022.1075465. eCollection 2022.

Authors

Zesen Ye¹, Panxia Wang², Guodong Feng¹, Quan Wang¹, Cui Liu¹, Jing Lu¹, Jianwen Chen¹, Peiqing Liu¹

Affiliations

¹ Laboratory of Pharmacology and Toxicology, National-Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation, Guangdong Province Engineering Laboratory for Druggability and New Drug Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
² School of Pharmaceutical Science, Guangzhou Medical University, Guangzhou, China.

Abstract

Background: Acute lung injury (ALI) is a life-threatening inflammatory disease without effective therapeutic regimen. Macrophage polarization plays a key role in the initiation and resolution of pulmonary inflammation. Therefore, modulating macrophage phenotype is a potentially effective way for acute lung injury. Cryptotanshinone (CTS) is a lipophilic bioactive compound extracted from the root of Salvia miltiorrhiza with a variety of pharmacological effects, especially the anti-inflammatory role. In this study, we investigated the therapeutic and immunomodulatory effects of CTS on ALI.

Materials and methods: The rat model of ALI was established by intratracheal instillation of LPS (5 mg/kg) to evaluate the lung protective effect of CTS in vivo and to explore the regulation of CTS on the phenotype of lung macrophage polarization. LPS (1 μg/mL) was used to stimulate RAW264.7 macrophages in vitro to further explore the effect of CTS on the polarization and metabolic reprogramming of RAW264.7 macrophages and to clarify the potential mechanism of CTS anti-ALI.

Results: CTS significantly improved lung function, reduced pulmonary edema, effectively inhibited pulmonary inflammatory infiltration, and alleviated ALI. Both in vivo and in vitro results revealed that CTS inhibited the differentiation of macrophage into the M1 phenotype and promoted polarization into M2 phenotype during ALI. Further in vitro studies indicated that CTS significantly suppressed LPS-induced metabolic transition from aerobic oxidation to glycolysis in macrophages. Mechanistically, CTS blocked LPS-induced metabolic transformation of macrophages by activating AMPK.

Conclusion: These findings demonstrated that CTS regulates macrophage metabolism by activating AMPK, and then induced M1-type macrophages to transform into M2-type macrophages, thereby alleviating the inflammatory response of ALI, suggesting that CTS might be a potential anti-ALI agent.

Keywords: AMPK; Cryptotanshinone; acute lung injury; macrophage polarization; metabolic reprogramming.

Grants and funding

All research were supported by grants from the National Natural Science Foundation of China (U21A20419 and 82104157), Natural Science Foundation of Guangdong Province (2022A1515012322), the Fundamental Research Funds for the Central Universities, Sun Yat-sen University (22qntd4510), Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01Y093), National Engineering and Technology Research Center for New drug Druggability Evaluation (Seed Program of Guangdong Province, 2017B090903004), Guangdong Provincial Key Laboratory of Construction Foundation (2017B030314030), and Guangdong Provincial Key Laboratory of Construction Foundation, No. 2019B030301005, Guangzhou Basic and Applied Basic Research Project (202102020173 and 202206080007), and the Discipline Construction Project of Guangdong Medical University (4SG21233G).