4.7 Article

The role of S100B/RAGE-enhanced ADAM17 activation in endothelial glycocalyx shedding after traumatic brain injury

期刊

JOURNAL OF NEUROINFLAMMATION
卷 19, 期 1, 页码 -

出版社

BMC
DOI: 10.1186/s12974-022-02412-2

关键词

Traumatic brain injury; Secondary injury; Blood-brain barrier; Endothelial glycocalyx; S100B; RAGE; ADAM17

资金

  1. National Nature Science Fund of China [81901997, 81870210, 82172139]
  2. Guangdong Natural Science Foundation of China [2020A1515010092, 2019A1515010295, 2019A1515012022]
  3. Certificate of China Postdoctoral Science Foundation [2019M652960, 2019M652965]
  4. Youth Scientific Research Staring Foundation for the Third Affiliated Hospital of Southern Medical University [2019Q006]
  5. Scientific Research Staring Foundation for Talent Introduction for Southern Medical University
  6. Guangdong International Training Program for Outstanding Young Scientific Talents of University

向作者/读者索取更多资源

Traumatic brain injury (TBI) is a major cause of disability and death. This study aimed to investigate the role of S100B and its receptor RAGE in mediating secondary injury after TBI. The results showed that TBI can activate the release of S100B, leading to the shedding of endothelial glycocalyx and increased vascular permeability, ultimately resulting in secondary brain and lung injury.
Background Traumatic brain injury (TBI) remains one of the main causes for disability and death worldwide. While the primary mechanical injury cannot be avoided, the prevention of secondary injury is the focus of TBI research. Present study aimed to elucidate the effects and mechanisms of S100B and its receptor RAGE on mediating secondary injury after TBI. Methods This study established TBI animal model by fluid percussion injury in rats, cell model by stretch-injured in astrocytes, and endothelial injury model with conditioned medium stimulation. Pharmacological intervention was applied to interfere the activities of S100B/RAGE/ADAM17 signaling pathway, respectively. The expressions or contents of S100B, RAGE, syndecan-1 and ADAM17 in brain and serum, as well as in cultured cells and medium, were detected by western blot. The distribution of relative molecules was observed with immunofluorescence. Results We found that TBI could activate the release of S100B, mostly from astrocytes, and S100B and RAGE could mutually regulate their expression and activation. Most importantly, present study revealed an obvious increase of syndecan-1 in rat serum or in endothelial cultured medium after injury, and a significant decrease in tissue and in cultured endothelial cells, indicating TBI-induced shedding of endothelial glycocalyx. The data further proved that the activation of S100B/RAGE signaling could promote the shedding of endothelial glycocalyx by enhancing the expression, translocation and activity of ADAM17, an important sheddase, in endothelial cells. The damage of endothelial glycocalyx consequently aggravated blood brain barrier (BBB) dysfunction and systemic vascular hyper-permeability, overall resulting in secondary brain and lung injury. Conclusions TBI triggers the activation of S100B/RAGE signal pathway. The regulation S100B/RAGE on ADAM17 expression, translocation and activation further promotes the shedding of endothelial glycocalyx, aggravates the dysfunction of BBB, and increases the vascular permeability, leading to secondary brain and lung injury. Present study may open a new corridor for the more in-depth understanding of the molecular processes responsible for cerebral and systemic vascular barrier impairment and secondary injury after TBI.

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