title: SH2 Domain-Containing Phosphatase-2 Is a Novel Antifibrotic Regulator in Pulmonary Fibrosis.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  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.affiliation: 1 Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Argyrios
authors.initials: A
authors.lastname: Tzouvelekis
authors.affiliation: 1 Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Guoying
authors.initials: G
authors.lastname: Yu
authors.affiliation: 2 Thoracic Aortic Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Christian L
authors.initials: CL
authors.lastname: Lino Cardenas
authors.affiliation: 1 Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Jose D
authors.initials: JD
authors.lastname: Herazo-Maya
authors.affiliation: 1 Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.affiliation: 1 Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Tony
authors.initials: T
authors.lastname: Woolard
authors.affiliation: 1 Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 1 Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Koji
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: 3 Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Hojin
authors.initials: H
authors.lastname: Lee
authors.affiliation: 3 Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Jae-Sung
authors.initials: JS
authors.lastname: Yi
authors.affiliation: 1 Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: DeIuliis
authors.affiliation: 1 Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Xylourgidis
authors.affiliation: 1 Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Farida
authors.initials: F
authors.lastname: Ahangari
authors.affiliation: 1 Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Patty J
authors.initials: PJ
authors.lastname: Lee
authors.affiliation: 4 Biomedical Sciences Research Center "Alexander Fleming," Vari, Athens, Greece; and.
authors.forename: Vassilis
authors.initials: V
authors.lastname: Aidinis
authors.affiliation: 1 Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Erica L
authors.initials: EL
authors.lastname: Herzog
authors.affiliation: 5 Department of Pathology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Robert
authors.initials: R
authors.lastname: Homer
authors.affiliation: 3 Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Anton M
authors.initials: AM
authors.lastname: Bennett
authors.affiliation: 1 Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Naftali
authors.identifier: http://orcid.org/0000-0001-5917-4601
authors.initials: N
authors.lastname: Kaminski
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D001706:Biopsy; D001761:Bleomycin / Q000008:administration & dosage; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005347:Fibroblasts / Q000473:pathology*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics* / Q000473:pathology; D047468:Immunoprecipitation / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D009596:Nitrophenols / Q000032:analysis; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000187:drug effects / Q000235:genetics*; D018709:Statistics, Nonparametric
chemical_list: D000903:Antibiotics, Antineoplastic; D009596:Nitrophenols; D001761:Bleomycin; C024719:4-nitrophenyl; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse
keywords: PTPN11; SHP2; antifibrotic therapy; lung fibrosis