SH2 Domain-Containing Phosphatase-2 Is a Novel Antifibrotic Regulator in Pulmonary Fibrosis
| Autor: | Jae Sung Yi, Hojin Lee, Argyrios Tzouvelekis, Jose D. Herazo-Maya, Rong Wang, Nikolaos Xylourgidis, Yi Zhang, Patty J. Lee, Tony Woolard, Vassilis Aidinis, Robert J. Homer, Guoying Yu, Naftali Kaminski, Erica L. Herzog, Christian L. Lino Cardenas, Farida Ahangari, Koji Sakamoto, Anton M. Bennett, Giuseppe DeIuliis |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Genetically modified mouse Pathology medicine.medical_specialty Pulmonary Fibrosis Biopsy Down-Regulation Protein Tyrosine Phosphatase Non-Receptor Type 11 Critical Care and Intensive Care Medicine Bleomycin Statistics Nonparametric Nitrophenols 03 medical and health sciences chemistry.chemical_compound Idiopathic pulmonary fibrosis Mice In vivo Pulmonary fibrosis Medicine Animals Humans Immunoprecipitation Phosphorylation Fibroblast Lung Antibiotics Antineoplastic business.industry Original Articles Protein-Tyrosine Kinases respiratory system Fibroblasts medicine.disease Idiopathic Pulmonary Fibrosis respiratory tract diseases PTPN11 Mice Inbred C57BL Disease Models Animal 030104 developmental biology medicine.anatomical_structure chemistry Tyrosine Erratum business Signal Transduction |
| Zdroj: | American Journal of Respiratory and Critical Care Medicine |
| ISSN: | 1535-4970 |
| Popis: | Idiopathic pulmonary fibrosis (IPF) is a chronic fatal lung disease with dismal prognosis and no cure. The potential role of the ubiquitously expressed SH2 domain-containing tyrosine phosphatase-2 (SHP2) as a therapeutic target has not been studied in IPF.To determine the expression, mechanistic role, and potential therapeutic usefulness of SHP2 in pulmonary fibrosis.The effects of SHP2 overexpression and inhibition on fibroblast response to profibrotic stimuli were analyzed in vitro in primary human and mouse lung fibroblasts. In vivo therapeutic effects were assessed in the bleomycin model of lung fibrosis by SHP2-lentiviral administration and transgenic mice carrying a constitutively active SHP2 mutation.SHP2 was down-regulated in lungs and lung fibroblasts obtained from patients with IPF. Immunolocalization studies revealed that SHP2 was absent within fibroblastic foci. Loss of SHP2 expression or activity was sufficient to induce fibroblast-to-myofibroblast differentiation in primary human lung fibroblasts. Overexpression of constitutively active SHP2 reduced the responsiveness of fibroblasts to profibrotic stimuli, including significant reductions in cell survival and myofibroblast differentiation. SHP2 effects were mediated through deactivation of fibrosis-relevant tyrosine kinase and serine/threonine kinase signaling pathways. Mice carrying the Noonan syndrome-associated gain-of-function SHP2 mutation (SHP2Our data suggest that SHP2 is an important regulator of fibroblast differentiation, and its loss as observed in IPF facilitates profibrotic phenotypic changes. Augmentation of SHP2 activity or expression should be investigated as a novel therapeutic strategy for IPF. |
| Databáze: | OpenAIRE |
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