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Summary:
Summary Background: We studied the effects of LL-37 prophylaxis or therapy on the outcome after intra-abdominal sepsis and tested whether additional preconditioning with fever-range hyperthermia augments host immune response and improves survival. Methods: A rat model of peritoneal contamination and infection (PCI) with human stool bacteria was used to simulate clinical trial conditions. In Trial 1 we compared 1 ) PCI only; 2 ) LL-37 prophylaxis (0.5 mg/kg, 12 h before infection) and 3 ) LL-37 therapy 3 time administration (0.5 mg/kg, -12h before PCI and +12h, +36h after infection), 20 rats/group. In Trial 2 we compared 1 ) PCI only; 2 ) LL-37 prophylaxis (0.5 mg/kg, 12 h before infection) and 3 ) LL-37 therapy (0.5 mg/kg, 1h after infection), 20 rats/group. In Trial 3, using 22 rats/group, we compared 1 ) PCI only; 2 ) LL-37 therapy; 3 ) hyperthermic preconditioning (41Â?C for 1h, 24 h before infection); and 4 ) hyperthermia combined with LL-37 therapy (0.5 mg/kg). The primary endpoint was mortality at 120 h. Secondary endpoints were systemic pro-inflammatory cytokine (TNF-Î?, IL-6, MIP-2) and heat shock protein (HSP)-70 levels. Results: In Trial 1 we achieved a survival rate of 40% in the control group. In the group with the antimicrobial protein LL-37 administrated once at -12h, before inoculum survival was increased to 70% and to 67% in the group with LL-37 administrated three times (at time point correspondingly to -12h; +12h; +36h in relation to PCI. In both groups survival rates were not significant different to the control. In Trial 2, 30% of the control group compared to 70% of the LL-37 therapy group survived (P=0.038). After LL-37 prophylaxis survival was 55%. Survival rate in trial 3 was 38% in the control group, 67% in the LL-37 therapy group, 59% in the hyperthermia preconditioning group and 90% in the combination group (hyperthermia preconditioned plus LL-37 therapy) (P = 0.01). Hyperthermic preconditioning plus LL-37 reduced pro-inflammatory cytokine concentrations after sepsis. Compared to controls MIP-2 levels were 1.5 ï?? 1.5 pg/ml versus 11 ï?? 6 pg/ml, (P = 0.028) and IL-6 levels were respectively 13 ï?? 8 pg/ml versus 86 ï?? 31 pg/ml, (P = 0.015). Conclusions: In this rat model of intra-abdominal sepsis, LL-37 therapy given alone was more effective in comparison to LL-37 given three times. The later was not successful to improve the outcome significantly. The combination preconditioning and LL-37 therapy was most effective. Additional hyperthermia, initiated 24 hours before contamination, reduced mortality and downgraded the systemic pro-inflammatory cytokine response.

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