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.
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Authors | Akihisa Matsuda, Asha Jacob, Rongqian Wu, Mian Zhou, Monowar Aziz, Ping Wang |
Journal | The Journal of surgical research
(J Surg Res)
Vol. 180
Issue 1
Pg. e37-46
(Mar 2013)
ISSN: 1095-8673 [Electronic] United States |
PMID | 22487387
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | Copyright © 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
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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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