Efficacy of YAP1-gene Knockdown to Inhibit Alveolar-Epithelial-Cell Senescence and Alleviate Idiopathic Pulmonary Fibrosis (IPF)
| Autor: | Y U Sun, Wei Xu, Min Li, Wei-Wei Song, Robert M. Hoffman, Mingjiong Zhang, Qiqing Huang, Jianqing Wu, Yumin Zan, Yuzhuo Wang, Weihong Zhao |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Senescence Cancer Research education Bleomycin Biochemistry Masson's trichrome stain Small hairpin RNA Mice chemistry.chemical_compound Idiopathic pulmonary fibrosis Pulmonary fibrosis Genetics Animals Humans Medicine Molecular Biology Cellular Senescence Adaptor Proteins Signal Transducing Gene knockdown Lung business.industry YAP-Signaling Proteins respiratory system medicine.disease Idiopathic Pulmonary Fibrosis respiratory tract diseases Disease Models Animal medicine.anatomical_structure chemistry Alveolar Epithelial Cells Cancer research business Signal Transduction Transcription Factors Research Article |
| Zdroj: | Cancer Genomics Proteomics |
| ISSN: | 1790-6245 1109-6535 |
| Popis: | Background/aim The prevalence of idiopathic pulmonary fibrosis (IPF) increases with age and is associated with senescence of alveolar epithelial cells (AECs). AEC senescence in pulmonary cells mediates IPF. We herein aimed to determine if YAP1 gene knockdown, a member of the Hippo/YAP signal pathway, in the bleomycin (BLM)-induced mouse model of IPF, inhibits onset of senescence of AECs and alleviates IPF. Materials and methods Adeno-associated viruses (AAVs) expressing Yes-associated protein 1 (YAP1) short hairpin RNA (shRNA) were delivered into the lung of BLM-induced IPF mice via intratracheal injection, to knockdown the YAP1 gene in AECs. The mice were assigned to 4 groups: G1: control (normal mice); G2: IPF mice; G3: IPF + AAV/YAP1; G4: IPF + AAV/scramble. After 28 days, AECs were examined for senescence using H&E staining, Masson's trichrome Staining, senescence-associated s-galactosidase (SA-β-gal) staining, western blotting and co-immunofluorescence staining, to determine the expression of YAP1, Smad-3 and p21, in order to determine the induction of senescence of ACEs. Results The severity of IPF determined by H&E staining, Masson's staining and immunofluorescence (IF) staining was positively correlated with the senescence of AECs. Down-regulation of YAP1 expression of the Hippo-signaling pathway, determined by western blotting in AECs, alleviated pulmonary fibrosis as determined by Masson's staining. Down regulation of YAP1 expression reduced the senescence of AECs as determined by s-galactosidase (SA-β-gal) staining, which alleviated the clinical symptoms of IPF mice, as determined by body weight and lung index. Conclusion Down-regulation of YAP1 expression in AECs inhibited AEC senescence which is thought to be the cause of IPF. Therefore, future studies can focus on inhibiting YAP1 to effectively treat IPF. |
| Databáze: | OpenAIRE |
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