title: 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.affiliation: Università Politecnica delle Marche, Clinica Malattie Infettive, c/o Ospedale Regionale, Via Conca 71, 60020 Torrette, Ancona, Italy.
authors.forename: Oscar
authors.initials: O
authors.lastname: Cirioni
authors.forename: Andrea
authors.initials: A
authors.lastname: Giacometti
authors.forename: Roberto
authors.initials: R
authors.lastname: Ghiselli
authors.forename: Cristina
authors.initials: C
authors.lastname: Bergnach
authors.forename: Fiorenza
authors.initials: F
authors.lastname: Orlando
authors.forename: Carmela
authors.initials: C
authors.lastname: Silvestri
authors.forename: Federico
authors.initials: F
authors.lastname: Mocchegiani
authors.forename: Alberto
authors.initials: A
authors.lastname: Licci
authors.forename: Barbara
authors.initials: B
authors.lastname: Skerlavaj
authors.forename: Marco
authors.initials: M
authors.lastname: Rocchi
authors.forename: Vittorio
authors.initials: V
authors.lastname: Saba
authors.forename: Margherita
authors.initials: M
authors.lastname: Zanetti
authors.forename: Giorgio
authors.initials: G
authors.lastname: Scalise
mesh_terms: 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
chemical_list: 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