Sophorolipids block lethal effects of septic shock in rats in a cecal ligation and puncture model of experimental sepsis

Objective: Sophorolipids, a family of natural and easily chemoenzymatically modified microbial glycolipids, are promising modulators of the immune response. The potential of the therapeutic effect of sophorolipids was investigated in vivo in a rat model of sepsis and in vitro by analysis of nitric oxide and cytokine production. Design: Prospective, randomized animal study. Setting: Experimental laboratory. Subjects: Male Sprague-Dawley rats, 200-240 g. Interventions: Infra-abdominal sepsis was induced in vivo in 166 rats via cecal ligation and puncture (CLP); 60 rats were used to characterize the model. The remaining rats were treated with sophorolipids or vehicle (dimethylsulfoxide [DMSO]/physiologic saline) by intravenous (iv) tail vein or intraperitoneal (IP) injection immediately post-CLP (25/group). Survival rates were compared at 36 hrs after surgery. In vitro, macrophages were cultured in lipopolysaccharide (LPS) +/- sophorolipid and assayed for nitric oxide (NO) production and gene expression profiles of inflammatory cytokines. In addition, splenic lymphocytes isolated from CLP rats +/- sophorolipid treatment (three per group) were analyzed for cytokine production by RNase protection assay. Measurements and Main Results: CLP with 16-gauge needles optimized sepsis induction and resultant mortality. Sophorolipid treatment improved rat survival by 34% (iv) and 14% (IP) in comparison with vehicle controls (p < .05 for iv treatment). Sophorolipids decreased LPS-induced macrophage NO production by 28% (p < .05). mRNA expression of interleukin (IL)-1 beta was downregulated by 42.5 +/- 4.7% (p < .05) and transforming growth factor (TGF)-beta 1 was upregulated by 11.7 +/- 1.5% (p < .05) in splenocytes obtained 6 hrs postsophorolipid treatment. LPS-treated macrophages cultured 36 hrs with sophorolipids showed increases in mRNA expression of IL-1 alpha (51.7%), IL-1 beta (31.3%), and IL-6 (66.8%) (p < .05). Conclusions: Administration of sophorolipids after induction of intro-abdominal sepsis significantly decreases mortality in this model. This may be mediated in part by decreased macrophage NO production and modulation of inflammatory responses.