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Recombinant human milk fat globule-EGF factor 8 produces dose-dependent benefits in sepsis.

AbstractPURPOSE:
Animal milk fat globule-EGF factor 8 (MFG-E8) has been shown to be beneficial in attenuating the inflammatory response in sepsis. In this study, we examined the effect of recombinant human MFG-E8 (rhMFG-E8) in an animal model of sepsis in an effort to develop it as a potential therapy against sepsis in humans.
METHODS:
Rats were subjected to sepsis by cecal ligation and puncture (CLP), and at 5 h post-CLP, they were given different doses of rhMFG-E8 (20, 40, 80, 160 μg/kg BW) in normal saline. At 20 h post-CLP, samples were collected for further analysis. A 10-day survival study was also performed.
RESULTS:
At 20 h after CLP, organ injury indicators, serum IL-6 and TNF-α, and plasma HMGB-1 levels were significantly increased as compared to sham-operated animals. Treatment with 20 μg/kg rhMFG-E8 significantly reduced these levels. With higher doses, further reductions in AST and ALT (59-62%), creatinine (65-68%), and lactate (46-57%), and serum IL-6 and TNF-α were obtained. The 160 μg/kg dose produced the greatest reduction in serum TNF-α. With treatment with 20 μg/kg rhMFG-E8, HMGB-1 levels decreased by 80%, returning back to sham values. In a 10-day survival study, vehicle-treated animals produced a 36% survival rate, while rhMFG-E8 significantly improved the survival rate to 68-72%. Treatment with increasing doses of rhMFG-E8 significantly reduced the number of apoptotic cells detected and markedly attenuated the tissue damages observed in the lungs.
CONCLUSIONS:
These data suggest that recombinant human MFG-E8 is beneficial in ameliorating sepsis in an animal model of sepsis.
AuthorsKavin G Shah, Rongqian Wu, Asha Jacob, Ernesto P Molmenti, Jeffrey Nicastro, Gene F Coppa, Ping Wang
JournalIntensive care medicine (Intensive Care Med) Vol. 38 Issue 1 Pg. 128-36 (Jan 2012) ISSN: 1432-1238 [Electronic] United States
PMID21946914 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Antigens, Surface
  • Biomarkers
  • Glycolipids
  • Glycoproteins
  • HMGB1 Protein
  • Interleukin-6
  • Mfge8 protein, mouse
  • Milk Proteins
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • milk fat globule
Topics
  • Animals
  • Antigens, Surface (administration & dosage, pharmacology, therapeutic use)
  • Biomarkers (blood)
  • Dose-Response Relationship, Drug
  • Glycolipids (therapeutic use)
  • Glycoproteins (therapeutic use)
  • HMGB1 Protein (drug effects)
  • Humans
  • Interleukin-6 (metabolism)
  • Lipid Droplets
  • Male
  • Milk Proteins (administration & dosage, pharmacology, therapeutic use)
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Proteins (therapeutic use)
  • Sepsis (drug therapy, pathology)
  • Survival Analysis
  • Tumor Necrosis Factor-alpha (drug effects)

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