SH2 domain-containing phosphatase-SHP-2 is a novel anti-fibrotic regulator in pulmonary fibrosis

Abstract

Rationale: Idiopathic Pulmonary Fibrosis (IPF) is a chronic fatal lung disease with dismal prognosis and ineffective treatment. The potential role of the ubiquitously expressed SH2 domain-containing-tyrosine phosphatase (SHP2) as a therapeutic target has not been studied in IPF Objectives: To determine the role of SHP2 in Pulmonary Fibrosis. Methods: The effects of SHP2 overexpression and inhibition on fibroblast response to pro-fibrotic stimuli were analyzed in-vitro in primary human and mouse lung fibroblasts and in-vivo in the bleomycin-model of lung fibrosis. Results: SHP2 was downregulated in lungs derived from patients with IPF at the mRNA and protein level and immunolocalization studies revealed that SHP2 expression 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 pro-fibrotic 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 homeostasis. Augmentation of SHP2 activity or expression should be investigated as a novel therapeutic strategy for IPF.