期刊
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
卷 313, 期 6, 页码 L1006-L1015出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00489.2016
关键词
1G6-D7; extracellular Hsp90 alpha; pulmonary fibrosis; fibroblast activation; ECM synthesis
资金
- National Natural Science Foundation of China [81470228, 81270087, 81300029, 81500023, 81670026]
- Precision Medicine Research of The National Key Research and Development Plan of China [2016YFC0905800]
- National Program on Key Basic Research Project of China (973 Program) [2012CB518203]
- Natural Science Foundation of Guangdong Province [2014A030310325, S2013040013505, 2015A030313236]
- Scientific and Technological Project of Guangdong Province [2016A020215117]
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.
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