title: Recombinant human milk fat globule-EGF factor 8 produces dose-dependent benefits in sepsis.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Surgery, Hofstra North Shore-LIJ School of Medicine, 350 Community Drive, Manhasset, NY 11030, USA.
authors.forename: Kavin G
authors.initials: KG
authors.lastname: Shah
authors.forename: Rongqian
authors.initials: R
authors.lastname: Wu
authors.forename: Asha
authors.initials: A
authors.lastname: Jacob
authors.forename: Ernesto P
authors.initials: EP
authors.lastname: Molmenti
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Nicastro
authors.forename: Gene F
authors.initials: GF
authors.lastname: Coppa
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D004305:Dose-Response Relationship, Drug; D006017:Glycolipids / Q000627:therapeutic use*; D006023:Glycoproteins / Q000627:therapeutic use*; D024243:HMGB1 Protein / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D066292:Lipid Droplets; D008297:Male; D008894:Milk Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000627:therapeutic use*; D018805:Sepsis / Q000188:drug therapy* / Q000473:pathology; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects
chemical_list: D000954:Antigens, Surface; D015415:Biomarkers; D006017:Glycolipids; D006023:Glycoproteins; D024243:HMGB1 Protein; D015850:Interleukin-6; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C110367:milk fat globule