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Milk fat globule--EGF factor VIII ameliorates liver injury after hepatic ischemia-reperfusion.

AbstractBACKGROUND:
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.
AuthorsAkihisa Matsuda, Asha Jacob, Rongqian Wu, Mian Zhou, Monowar Aziz, Ping Wang
JournalThe Journal of surgical research (J Surg Res) Vol. 180 Issue 1 Pg. e37-46 (Mar 2013) ISSN: 1095-8673 [Electronic] United States
PMID22487387 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
CopyrightCopyright © 2013 Elsevier Inc. All rights reserved.
Chemical References
  • Antigens, Surface
  • MFGE8 protein, rat
  • Mfge8 protein, mouse
  • Milk Proteins
  • NF-kappa B
  • PPAR gamma
  • Recombinant Proteins
  • Toll-Like Receptor 4
  • Intercellular Adhesion Molecule-1
Topics
  • Animals
  • Antigens, Surface (physiology, therapeutic use)
  • Apoptosis (drug effects)
  • Intercellular Adhesion Molecule-1 (analysis)
  • Liver (blood supply)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Milk Proteins (therapeutic use)
  • NF-kappa B (physiology)
  • Oxidative Stress
  • PPAR gamma (physiology)
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Proteins (therapeutic use)
  • Reperfusion Injury (drug therapy)
  • Toll-Like Receptor 4 (analysis)

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