Citrus alkaline extracts prevent endoplasmic reticulum stress in type II alveolar epithelial cells to ameliorate pulmonary fibrosis via the ATF3/PINK1 pathway |
| |
| Institution: | 1. Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China;2. Jiangsu Key Laboratory of Pediatric Respiratory Disease, Institute of Pediatrics, Nanjing University of Chinese Medicine, Nanjing, China;3. Department of Respiratory and Critical Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China;4. Physiology Department, Xuzhou Medical University, Xuzhou, China;5. Arizona Metabolomics Laboratory, College of Health Solutions, Arizona State University, Scottsdale, AZ, USA;6. Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ, USA;7. State Key Lab of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China;1. Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40202, USA;2. Cardiovascular Research Institute, University of Kansas Medical Center, Kansas City, KS 66160, USA |
| |
| Abstract: | BackgroundIdiopathic pulmonary fibrosis is a chronic, progressive, fibrotic disease. Although the pathogenesis remains unclear, the effect of endoplasmic reticulum (ER) stress in type II alveolar epithelial cells (AEC IIs) is increasingly thought to be a critical mechanism.PurposeWe investigated the effects of citrus alkaline extracts (CAE) on AEC IIs and elucidated the underlying mechanism for their possible use in ameliorating pulmonary fibrosis (PF).MethodsA bleomycin-induced mouse model of PF, and an in vitro tunicamycin (TM) -induced ER stress model in A549 cells were successfully established. Accumulation of collagen in lung tissues in vivo was assessed using histological analysis and western blotting. The expression levels of the ER-stress marker BiP and other related proteins were assessed by western blotting and immunofluorescence staining. Mitochondrial membrane potential was assessed to evaluate mitochondrial homeostasis.ResultsCAE mitigated collagen deposition to ameliorate PF in vivo. CAE suppressed the bleomycin or TM-induced increases in ER-stress biomarker, BiP, and PERK pathway proteins, resulting in a decrease in ER stress in mouse lung tissues and A549 cells, respectively. Additionally, CAE treatment suppressed the bleomycin or TM-induced increase in the ER-stress downstream proteins, activating ATF3 and increased the levels of PINK1 in AEC IIs, both in vivo and in vitro. The reduced mitochondrial homeostasis induced by TM was restored by CAE-treatment in A549 cells. Furthermore, conditioned media from TM-treated A549 cells increased collagen deposition in MRC5 cells mainly via TGF-β1. The increased collagen deposition was not seen using conditioned media from CAE-treated A549 cells.ConclusionThese results provide novel insights into the potential mechanism of CAE in inhibiting ER stress in AEC IIs, and suggests that it has great potential to ameliorate PF via the ATF3/PINK1 pathway. |
| |
| Keywords: | |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
