Effects of the antimicrobial peptide LL-37 and hyperthermic preconditioning in septic rats.
BACKGROUND
The authors tested the effects of LL-37 prophylaxis or therapy on the outcome after intraabdominal sepsis and examined whether hyperthermic preconditioning plus LL-37 therapy augments host immune response and improves survival.


METHODS
A rat model of peritoneal contamination and infection (PCI) with human stool was used to simulate clinical conditions. In trial 1, the authors compared (1) PCI, (2) LL-37 prophylaxis (0.5 mg/kg, 12 h before PCI), and (3) LL-37 therapy (0.5 mg/kg, 1 h after PCI). In trial 2, the authors compared (1) PCI, (2) LL-37 therapy, (3) hyperthermic preconditioning (41 degrees C for 1 h, 24 h before PCI), and (4) LL-37 therapy and hyperthermic preconditioning. The primary endpoint was mortality at 120 h. In trial 2, secondary endpoints were systemic levels of tumor necrosis factor alpha, interleukin 6, macrophage inflammatory protein 2, and heat shock protein 70; leukocyte counts; and neutrophil granulocyte phagocytosis.


RESULTS
In trial 1, 30% of the control group compared with 70% of the LL-37 therapy group survived, but 55% after LL-37 prophylaxis survived (P = 0.038). In trial 2, 38% of the controls, 67% of the LL-37 therapy, 59% of the hyperthermic preconditioned, and 90% of the hyperthermic preconditioned plus LL-37 therapy group survived (P = 0.01). LL-37 therapy plus hyperthermic preconditioning reduced proinflammatory cytokine concentrations after sepsis; specifically compared with controls, macrophage inflammatory protein-2 and interleukin-6 levels were 1.5 +/- 1.5 versus 11 +/- 6 pg/ml (P = 0.028) and 13 +/- 8 versus 86 +/- 31 pg/ml, (P = 0.015), respectively.


CONCLUSIONS
In this model of intraabdominal sepsis, LL-37 therapy improved outcome. Hyperthermic preconditioning per se was not successful, but in combination with LL-37 therapy, the survival rate after sepsis was increased and the proinflammatory cytokine response was downgraded.
Torossian
Alexander
A
Department of Anesthesia and Critical Care, University of Marburg, Marburg, Germany. alexander-torossian@t-online.de
Gurschi
Eugeniu
E
Bals
Robert
R
Vassiliou
Timon
T
Wulf
Hinnerk F
HF
Bauhofer
Artur
A
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D054804:Cathelicidins; D054426:Chemokine CXCL2; D004195:Disease Models, Animal; D005243:Feces / Q000382:microbiology; D006098:Granulocytes; D018840:HSP70 Heat-Shock Proteins / Q000097:blood; D006979:Hyperthermia, Induced / Q000379:methods*; D015850:Interleukin-6 / Q000097:blood; D007962:Leukocytes; D008297:Male; D015846:Monokines / Q000097:blood; D009504:Neutrophils; D010538:Peritonitis / Q000276:immunology / Q000382:microbiology / Q000628:therapy*; D010587:Phagocytosis; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000628:therapy*; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D054426:Chemokine CXCL2; D018840:HSP70 Heat-Shock Proteins; D015850:Interleukin-6; D015846:Monokines; D014409:Tumor Necrosis Factor-alpha