1. Academic Validation
  2. Tetrandrine alleviates pulmonary fibrosis by inhibiting alveolar epithelial cell senescence through PINK1/Parkin-mediated mitophagy

Tetrandrine alleviates pulmonary fibrosis by inhibiting alveolar epithelial cell senescence through PINK1/Parkin-mediated mitophagy

  • Eur J Pharmacol. 2024 Mar 2:176459. doi: 10.1016/j.ejphar.2024.176459.
Lanhe Chu 1 Jinzhong Zhuo 1 Haohua Huang 1 Weimou Chen 1 Wenshan Zhong 1 Jinming Zhang 1 Xiaojing Meng 2 Fei Zhou 2 Shaoxi Cai 1 Mengchen Zou 3 Hangming Dong 4
Affiliations

Affiliations

  • 1 Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • 2 School of Public Health, Southern Medical University, Guangzhou, China.
  • 3 Department of Endocrinology, Nanfang Hospital, Southern Medical University, Guangzhou, China. Electronic address: zoumc163@163.com.
  • 4 Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China. Electronic address: dhm@smu.edu.cn.
Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal and insidious interstitial lung disease. So far, there are no effective drugs for preventing the disease process. Cellular senescence plays a critical role in the development of IPF, with the senescence and insufficient Mitophagy of alveolar epithelial cells being implicated in its pathogenesis. Tetrandrine is a natural alkaloid which is now produced synthetically. It was known that the tetrandrine has anti-fibrotic effects, but the efficacy and mechanisms are still not well evaluated. Here, we reveal the roles of tetrandrine on AECs senescence and the antifibrotic effects by using a bleomycin challenged mouse model of pulmonary fibrosis and a bleomycin-stimulated mouse alveolar epithelial cell line (MLE-12). We performed the β-galactosidase staining, immunohistochemistry and fluorescence to assess senescence in MLE-12 cells. The Mitophagy levels were detected by co-localization of LC3 and COVIX. Our findings indicate that tetrandrine suppressed bleomycin-induced fibroblast activation and ultimately blocked the increase of collagen deposition in mouse model lung tissue. It has significantly inhibited the bleomycin-induced senescence and senescence-associated secretory phenotype (SASP) in alveolar epithelial cells (AECs). Mechanistically, tetrandrine suppressed the decrease of mitochondrial autophagy-related protein expression to rescue the bleomycin-stimulated impaired Mitophagy in MLE-12 cells. We revealed that knockdown the putative kinase 1 (PINK1) gene by a short interfering RNA (siRNA) could abolish the ability of tetrandrine and reverse the MLE-12 cells senescence, which indicated the Mitophagy of MLE-12 cells is PINK1 dependent. Our data suggest the tetrandrine could be a novel and effective drug candidate for lung fibrosis and senescence-related fibrotic diseases.

Keywords

Mitophagy; Pulmonary fibrosis; Senescence; Tetrandrine.

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