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

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 that ATG4B protein and autophagy are essential to mitigate ER stress and to prevent tunicamycin-induced epithelial apoptosis and lung fibrosis.

SUBMITTER: Maciel M

PROVIDER: S-EPMC6128419 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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

Maciel Mariana M Hernández-Barrientos Daniel D Herrera Iliana I Selman Moisés M Pardo Annie A Cabrera Sandra S

Aging 20180801 8

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 h ...[more]

PMID: 30147026

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Project description:Myeloperoxidase (MPO), oxidative stress (OS), and endoplasmic reticulum (ER) stress are increased in the lungs of rat pups raised in hyperoxia, an established model of bronchopulmonary dysplasia (BPD). However, the relationship between OS, MPO, and ER stress has not been examined in hyperoxia rat pups. We treated Sprague-Dawley rat pups with tunicamycin or hyperoxia to determine this relationship. ER stress was detected using immunofluorescence, transcriptomic, proteomic, and electron microscopic analyses. Immunofluorescence observed increased ER stress in the lungs of hyperoxic rat BPD and human BPD. Proteomic and morphometric studies showed that tunicamycin directly increased ER stress of rat lungs and decreased lung complexity with a BPD phenotype. Previously, we showed that hyperoxia initiates a cycle of destruction that we hypothesized starts from increasing OS through MPO accumulation and then increases ER stress to cause BPD. To inhibit ER stress, we used tauroursodeoxycholic acid (TUDCA), a molecular chaperone. To break the cycle of destruction and reduce OS and MPO, we used N-acetyl-lysyltyrosylcysteine amide (KYC). The fact that TUDCA improved lung complexity in tunicamycin- and hyperoxia-treated rat pups supports the idea that ER stress plays a causal role in BPD. Additional support comes from data showing TUDCA decreased lung myeloid cells and MPO levels in the lungs of tunicamycin- and hyperoxia-treated rat pups. These data link OS and MPO to ER stress in the mechanisms mediating BPD. KYC's inhibition of ER stress in the tunicamycin-treated rat pup's lung provides additional support for the idea that MPO-induced ER stress plays a causal role in the BPD phenotype. ER stress appears to expand our proposed cycle of destruction. Our results suggest ER stress evolves from OS and MPO to increase neonatal lung injury and impair growth and development. The encouraging effect of TUDCA indicates that this compound has the potential for treating BPD.

Project description:Myeloperoxidase (MPO), oxidative stress (OS), and endoplasmic reticulum (ER) stress are all increased in the lungs of neonatal rat pups raised in hyperoxia (HOX, >90% O2), an established model of bronchopulmonary dysplasia (BPD). However, the relationship between OS, MPO, and ER stress has not been examined in HOX rat pups. To determine the relationship between OS, MPO, and ER stress in BPD we treated Sprague-Dawley neonatal rat pups with Tunicamycin (Tun) or with HOX. Tun directly induces ER stress and simplifies neonatal lung alveolarization. Previously, we showed that HOX induces a cycle of destruction that we hypothesize through increased OS, MPO, and ER stress to induce BPD. To inhibit ER stress specifically, we used tauroursodeoxycholic acid (TUDCA), a molecular chaperone. To break the cycle of destruction and reduce OS and MPO we used N-acetyl-lysyltyrosylcysteine-amide (KYC), a systems pharmacology agent. Lung structure was studied morphometrically. ER stress was detected using immunofluorescence (IF), transcriptomic, proteomic, and electron microscopic analyses. Increased ER stress was observed in the lungs of HOX rat pups and also in human BPD lungs by IF. Morphometric and proteomic studies of rat lungs showed that Tun treatment decreased lung complexity and increased ER stress and BPD severity. The fact that TUDCA improved lung complexity in Tun-treated neonatal rat pups, and decreased BPD induced by HOX provides strong support for the idea that ER stress plays a causal role in BPD. Additional support comes from data showing TUDCA decreased lung myeloid cells and MPO levels in the lungs of both Tun- and HOX-treated neonatal rat pups. These data link OS and MPO to ER stress in the mechanisms mediating BPD. KYC's effective inhibition of ER stress in the lungs of Tun-treated rat pups provides additional support for the idea that MPO-induced ER stress plays a direct causal role in BPD. Thus, ER stress appears to expand our proposed cycle of destruction. Our results suggest ER stress evolves from OS and MPO to increase neonatal lung injury and impaired neonatal lung growth and development. The encouraging effect of TUDCA indicates chemical chaperone has the potential in treating BPD. Using multiomic data to investigate the role of endoplasmic reticulum stress in the development of BPD in rat model.

Dataset Information

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

Publications

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

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