TY - JOUR
T1 - Sirtuin1 protects against systemic sclerosis–related pulmonary fibrosis by decreasing proinflammatory and profibrotic processes
AU - Chu, Haiyan
AU - Jiang, Shuai
AU - Liu, Qingmei
AU - Ma, Yanyun
AU - Zhu, Xiaoxia
AU - Liang, Minrui
AU - Shi, Xiangguang
AU - Ding, Weifeng
AU - Zhou, Xiaodong
AU - Zou, Hejian
AU - Qian, Feng
AU - Shaul, Philip W.
AU - Jin, Li
AU - Wang, Jiucun
N1 - Funding Information:
This work was partially supported by grants from the National Science Foundation of China grants 31521003 and 81470254, International S&T Cooperation Program of China grant 2013DFA30870, National Institutes of Health National Institute of Allergy and Infectious Diseases U01 grant 1U01AI090909, and the 111 Project grant B13016 from the Ministry of Education of China. The authors appreciate the computational support provided by the High-End Computing Center located at Fudan University (Shanghai, China).
Funding Information:
*These authors contributed equally to this work. ‡These authors contributed equally to this work. This work was partially supported by grants from the National Science Foundation of China grants 31521003 and 81470254, International S&T Cooperation Program of China grant 2013DFA30870, National Institutes of Health National Institute of Allergy and Infectious Diseases U01 grant 1U01AI090909, and the 111 Project grant B13016 from the Ministry of Education of China.
Publisher Copyright:
Copyright © 2018 by the American Thoracic Society.
PY - 2018/1
Y1 - 2018/1
N2 - Pulmonary fibrosis is the leading cause of death in systemic sclerosis (SSc). Sirtuin1 (SIRT1) is a deacetylase with known antiinflammatory and antifibrotic activity in the liver, kidney, and skin. The role of SIRT1 in SSc-related pulmonary fibrosis is unknown. In the present work, we determined that the expression of SIRT1 in peripheral blood mononuclear cells of patients with SSc with pulmonary fibrosis is lower than that in patients with SSc without pulmonary fibrosis. In in vivo studies of bleomycin-induced lung fibrosis in mice, SIRT1 activation with resveratrol reduced collagen production when it was administered either prophylactically during the inflammatory stage or after the development of fibrosis. Furthermore, SIRT1 activation or overexpression inhibited tumor necrosis factor-a–induced inflammatory responses in vitro in human fetal lung fibroblasts, depletion of SIRT1 in fibroblasts enhanced inflammation, and these effects were related to changes in the acetylation of NF-kB. In addition, SIRT1 activation or exogenous overexpression inhibited collagen production in vitro, and these manipulations also inhibited fibrosis via inactivation of transforming growth factor-b/mothers against decapentaplegic homolog and mammalian target of rapamycin signaling. Taken together, our results show that a loss of SIRT1 may participate in the pathogenesis of SSc-related pulmonary fibrosis, and that SIRT1 activation is an effective treatment for both the early (inflammatory) and late (fibrotic) stages of pulmonary fibrosis. Thus, SIRT1 may be a promising therapeutic target in the management of SSc-related pulmonary fibrosis.
AB - Pulmonary fibrosis is the leading cause of death in systemic sclerosis (SSc). Sirtuin1 (SIRT1) is a deacetylase with known antiinflammatory and antifibrotic activity in the liver, kidney, and skin. The role of SIRT1 in SSc-related pulmonary fibrosis is unknown. In the present work, we determined that the expression of SIRT1 in peripheral blood mononuclear cells of patients with SSc with pulmonary fibrosis is lower than that in patients with SSc without pulmonary fibrosis. In in vivo studies of bleomycin-induced lung fibrosis in mice, SIRT1 activation with resveratrol reduced collagen production when it was administered either prophylactically during the inflammatory stage or after the development of fibrosis. Furthermore, SIRT1 activation or overexpression inhibited tumor necrosis factor-a–induced inflammatory responses in vitro in human fetal lung fibroblasts, depletion of SIRT1 in fibroblasts enhanced inflammation, and these effects were related to changes in the acetylation of NF-kB. In addition, SIRT1 activation or exogenous overexpression inhibited collagen production in vitro, and these manipulations also inhibited fibrosis via inactivation of transforming growth factor-b/mothers against decapentaplegic homolog and mammalian target of rapamycin signaling. Taken together, our results show that a loss of SIRT1 may participate in the pathogenesis of SSc-related pulmonary fibrosis, and that SIRT1 activation is an effective treatment for both the early (inflammatory) and late (fibrotic) stages of pulmonary fibrosis. Thus, SIRT1 may be a promising therapeutic target in the management of SSc-related pulmonary fibrosis.
KW - Inflammation
KW - NF-kB pathway
KW - Pulmonary fibrosis
KW - Systemic sclerosis
KW - Transforming growth factor-b/mammalian target of rapamycin pathway
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U2 - 10.1165/rcmb.2016-0192OC
DO - 10.1165/rcmb.2016-0192OC
M3 - Article
C2 - 28800254
AN - SCOPUS:85039861203
SN - 1044-1549
VL - 58
SP - 28
EP - 39
JO - American journal of respiratory cell and molecular biology
JF - American journal of respiratory cell and molecular biology
IS - 1
ER -