論文 - 詳細
| RRC ID | 27894 |
|---|---|
| 著者 | Patel AS, Lin L, Geyer A, Haspel JA, An CH, Cao J, Rosas IO, Morse D. |
| タイトル | Autophagy in idiopathic pulmonary fibrosis. |
| ジャーナル | PLoS One |
| Abstract |
BACKGROUND:Autophagy is a basic cellular homeostatic process important to cell fate decisions under conditions of stress. Dysregulation of autophagy impacts numerous human diseases including cancer and chronic obstructive lung disease. This study investigates the role of autophagy in idiopathic pulmonary fibrosis. METHODS:Human lung tissues from patients with IPF were analyzed for autophagy markers and modulating proteins using western blotting, confocal microscopy and transmission electron microscopy. To study the effects of TGF-β(1) on autophagy, human lung fibroblasts were monitored by fluorescence microscopy and western blotting. In vivo experiments were done using the bleomycin-induced fibrosis mouse model. RESULTS:Lung tissues from IPF patients demonstrate evidence of decreased autophagic activity as assessed by LC3, p62 protein expression and immunofluorescence, and numbers of autophagosomes. TGF-β(1) inhibits autophagy in fibroblasts in vitro at least in part via activation of mTORC1; expression of TIGAR is also increased in response to TGF-β(1). In the bleomycin model of pulmonary fibrosis, rapamycin treatment is antifibrotic, and rapamycin also decreases expression of á-smooth muscle actin and fibronectin by fibroblasts in vitro. Inhibition of key regulators of autophagy, LC3 and beclin-1, leads to the opposite effect on fibroblast expression of á-smooth muscle actin and fibronectin. CONCLUSION:Autophagy is not induced in pulmonary fibrosis despite activation of pathways known to promote autophagy. Impairment of autophagy by TGF-β(1) may represent a mechanism for the promotion of fibrogenesis in IPF. |
| 巻・号 | 7(7) |
| ページ | e41394 |
| 公開日 | 2012-1-1 |
| DOI | 10.1371/journal.pone.0041394 |
| PII | PONE-D-12-06604 |
| PMID | 22815997 |
| PMC | PMC3399849 |
| MeSH | Adaptor Proteins, Signal Transducing / biosynthesis Animals Apoptosis Regulatory Proteins / biosynthesis Autophagy* Beclin-1 Cell Lineage Fibroblasts / metabolism Fibronectins / biosynthesis Gene Expression Regulation Homeostasis Humans Idiopathic Pulmonary Fibrosis / pathology* Intracellular Signaling Peptides and Proteins / biosynthesis Lung / metabolism Lung / pathology Mechanistic Target of Rapamycin Complex 1 Membrane Proteins / biosynthesis Mice Mice, Inbred C57BL Microscopy, Fluorescence / methods Microtubule-Associated Proteins / biosynthesis Multiprotein Complexes / biosynthesis Phosphoric Monoester Hydrolases Sequestosome-1 Protein TOR Serine-Threonine Kinases / biosynthesis Transforming Growth Factor beta / metabolism |
| IF | 2.74 |
| 引用数 | 185 |
| WOS 分野 | CELL BIOLOGY |
| リソース情報 | |
| 実験動物マウス | RBRC00806 |