title: Heparin-binding epidermal growth factor-like growth factor (HB-EGF) preserves gut barrier function by blocking neutrophil-endothelial cell adhesion after hemorrhagic shock and resuscitation in mice.
abstract: BACKGROUND
  We have shown that heparin-binding epidermal growth factor-like growth factor (HB-EGF) protects the intestines from injury in several different animal models, including hemorrhagic shock and resuscitation (HS/R). The current study was designed to explore the mechanisms underlying the anti-inflammatory role of HB-EGF in preservation of gut barrier function after injury.
  
  
  METHODS
  In vivo, HS/R was induced in wild-type and neutropenic mice, with or without administration of HB-EGF, and intestinal permeability determined by use of the everted gut sac method. In vitro, cultured human umbilical vein endothelial cells (HUVECs) and freshly isolated human peripheral blood mononuclear cells (PMNs) were used to determine the effects of HB-EGF on HUVEC-PMN adhesion, reactive oxygen species production in PMN, adhesion molecule expression in HUVEC and PMN, and the signaling pathways involved.
  
  
  RESULTS
  We found that administration of HB-EGF to healthy mice led to preservation of gut barrier function after HS/R. Likewise, induction of neutropenia in mice also led to preservation of gut barrier function after HS/R. Administration of HB-EGF to neutropenic mice did not lead to further improvement in gut barrier function. In vitro studies showed that HB-EGF decreased neutrophil-endothelial cell (PMN-EC) adherence by down-regulating adhesion molecule expression in EC via the phosphoinositide 3-kinase-Akt pathway, and by inhibiting adhesion molecule surface mobilization and reactive oxygen species production in PMN.
  
  
  CONCLUSIONS
  These results indicate that HB-EGF preserves gut barrier function by inhibiting PMN and EC activation, thereby blocking PMN-EC adherence after HS/R in mice, and support the future use of HB-EGF in disease states manifested by hypoperfusion injury.
authors.affiliation: Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
authors.forename: Hong-yi
authors.initials: HY
authors.lastname: Zhang
authors.forename: Iyore
authors.initials: I
authors.lastname: James
authors.forename: Chun-Liang
authors.initials: CL
authors.lastname: Chen
authors.forename: Gail E
authors.initials: GE
authors.lastname: Besner
mesh_terms: D000328:Adult; D000818:Animals; D002448:Cell Adhesion; D042783:Endothelial Cells / Q000502:physiology*; D005260:Female; D066257:Heparin-binding EGF-like Growth Factor; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D007413:Intestinal Mucosa / Q000502:physiology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D018375:Neutrophil Activation; D009504:Neutrophils / Q000502:physiology*; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000276:immunology*; D015398:Signal Transduction
chemical_list: C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins