Sophorolipids improve sepsis survival: effects of dosing and derivatives.
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.
Hardin
Rosemarie
R
Department of Surgery, SUNY Downstate Medical Center, Brooklyn, New York, USA.
Pierre
Joelle
J
Schulze
Robert
R
Mueller
Cathy M
CM
Fu
Sophia L
SL
Wallner
Sabine R
SR
Stanek
Albert
A
Shah
Vishal
V
Gross
Richard A
RA
Weedon
Jeremy
J
Nowakowski
Maja
M
Zenilman
Michael E
ME
Bluth
Martin H
MH
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
D004952:Esters; D006017:Glycolipids; C067958:16-(2'-O-glucopyranosylglucopyranosyloxy)hexadecanoic acid 1',4''-lactone 6',6''-diacetate