Mai-wei-yang-fei decoction protects against pulmonary fibrosis by reducing telomere shortening and inhibiting AECII senescence via FBW7/TPP1 regulation

Abstract

Background: Pulmonary fibrosis (PF) is a fatal disease associated with ageing. The senescence of alveolar epithelial type II cells (AECIIs) can drive PF. Therefore, reducing AECII senescence is a promising treatment to prevent PF. Mai-wei-yang-fei decoction (MWYF) has shown significant clinical efficacy in the treatment of patients with PF. However, its mechanism of action remains unclear.

Purpose: To investigate the role and underlying mechanism of MWYF in protecting against PF.

Methods: The main chemical components of MWYF were identified using UPLC-MS. The mouse and in vitro cell models of PF were established using BLM. Micro-CT, H&E, and Masson staining were used to observe the protective effect of MWYF on mice with PF. Immunohistochemistry, β-galactosidase staining, and IF-FISH were used to observe the inhibitory effect of MWYF on senescence and telomere shortening in mouse lung tissue or A549 cells. The Transwell assay and cell co-culture method were used to observe the effect of MWYF on the migration and activation of lung fibroblasts by inhibiting AECII senescence. Finally, lentiviral vector was used to overexpress FBW7 gene in A549 cells in vitro to observe the mechanism pathway of MWYF inhibiting AECII senescence and telomere shortening.

Results: MWYF was effective in protecting against bleomycin (BLM)-induced PF. Furthermore, MWYF alleviated cellular senescence by reducing the DNA damage response (DDR) and shortening of the telomere in AECⅡs in mouse lung tissues. Mechanistically, genes related to telomere disorders were detected in BLM-induced PF mouse models using q-PCR. MWYF mainly inhibited telomere shortening by regulating FBW7 and reducing the degradation of TPP1. In vitro, MWYF reduced BLM-induced senescence in A549 cells, as well as proliferation and migration of MRC5 cells, by inhibiting DDR and telomere shortening via regulation of the FBW7/TPP1 axis.

Conclusion: MWYF is a potential therapeutic agent against PF, as it inhibits telomere shortening and reduces AECII senescence by regulating FBW7/TPP1.

Keywords: Alveolar epithelial type II cell; Cell senescence; Mai-wei-yang-fei decoction; Pulmonary fibrosis; Telomere shortening.