title: Radicicol, an Hsp90 inhibitor, inhibits intestinal inflammation and leakage in abdominal sepsis.
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.
  
  
  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%.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Heptobiliary Surgery, Zhongshan Hospital, Xiamen University, Xiamen, China.
authors.forename: Yilin
authors.initials: Y
authors.lastname: Zhao
authors.forename: Zheng-Jie
authors.initials: ZJ
authors.lastname: Huang
authors.forename: Milladur
authors.initials: M
authors.lastname: Rahman
authors.forename: Qi
authors.initials: Q
authors.lastname: Luo
authors.forename: Henrik
authors.initials: H
authors.lastname: Thorlacius
mesh_terms: D000005:Abdomen; D000818:Animals; D054426:Chemokine CXCL2 / Q000032:analysis; D003092:Colitis / Q000517:prevention & control*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D036904:Leukocyte Rolling / Q000187:drug effects; D018942:Macrolides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010539:Permeability; D018805:Sepsis / Q000188:drug therapy* / Q000276:immunology
chemical_list: D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D018841:HSP90 Heat-Shock Proteins; D018942:Macrolides; C035359:monorden