Impaired autophagic activity and ATG4B deficiency are associated with increased endoplasmic reticulum stress-induced lung injury
| Autor: | Annie Pardo, Mariana Maciel, Moisés Selman, Daniel Hernández-Barrientos, Sandra Cabrera, Iliana Herrera |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
autophagy Autophagy-Related Proteins Respiratory Mucosa Lung injury Endoplasmic Reticulum Cell Line 03 medical and health sciences chemistry.chemical_compound Idiopathic pulmonary fibrosis 0302 clinical medicine Medicine Animals Lung business.industry Endoplasmic reticulum Tunicamycin Autophagy lung fibrosis aging Epithelial Cells Cell Biology respiratory system medicine.disease respiratory tract diseases ATG4B Cysteine Endopeptidases 030104 developmental biology medicine.anatomical_structure Proteostasis epithelial apoptosis chemistry Gene Expression Regulation 030220 oncology & carcinogenesis Unfolded protein response Cancer research business ER stress Research Paper |
| Zdroj: | Aging (Albany NY) |
| ISSN: | 1945-4589 |
| Popis: | Aging is the main risk factor for the development of idiopathic pulmonary fibrosis (IPF), a progressive and usually lethal lung disorder. Although the pathogenic mechanisms are uncertain, endoplasmic reticulum (ER) stress and impaired proteostasis that have been linked with aging are strongly associated with the pathogenesis of IPF. Using the Atg4b-deficient mice as a model, that partially reproduces the autophagy deficient conditions reported in aging and IPF lungs, we show for the first time how autophagy impairment and ER stress induction, contribute simultaneously to development of lung fibrosis in vivo. Increased expression of ER stress markers, inflammation and apoptosis of alveolar epithelial cells were observed in Atg4b-deficient mice compared to WT mice, when treated with the ER stress inducer tunicamycin. After tunicamycin treatment, Atg4b null lungs showed accumulation of its substrate LC3-I, demonstrating that these mice failed to induce autophagy despite the ER stress conditions. We also showed that compromised autophagy in lungs from Atg4b null mice is associated with exacerbated lung damage, epithelial apoptosis and the development of lung fibrosis at 21 days after tunicamycin treatment. Our findings indicate that ATG4B protein and autophagy are essential to mitigate ER stress and to prevent tunicamycin-induced epithelial apoptosis and lung fibrosis. |
| Databáze: | OpenAIRE |
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