Impaired autophagic activity and ATG4B deficiency are associated with increased endoplasmic reticulum stress-induced lung injury

Aging
Mariana MacielSandra Cabrera

Abstract

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 tha...Continue Reading

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Citations

Jun 5, 2020·The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society·Sandra CabreraAnnie Pardo
May 8, 2020·Cell Death and Differentiation·Francesca CastoldiGuido Kroemer
Apr 24, 2019·The American Journal of the Medical Sciences·Nichelle I WintersTimothy S Blackwell
Sep 11, 2021·Laboratory Investigation; a Journal of Technical Methods and Pathology·Xiaosen OuyangJianhua Zhang

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Methods Mentioned

BETA
glycosylation
flow cytometry
light microscopy
transgenic
PCR
protein assay

Software Mentioned

Nis Elements
Nikon
Graphpad Prism
NIS
Elements
Elements Nikon
FlowJo

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