Divergent roles for Clusterin in Lung Injury and Repair
| Autor: | Alan M. Carruthers, Darryl A. Knight, Milena S. Espindola, David M. Habiel, Elena Miranda, Richard N. Hanna, Ethan Grant, Hao Liu, Timothy Burwell, Arthur Lewis, Cory M. Hogaboam, Lynne Murray, Fernanda Pilataxi, Ana Camelo, Ana Lucia Coelho, Matthew J. Bell, Bethany B. Moore, Lori A. Clarke |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Pathology Cytoplasm lcsh:Medicine Datasets as Topic Apoptosis DNA Mismatch Repair Mice Pulmonary Disease Chronic Obstructive 0302 clinical medicine DNA Breaks Double-Stranded RNA Small Interfering lcsh:Science Lung Cellular localization Mice Knockout Multidisciplinary biology Chemistry respiratory system Middle Aged 3. Good health 030220 oncology & carcinogenesis Gene Knockdown Techniques Female Intracellular medicine.medical_specialty DNA damage DNA repair Respiratory Mucosa Lung injury Article Cell Line 03 medical and health sciences Bleomycin medicine Extracellular Animals Humans Aged Clusterin Gene Expression Profiling lcsh:R Epithelial Cells Fibrosis eye diseases Idiopathic Pulmonary Fibrosis respiratory tract diseases Mice Inbred C57BL Disease Models Animal 030104 developmental biology MSH2 Case-Control Studies Cancer research biology.protein lcsh:Q sense organs Extracellular Space |
| Zdroj: | Scientific Reports Scientific Reports, Vol 7, Iss 1, Pp 1-14 (2017) |
| ISSN: | 2045-2322 |
| Popis: | Lung fibrosis is an unabated wound healing response characterized by the loss and aberrant function of lung epithelial cells. Herein, we report that extracellular Clusterin promoted epithelial cell apoptosis whereas intracellular Clusterin maintained epithelium viability during lung repair. Unlike normal and COPD lungs, IPF lungs were characterized by significantly increased extracellular Clusterin whereas the inverse was evident for intracellular Clusterin. In vitro and in vivo studies demonstrated that extracellular Clusterin promoted epithelial cell apoptosis while intercellular Clusterin modulated the expression of the DNA repair proteins, MSH2, MSH6, OGG1 and BRCA1. The fibrotic response in Clusterin deficient (CLU−/−) mice persisted after bleomycin and it was associated with increased DNA damage, reduced DNA repair responses, and elevated cellular senescence. Remarkably, this pattern mirrored that observed in IPF lung tissues. Together, our results show that cellular localization of Clusterin leads to divergent effects on epithelial cell regeneration and lung repair during fibrosis. |
| Databáze: | OpenAIRE |
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