title: Milk fat globule--EGF factor VIII ameliorates liver injury after hepatic ischemia-reperfusion.
abstract: BACKGROUND
  Hepatic ischemia-reperfusion (I/R) injury is a serious clinical complication that may compromise liver function because of extensive hepatocyte loss. Therefore, the development of novel and effective therapies for hepatic I/R is critical for the improvement of patient outcome. It has been previously shown that administration of milk fat globule-EGF factor VIII (MFG-E8), a membrane-associated secretory glycoprotein, exerts significant beneficial effects under acute inflammatory conditions through multiple physiological processes associated with tissue remodeling.
  
  
  METHODS
  To determine whether administration of recombinant human (rh) MFG-E8 attenuates liver injury in an animal model of hepatic I/R, male adult rats were subjected to 70% hepatic ischemia for 90 min, followed by reperfusion. At the beginning of reperfusion, rats were treated intravenously with normal saline (vehicle) or rhMFG-E8 (160 μg/kg) over a period of 30 min. MFG-E8 levels and various measurements were assessed 4 h after reperfusion. In addition, survival study was conducted in MFG-E8(-/-) and rhMFG-E8-treated wild-type (WT) mice using a total hepatic ischemia model.
  
  
  RESULTS
  Liver and plasma MFG-E8 protein levels were significantly decreased after hepatic I/R. Administration of rhMFG-E8 significantly improved liver injury, suppressed apoptosis, attenuated inflammation and oxidative stress, and downregulated NF-κB pathway. We also noticed that rhMFG-E8 treatment restored the downregulated PPAR-γ expression after hepatic I/R. MFG-E8(-/-) mice showed deterioration on survival and, in contrast, rhMFG-E8-treated WT mice showed a significant improvement of survival compared with vehicle-treated WT mice.
  
  
  CONCLUSIONS
  MFG-E8-mediated multiple physiological events may represent an effective therapeutic option in tissue injury following an episode of hepatic I/R.
authors.affiliation: Department of Surgery, Hofstra North Shore-LIJ School of Medicine, Manhasset, New York, USA.
authors.forename: Akihisa
authors.initials: A
authors.lastname: Matsuda
authors.forename: Asha
authors.initials: A
authors.lastname: Jacob
authors.forename: Rongqian
authors.initials: R
authors.lastname: Wu
authors.forename: Mian
authors.initials: M
authors.lastname: Zhou
authors.forename: Monowar
authors.initials: M
authors.lastname: Aziz
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000502:physiology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D008099:Liver / Q000098:blood supply*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008894:Milk Proteins / Q000627:therapeutic use; D016328:NF-kappa B / Q000502:physiology; D018384:Oxidative Stress; D047495:PPAR gamma / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000188:drug therapy*; D051197:Toll-Like Receptor 4 / Q000032:analysis
chemical_list: D000954:Antigens, Surface; C499941:MFGE8 protein, rat; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D016328:NF-kappa B; D047495:PPAR gamma; D011994:Recombinant Proteins; D051197:Toll-Like Receptor 4; D018799:Intercellular Adhesion Molecule-1