LL-37 protects rats against lethal sepsis caused by gram-negative bacteria.

Abstract

We investigated the efficacy of LL-37, the C-terminal part of the only cathelicidin in humans identified to date (termed human cationic antimicrobial protein), in three experimental rat models of gram-negative sepsis. Adult male Wistar rats (i) were given an intraperitoneal injection of 1 mg Escherichia coli 0111:B4 LPS, (ii) were given 2 x 10(10) CFU of Escherichia coli ATCC 25922, or (iii) had intra-abdominal sepsis induced via cecal ligation and puncture. For each model, all animals were randomized to receive intravenously isotonic sodium chloride solution, 1-mg/kg LL-37, 1-mg/kg polymyxin B, 20-mg/kg imipenem, or 60-mg/kg piperacillin. Lethality; growth of bacteria in blood, peritoneum, spleen, liver, and mesenteric lymph nodes; and endotoxin and tumor necrosis factor alpha (TNF-alpha) concentrations in plasma were evaluated. All compounds reduced lethality compared to levels in controls. Endotoxin and TNF-alpha plasma levels were significantly higher in conventional antibiotic-treated rats than in LL-37- and polymyxin B-treated animals. All drugs tested significantly reduced bacterial growth compared to saline treatment. No statistically significant differences between LL-37 and polymyxin B were noted for antimicrobial and antiendotoxin activities. LL-37 and imipenem proved to be the most effective treatments in reducing all variables measured. Due to its multifunctional properties, LL-37 may become an important future consideration for the treatment of sepsis.

• Authors: Oscar Cirioni, Andrea Giacometti, Roberto Ghiselli, Cristina Bergnach, Fiorenza Orlando, Carmela Silvestri, Federico Mocchegiani, Alberto Licci, Barbara Skerlavaj, Marco Rocchi, Vittorio Saba, Margherita Zanetti, Giorgio Scalise
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 50 Issue 5 Pg. 1672-9 (May 2006) ISSN: 0066-4804 [Print] United States
• PMID: 16641434 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Antimicrobial Cationic Peptides
• Endotoxins
• Nitrites
• Tumor Necrosis Factor-alpha
• Imipenem
• Polymyxin B
• Piperacillin
• Cathelicidins

Topics

• Animals
• Anti-Bacterial Agents (administration & dosage, therapeutic use)
• Antimicrobial Cationic Peptides (pharmacology, therapeutic use)
• Cecum (microbiology)
• Disease Models, Animal
• Endotoxins (blood)
• Escherichia coli (classification, drug effects)
• Escherichia coli Infections (drug therapy, microbiology)
• Gram-Negative Bacteria (classification, drug effects)
• Imipenem (administration & dosage)
• Injections, Intraperitoneal
• Male
• Nitrites (metabolism)
• Piperacillin (administration & dosage)
• Polymyxin B (administration & dosage)
• Random Allocation
• Rats
• Rats, Wistar
• Serotyping
• Shock, Septic (drug therapy, microbiology)
• Tumor Necrosis Factor-alpha (analysis)
• Cathelicidins