LL-37 protects rats against lethal sepsis caused by gram-negative bacteria.
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.
Cirioni
Oscar
O
Università Politecnica delle Marche, Clinica Malattie Infettive, c/o Ospedale Regionale, Via Conca 71, 60020 Torrette, Ancona, Italy.
Giacometti
Andrea
A
Ghiselli
Roberto
R
Bergnach
Cristina
C
Orlando
Fiorenza
F
Silvestri
Carmela
C
Mocchegiani
Federico
F
Licci
Alberto
A
Skerlavaj
Barbara
B
Rocchi
Marco
M
Saba
Vittorio
V
Zanetti
Margherita
M
Scalise
Giorgio
G
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology* / Q000627:therapeutic use; D002432:Cecum / Q000382:microbiology; D004195:Disease Models, Animal; D004731:Endotoxins / Q000097:blood; D004926:Escherichia coli / Q000145:classification / Q000187:drug effects; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000382:microbiology; D006090:Gram-Negative Bacteria / Q000145:classification / Q000187:drug effects*; D015378:Imipenem / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D008297:Male; D009573:Nitrites / Q000378:metabolism; D010878:Piperacillin / Q000008:administration & dosage; D011112:Polymyxin B / Q000008:administration & dosage; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012703:Serotyping; D012772:Shock, Septic / Q000188:drug therapy* / Q000382:microbiology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D054804:Cathelicidins
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D004731:Endotoxins; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D015378:Imipenem; D011112:Polymyxin B; D010878:Piperacillin; D054804:Cathelicidins