title: Sophorolipids improve sepsis survival: effects of dosing and derivatives.
abstract: BACKGROUND
  Sophorolipids, a family of natural and easily chemo-enzymatically modified microbial glycolipids, are promising modulators of the immune response. We have previously demonstrated that sophorolipids mediate anti-inflammatory effects, including decreasing sepsis-related mortality at 36 h in vivo in a rat model of septic peritonitis and in vitro by decreasing nitric oxide and inflammatory cytokine production. Here we assessed the effect of sophorolipids on sepsis-related mortality when administered as a (1) single bolus versus sequential dosing and (2) natural mixture versus individual derivatives compared with vehicle alone.
  
  
  METHODS
  Intra-abdominal sepsis was induced in male, Sprague Dawley rats, 200 to 240 g, via cecal ligation and puncture. Sophorolipids (5-750 mg/kg) or vehicle (ethanol/sucrose/physiological saline) were injected intravenously (i.v.) via tail vein or inferior vena cava at the end of the operation either as a single dose or sequentially (q24 h x 3 doses); natural mixture was compared with select sophorolipid derivatives (n = 10-15 per group). Sham-operated animals served as nonsepsis controls. Survival rates were compared at 1 through 6 d post sepsis induction and tissue was analyzed by histopathology. Significance was determined by Kruskal-Wallis analysis with Bonferroni adjustment and Student's t-test.
  
  
  RESULTS
  Sophorolipid treatment at 5 mg/kg body weight improved survival in rats with cecal ligation and puncture-induced septic shock by 28% at 24 h and 42% at 72 h for single dose, 39% at 24 h and 26% at 72 h for sequential doses, and 23% overall survival for select sophorolipid derivatives when compared with vehicle control (P < 0.05 for sequential dosing). Toxicity was evident and dose-dependent with very high doses of sophorolipid (375-750 mg/kg body weight) with histopathology demonstrating interstitial and intra-alveolar edema with areas of microhemorrhage in pulmonary tissue when compared with vehicle controls (P < 0.05). No mortality was observed in sham operated controls at all doses tested.
  
  
  CONCLUSIONS
  Administration of sophorolipids after induction of intra-abdominal sepsis improves survival. The demonstration that sophorolipids can reduce sepsis-related mortality with different dosing regimens and derivatives provides continuing evidence toward a promising new therapy. Toxicity is evident at 75 to 150x the therapeutic dose in septic animals.
authors: Department of Surgery, SUNY Downstate Medical Center, Brooklyn, New York, USA.
authors: Rosemarie
authors: R
authors: Hardin
authors: Joelle
authors: J
authors: Pierre
authors: Robert
authors: R
authors: Schulze
authors: Cathy M
authors: CM
authors: Mueller
authors: Sophia L
authors: SL
authors: Fu
authors: Sabine R
authors: SR
authors: Wallner
authors: Albert
authors: A
authors: Stanek
authors: Vishal
authors: V
authors: Shah
authors: Richard A
authors: RA
authors: Gross
authors: Jeremy
authors: J
authors: Weedon
authors: Maja
authors: M
authors: Nowakowski
authors: Michael E
authors: ME
authors: Zenilman
authors: Martin H
authors: MH
authors: Bluth
mesh_terms: D000107:Acetylation; D000818:Animals; D002432:Cecum / Q000293:injuries; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004952:Esters / Q000737:chemistry / Q000494:pharmacology; D006017:Glycolipids / Q000737:chemistry / Q000494:pharmacology*; D007275:Injections, Intravenous; D008026:Ligation; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D015996:Survival Rate; D014951:Wounds, Stab
chemical_list: D004952:Esters; D006017:Glycolipids; C067958:16-(2'-O-glucopyranosylglucopyranosyloxy)hexadecanoic acid 1',4''-lactone 6',6''-diacetate