Andrographolide alleviates bleomycin-induced NLRP3 inflammasome activation and epithelial-mesenchymal transition in lung epithelial cells by suppressing AKT/mTOR signaling pathway

Jingpei Li; Xiaohan Yang; Penghui Yang; Ke Xu; Xiaomin Peng; Weipeng Cai; Simin Zhao; Lei Hu; Zhuoyi Li; Fei Cui; Wei Wang; Guilin Peng; Xin Xu; Jianxing He; Jun Liu

doi:10.21037/atm-20-7973

Andrographolide alleviates bleomycin-induced NLRP3 inflammasome activation and epithelial-mesenchymal transition in lung epithelial cells by suppressing AKT/mTOR signaling pathway

Ann Transl Med. 2021 May;9(9):764. doi: 10.21037/atm-20-7973.

Authors

Jingpei Li^{1

2}, Xiaohan Yang³, Penghui Yang^{1

2}, Ke Xu^{1

2}, Xiaomin Peng^{1

2}, Weipeng Cai^{1

2}, Simin Zhao^{1

2}, Lei Hu⁴, Zhuoyi Li^{1

2}, Fei Cui^{1

2}, Wei Wang^{1

2}, Guilin Peng^{1

2}, Xin Xu^{1

2}, Jianxing He^{1

2}, Jun Liu^{1

2}

Affiliations

¹ Department of Thoracic Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
² State Key Lab of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
³ Medical Genetic Centre, Guangdong Women and Children Hospital, Guangzhou, China.
⁴ Department of Pharmacy, Peking University People's Hospital, Beijing, China.

Abstract

Background: Andrographolide (Andro), a diterpenoid extracted from Andrographis paniculata, has been shown to attenuate pulmonary fibrosis in rodents; however, the potential mechanisms remain largely unclear. This study investigated whether and how Andro alleviates bleomycin (BLM)-induced NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation and epithelial-mesenchymal transition (EMT) in the lung epithelial cells.

Methods: The in vivo effects of Andro were evaluated in a rat model of BLM-induced pulmonary fibrosis. The roles of Andro in BLM-induced NLRP3 inflammasome activation, EMT and AKT/mTOR signaling were investigated using human alveolar epithelial A549 cells.

Results: We found that Andro signiﬁcantly alleviated pulmonary edema and histopathological changes, decreased weight loss, and reduced collagen deposition. Andro downregulated the levels of NLRP3, the adaptor molecule apoptosis-associated speck-like protein containing a CARD (ASC), and Caspase-1 in the lungs of BLM-treated rats, suggesting the inhibitory effect of Andro on NLRP3 inflammasome activation in vivo. Additionally, the symptoms of BLM-mediated EMT phenotype in the lung were also attenuated after Andro administration. In vitro, Andro also markedly inhibited BLM-induced NLRP3 inflammasome activation and EMT in A549 cells. Moreover, Andro inhibited BLM-induced phosphorylation of AKT and mTOR in A549 cells, suggesting that AKT/mTOR inactivation mediates Andro-induced effects on BLM-induced NLRP3 inflammasome activation and EMT.

Conclusions: These data indicate that Andro can reduce BLM-induced pulmonary ﬁbrosis through suppressing NLRP3 inflammasome activation and EMT in lung epithelial cells via AKT/mTOR signaling pathway.

Keywords: AKT/mTOR signaling; Andrographolide (Andro); NOD-like receptor family pyrin domain containing 3 inflammasome (NLRP3 inflammasome); bleomycin (BLM); epithelial-mesenchymal transition (EMT).