title: miR-34a promotes fibrosis in aged lungs by inducing alveolarepithelial dysfunctions.
abstract: Idiopathic pulmonary fibrosis is a well-known age-related disease. However, much less recognized has been the aging associated pathogenesis of this disorder. As we and others previously showed that dysregulation of micro-RNAs (miRNAs) was an important mechanism involved in pulmonary fibrosis, the role of these molecules in this pathology in the aged population has not been investigated (Cushing L, Kuang PP, Qian J, Shao F, Wu J, Little F, Thannickal VJ, Cardoso WV, Lü J.Am J Respir Cell Mol Biol45: 287-294, 2011; Liu G, Friggeri A, Yang Y, Milosevic J, Ding Q, Thannickal VJ, Kaminski N, Abraham E.J Exp Med207: 1589-1597, 2010; Pandit KV, Corcoran D, Yousef H, Yarlagadda M, Tzouvelekis A, Gibson KF, Konishi K, Yousem SA, Singh M, Handley D, Richards T, Selman M, Watkins SC, Pardo A, Ben-Yehudah A, Bouros D, Eickelberg O, Ray P, Benos PV, Kaminski N.Am J Respir Crit Care Med182: 220-229, 2010). In this study, by using a lung fibrosis model established in old mice, we found that ablation of miR-34a protected aged animals from developing experimental lung fibrosis. miR-34a was upregulated in lung epithelial cells, but not in lung fibroblasts of aged mice, and miR-34a expression was further increased in epithelial cells of the fibrotic lungs of these old animals. We found that miR-34a induced dysfunctions in alveolar epithelial cells (AECs), as evidenced by increased cellular senescence and apoptosis and mitochondrial aberrations. More importantly, these abnormalities were attenuated in AECs of the fibrotic lungs of aged miR-34a-/- mice. We found that miR-34a targeted Sirt1, a master anti-aging regulator, and two key cell cycle modulators, E2F3 and cyclin E2, in lung epithelial cells, and the repression of these targets was relieved in miR-34a-deficient AECs. In summary, our data suggest that elevated AEC miR-34a plays a critical role in the pathogenesis of pulmonary fibrosis in the aged population. Our study also indicates miR-34a to be a more precise miRNA target for treating this disease that overwhelmingly affects people of advanced age.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Huachun
authors.initials: H
authors.lastname: Cui
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.|Department of Geriatrics and Institute of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Ge
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Na
authors.initials: N
authors.lastname: Xie
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Sami
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Rui-Ming
authors.initials: RM
authors.lastname: Liu
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Thannickal
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and gliu@uab.edu.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
mesh_terms: D000375:Aging / Q000235:genetics* / Q000473:pathology*; D056809:Alveolar Epithelial Cells / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001761:Bleomycin; D002460:Cell Line; D049109:Cell Proliferation; D016922:Cellular Senescence; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D010641:Phenotype; D015854:Up-Regulation / Q000235:genetics
chemical_list: C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D001761:Bleomycin
keywords: aging; alveolar epithelial cell; apoptosis; lung fibrosis; micro-RNA; senescence