PT  - JOURNAL ARTICLE
AU  - Argyris Tzouvelekis
AU  - Guoyin Yu
AU  - Farida Ahangari
AU  - Anton Bennett
AU  - Theodoros Karampitsakos
AU  - Demosthenes Bouros
AU  - Evangelos Bouros
AU  - Naftali Kaminski
TI  - SH2 domain-containing Phosphatase-(SHP)-2 blunts fibrotic responses through regulation of fibroblast mitochondrial metabolism and autophagy
AID  - 10.1183/13993003.congress-2019.PA583
DP  - 2019 Sep 28
TA  - European Respiratory Journal
PG  - PA583
VI  - 54
IP  - suppl 63
4099  - http://erj.ersjournals.com/content/54/suppl_63/PA583.short
4100  - http://erj.ersjournals.com/content/54/suppl_63/PA583.full
SO  - Eur Respir J2019 Sep 28; 54
AB  - Background: We have previously shown that SHP2 downregulation may predispose fibroblasts to differentiate into myofibroblasts. Recent data has shown that SHP2 overexpression enhances mitochondrial metabolism.Objective: To determine whether SHP2 attenuates fibrotic responses through regulation of fibroblast mitochondrial metabolismMethods and Results: Transfection of NHLF with a constitutively active SHP2 mutant (E76A) produced reductions in PDGFBB-induced proliferation and increases on the apoptotic activity compared to cells transfected with an empty plasmid. Similarly primary mouse lung fibroblasts (MLFs) derived from mice carrying a conditional knockin mutation (D61G/+) that renders SHP2 catalytic domain constitutively active exhibited reduced proliferation and increased apoptosis (TUNEL, caspase 3/7 activity) compared to wild-type ones. SHP2 overexpression led to impaired mitochondrial function as assessed by decreased mitochondrial membrane potential and increased reactive oxygen species production. SHP2 overexpressing MLFs exhibited increased protein levels of autophagy markers (LC3B-II and p-62). Electron microscope analysis revealed that SHP2 D61G/+ MLFs were characterized by damaged mitochondria with increased number of autophagosomes compared to wild-type ones. SHP2 D61G/+ mice showed attenuated fibrotic responses to bleomycin with enhanced AMPK and decreased mTORC1 activity.Conclusions: SHP2 attenuates fibrotic responses through negative regulation of fibroblast mitochondrial metabolism and induction of autophagy. SHP2 activation may represent a promising therapeutic strategy for patients with IPF.FootnotesCite this article as: European Respiratory Journal 2019; 54: Suppl. 63, PA583.This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only).