Open Access25‐Hydroxycholesterol protects against acute lung injury via targeting MD ‐2
Author(s) -
Ouyang Wei,
Zhou Hui,
Liu Chao,
Wang Shiwei,
Han Yu,
Xia Jingyan,
Xu Feng
Publication year - 2018
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13820
Subject(s) - chemistry , lipopolysaccharide , pharmacology , inflammation , protein kinase b , proinflammatory cytokine , in vitro , receptor , immunology , cancer research , signal transduction , medicine , biochemistry
Acute lung injury ( ALI ) is mainly caused by uncontrolled inflammatory response, and it remains without effective therapeutic options. 25‐hydroxycholesterol (25 HC ) has been reported to be a potent regulator of inflammation. The aim of this study was to investigate the effects of 25HC on lipopolysaccharide ( LPS )‐induced ALI . C57BL/6 mice were pretreated with 25 HC intraperitoneally before intratracheal exposure to LPS . Our results showed that 25 HC pretreatment improved survival rate, attenuated the pathological changes of the lung and decreased the release of inflammatory cytokines in mice. Consistently, 25 HC reduced expression of Toll‐like receptor ( TLR 4)‐mediated inflammatory cytokines in vitro. These effects of 25 HC were obtained by preventing LPS binding to TLR 4 via interaction with myeloid differentiation protein 2 ( MD ‐2). Crystal structure analysis suggested that 25 HC could bind MD ‐2 with high affinity into its hydrophobic pocket. Furthermore, LPS ‐induced activation of Akt/ NF ‐κB pathway was partially down‐regulated by 25 HC pretreatment. In summary, this study demonstrates that 25 HC could inhibit the overwhelming inflammatory response through MD ‐2 interaction, which suppresses Akt/ NF ‐κB signalling pathway. These findings suggest 25 HC may be a promising candidate for ALI prevention.