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Radicicol, an Hsp90 inhibitor, inhibits intestinal inflammation and leakage in abdominal sepsis.

Zhao, Yilin LU ; Huang, Zheng-Jie ; Rahman, Milladur LU orcid ; Luo, Qi and Thorlacius, Henrik LU (2013) In Journal of Surgical Research 182(2). p.312-318
Abstract
BACKGROUND: Intestinal injury is a key feature in sepsis. Inhibitors of heat shock protein 90 (Hsp90) have been shown to exert protective effects in models of inflammation. Herein, we hypothesized that Hsp90 might regulate intestinal inflammation and leakage in abdominal sepsis. MATERIALS AND METHODS: Male C57BL/6 mice were pretreated with radicicol (60 mg/kg), which is a specific inhibitor of Hsp90, prior to cecal ligation and puncture (CLP). Intravital fluorescence microscopy was used to quantify leukocyte-endothelium interactions in the colonic microcirculation 6 h after CLP. Colonic tissue was harvested to determine levels of myeloperoxidase, tumor necrosis factor-α and CXC chemokines. Intestinal injury was examined by histology.... (More)
BACKGROUND: Intestinal injury is a key feature in sepsis. Inhibitors of heat shock protein 90 (Hsp90) have been shown to exert protective effects in models of inflammation. Herein, we hypothesized that Hsp90 might regulate intestinal inflammation and leakage in abdominal sepsis. MATERIALS AND METHODS: Male C57BL/6 mice were pretreated with radicicol (60 mg/kg), which is a specific inhibitor of Hsp90, prior to cecal ligation and puncture (CLP). Intravital fluorescence microscopy was used to quantify leukocyte-endothelium interactions in the colonic microcirculation 6 h after CLP. Colonic tissue was harvested to determine levels of myeloperoxidase, tumor necrosis factor-α and CXC chemokines. Intestinal injury was examined by histology. Intestinal barrier function was quantified by leakage of fluorescein isothiocyanate-dextran from the vascular system out into the abdominal cavity after intravenous injection. RESULTS: We found that radicicol significantly decreased CLP-induced leukocyte rolling and adhesion in colonic venules. Inhibition of Hsp90 reduced colonic levels of myeloperoxidase by 24% in septic animals. Moreover, radicicol significantly decreased CLP-provoked formation of CXC chemokines but had no significant effect on tumor necrosis factor-α levels in the colon. Notably, Hsp90 inhibition significantly attenuated intestinal tissue injury evoked by CLP. Lastly, it was found that radicicol reduced sepsis-induced intestinal leakage by 43%. CONCLUSION: Our novel findings suggest that targeting Hsp90 protects against intestinal inflammation and leakage and might be a useful strategy to ameliorate intestinal failure in polymicrobial sepsis. (Less)
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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Surgical Research
volume
182
issue
2
pages
312 - 318
publisher
Elsevier
external identifiers
  • wos:000318907900026
  • pmid:23138048
  • scopus:84877697096
ISSN
1095-8673
DOI
10.1016/j.jss.2012.10.038
language
English
LU publication?
yes
id
309450b9-8b20-48cd-9f8d-1301b4b6e635 (old id 3219117)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/23138048?dopt=Abstract
date added to LUP
2016-04-01 10:08:32
date last changed
2022-04-12 02:17:10
@article{309450b9-8b20-48cd-9f8d-1301b4b6e635,
  abstract     = {{BACKGROUND: Intestinal injury is a key feature in sepsis. Inhibitors of heat shock protein 90 (Hsp90) have been shown to exert protective effects in models of inflammation. Herein, we hypothesized that Hsp90 might regulate intestinal inflammation and leakage in abdominal sepsis. MATERIALS AND METHODS: Male C57BL/6 mice were pretreated with radicicol (60 mg/kg), which is a specific inhibitor of Hsp90, prior to cecal ligation and puncture (CLP). Intravital fluorescence microscopy was used to quantify leukocyte-endothelium interactions in the colonic microcirculation 6 h after CLP. Colonic tissue was harvested to determine levels of myeloperoxidase, tumor necrosis factor-α and CXC chemokines. Intestinal injury was examined by histology. Intestinal barrier function was quantified by leakage of fluorescein isothiocyanate-dextran from the vascular system out into the abdominal cavity after intravenous injection. RESULTS: We found that radicicol significantly decreased CLP-induced leukocyte rolling and adhesion in colonic venules. Inhibition of Hsp90 reduced colonic levels of myeloperoxidase by 24% in septic animals. Moreover, radicicol significantly decreased CLP-provoked formation of CXC chemokines but had no significant effect on tumor necrosis factor-α levels in the colon. Notably, Hsp90 inhibition significantly attenuated intestinal tissue injury evoked by CLP. Lastly, it was found that radicicol reduced sepsis-induced intestinal leakage by 43%. CONCLUSION: Our novel findings suggest that targeting Hsp90 protects against intestinal inflammation and leakage and might be a useful strategy to ameliorate intestinal failure in polymicrobial sepsis.}},
  author       = {{Zhao, Yilin and Huang, Zheng-Jie and Rahman, Milladur and Luo, Qi and Thorlacius, Henrik}},
  issn         = {{1095-8673}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{312--318}},
  publisher    = {{Elsevier}},
  series       = {{Journal of Surgical Research}},
  title        = {{Radicicol, an Hsp90 inhibitor, inhibits intestinal inflammation and leakage in abdominal sepsis.}},
  url          = {{http://dx.doi.org/10.1016/j.jss.2012.10.038}},
  doi          = {{10.1016/j.jss.2012.10.038}},
  volume       = {{182}},
  year         = {{2013}},
}