SH2 Domain–Containing Phosphatase-2 Is a Novel Antifibrotic Regulator in Pulmonary Fibrosis
Year: 2016
Type: article
Abstract: Rationale 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. Objectives To determine the expression, mechanistic role, and potential therapeutic usefulness of SHP2 in pulmonary fibrosis. Methods 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. Measurements and Main Results 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 (SHP2D61G/+) were resistant to bleomycin-induced pulmonary fibrosis. Restoration of SHP2 levels in vivo through lentiviral delivery blunted bleomycin-induced pulmonary fibrosis. Conclusions Our 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.
Authors: Argyrios Tzouvelekis, Guoying Yu, Christian L. Lino Cardenas, Jose D. Herazo-Maya, Rong Wang, Tony Woolard, Yi Zhang, Koji Sakamoto, Hojin Lee, Jae-Sung Yi, Giuseppe DeIuliis, Nikolaos Xylourgidis, Farida Ahangari, Patty J. Lee, Vassilis Aidinis, Erica L. Herzog, Robert Homer, Anton M. Bennett, Naftali Kaminski
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: University of South Carolina, National Institutes of Health, Division of Rheumatology and Immunology, Medical University of South Carolina, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: G10138145, G1140502595, G203629335, G2575799648, G2718973925, Gene networks beyond organ boundaries; heart, lung and pulmonary vascular disease, G5489004377, Neuronally Active Proteins in IPF, Alveolar DevMAP, Neuroimmune Molecules in Scleroderma Lung Fibrosis, G806062132, G9000017845, G9000035563, G9000041500, G9000063337, G9000082755, G9000161133, G9000165057, G9000308438
OpenAlex ID: W2530928699