title: Essential role for the ATG4B protease and autophagy in bleomycin-induced pulmonary fibrosis.
abstract: Autophagy is a critical cellular homeostatic process that controls the turnover of damaged organelles and proteins. Impaired autophagic activity is involved in a number of diseases, including idiopathic pulmonary fibrosis suggesting that altered autophagy may contribute to fibrogenesis. However, the specific role of autophagy in lung fibrosis is still undefined. In this study, we show for the first time, how autophagy disruption contributes to bleomycin-induced lung fibrosis in vivo using an Atg4b-deficient mouse as a model. Atg4b-deficient mice displayed a significantly higher inflammatory response at 7 d after bleomycin treatment associated with increased neutrophilic infiltration and significant alterations in proinflammatory cytokines. Likewise, we found that Atg4b disruption resulted in augmented apoptosis affecting predominantly alveolar and bronchiolar epithelial cells. At 28 d post-bleomycin instillation Atg4b-deficient mice exhibited more extensive and severe fibrosis with increased collagen accumulation and deregulated extracellular matrix-related gene expression. Together, our findings indicate that the ATG4B protease and autophagy play a crucial role protecting epithelial cells against bleomycin-induced stress and apoptosis, and in the regulation of the inflammatory and fibrotic responses.
authors.affiliation: a Facultad de Ciencias; Universidad Nacional Autónoma de México ; Mexico DF , Mexico.
authors.forename: Sandra
authors.initials: S
authors.lastname: Cabrera
authors.forename: Mariana
authors.initials: M
authors.lastname: Maciel
authors.forename: Iliana
authors.initials: I
authors.lastname: Herrera
authors.forename: Teresa
authors.initials: T
authors.lastname: Nava
authors.forename: Fabián
authors.initials: F
authors.lastname: Vergara
authors.forename: Miguel
authors.initials: M
authors.lastname: Gaxiola
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
authors.forename: Moisés
authors.initials: M
authors.lastname: Selman
authors.forename: Annie
authors.initials: A
authors.lastname: Pardo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D000071183:Autophagy-Related Proteins; D001761:Bleomycin / Q000494:pharmacology*; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects*; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism*; D018345:Mice, Knockout
chemical_list: D000071183:Autophagy-Related Proteins; D016207:Cytokines; D001761:Bleomycin; C582881:Atg4b protein, mouse; D003546:Cysteine Endopeptidases
keywords: ACTA2, actin, α 2, smooth muscle, aorta; ATG3, autophagy-related 3; ATG4B; ATG4B, autophagy-related 4B; ATG5, autophagy-related 5; ATG7, autophagy-related 7; ATG9B, autophagy-related 9B; BAX, BCL2-associated X protein; CASP3, caspase 3, apoptosis-related cysteine peptidase; CAV1, caveolin 1, caveolae protein, 22kDa; CCL3, chemokine (C-C motif) ligand 3; CXCL1, chemokine (C-X-C motif) ligand 1 (melanoma growth stimulating activity α); CXCR2, chemokine (C-X-C motif) receptor 2; DRAM2, DNA-damage regulated autophagy modulator 2; GFP-LC3B, green fluorescent protein-LC3B; IFNG, interferon, gamma; IL12B, interleukin 12B; IL13, interleukin 13; IPF, idiopathic pulmonary fibrosis; MAP1LC3B/LC3B, microtubule-associated protein 1 light chain 3 β; RELA, v-rel reticuloendotheliosis viral oncogene homolog A; SQSTM1, sequestosome 1; TGFB1, transforming growth factor, β 1; TGFBR2, transforming growth factor, β receptor II (70/80kDa); TNF, tumor necrosis factor; TUBB4, tubulin, β 4, class IV; WT, wild type; autophagin-1; autophagy; cysteine peptidase; epithelial cell; idiopathic pulmonary fibrosis; lung fibrosis