Blockade of extracellular heat shock protein 90α by 1G6-D7 attenuates pulmonary fibrosis through inhibiting ERK signaling

被引：35
|
作者：
Dong, Hangming [1 ]
Luo, Lishan [1 ,2 ]
Zou, Mengchen [1 ]
Huang, Chaowen [1 ]
Wan, Xuan [1 ]
Hu, Yahui [1 ]
Le, Yanqing [1 ]
Zhao, Haijin [1 ]
Li, Wei [3 ,4 ]
Zou, Fei [5 ]
Cai, Shaoxi [1 ]
机构：
[1] Southern Med Univ, Nanfang Hosp, Dept Resp & Crit Care Med, Chron Airways Dis Lab, Guangzhou 510515, Guangdong, Peoples R China
[2] Huizhou Municipal Cent Hosp, Dept Resp Med, Huizhou, Peoples R China
[3] Univ Southern Calif, Keck Med Ctr, Dept Dermatol, Los Angeles, CA USA
[4] Univ Southern Calif, Keck Med Ctr, Norris Comprehens Canc Ctr, Los Angeles, CA USA
[5] Southern Med Univ, Sch Publ Hlth & Trop Med, Guangzhou, Guangdong, Peoples R China
来源：
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY | 2017年 / 313卷 / 06期
基金：
中国国家自然科学基金;
关键词：
1G6-D7; extracellular Hsp90 alpha; pulmonary fibrosis; fibroblast activation; ECM synthesis; SKIN CELL-MIGRATION; HSP90; RECEPTOR; HSP90-ALPHA; MOTILITY; HYPOXIA; PATHOGENESIS; PUBLICATION; MECHANISMS; SECRETION;
D O I：
10.1152/ajplung.00489.2016
中图分类号：
Q4 [生理学];
学科分类号：
071003 ;
摘要：
Pulmonary fibrosis is characterized by lung fibroblast activation and ECM deposition and has a poor prognosis. Heat shock protein 90 (Hsp90) participates in organ fibrosis, and extracellular Hsp90 alpha (eHsp90 alpha) promotes fibroblast activation and migration. This study aimed to investigate whether a selective anti-Hsp90 alpha monoclonal antibody, 1G6-D7, could attenuate lung fibrosis and whether 1G6-D7 presents a protective effect by inactivating the profibrotic pathway. Our results showed that eHsp90 alpha was increased in mice with BLM-induced pulmonary fibrosis and that 1G6-D7 attenuated inflammation and collagen deposition in the lung. TGF-beta 1 induced eHsp90 alpha secretion, concomitantly promoting HFL-1 activation and ECM synthesis. 1G6-D7-mediated inhibition of eHsp90 alpha significantly blocked these effects, meanwhile inhibiting downstream profibrotic pathways such as ERK, Akt, and P38. Human recombinant (hr) Hsp90 alpha mimicked the effects of TGF-beta 1, by activating profibrotic pathways and by upregulating LRP-1. Moreover, ERK inhibition effectively blocked the effect of (hr) Hsp90 alpha. In conclusion, 1G6-D7 significantly protects against BLM-induced pulmonary fibrosis by ameliorating fibroblast activation and ECM production, which may be through blocking ERK signaling. Our results suggest a safer molecular therapy, 1G6-D7, in pulmonary fibrosis.
引用
收藏
页码：L1006 / L1015
页数：10
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