Cathelicidin peptide sheep myeloid antimicrobial peptide-29 prevents endotoxin-induced mortality in rat models of septic shock.
The present study was designed to investigate the antiendotoxin activity and therapeutic efficacy of sheep myeloid antimicrobial peptide (SMAP)-29, a cathelicidin-derived peptide. The in vitro ability of SMAP-29 to bind LPS from Escherichia coli 0111:B4 was determined using a sensitive limulus chromogenic assay. Two rat models of septic shock were performed: (1) rats were injected intraperitoneally with 1 mg E. coli 0111:B4 LPS and (2) intraabdominal sepsis was induced via cecal ligation and single puncture. All animals were randomized to receive parenterally isotonic sodium chloride solution, 1 mg/kg SMAP-29, 1 mg/kg polymyxin B or 20 mg/kg imipenem. The main outcome measures were: abdominal exudate and plasma bacterial growth, plasma endotoxin and tumor necrosis factor-alpha concentrations, and lethality. The in vitro study showed that SMAP-29 completely inhibited the LPS procoagulant activity at approximately 10 microM peptide concentration. The in vivo experiments showed that all compounds reduced the lethality when compared with control animals. SMAP-29 achieved a substantial decrease in endotoxin and tumor necrosis factor-alpha plasma concentrations when compared with imipenem and saline treatment and exhibited a slightly lower antimicrobial activity than imipenem. No statistically significant differences were noted between SMAP-29 and polymyxin B. SMAP-29, because of its double antiendotoxin and antimicrobial activities, could be an interesting compound for septic shock treatment.
Giacometti
Andrea
A
Institute of Infectious Diseases and Public Health, I.N.R.C.A. I.R.R.C.S., Università Politecnica delle Marche, Ancona, Italy. anconacmi@interfree.it
Cirioni
Oscar
O
Ghiselli
Roberto
R
Mocchegiani
Federico
F
D'Amato
Giuseppina
G
Circo
Raffaella
R
Orlando
Fiorenza
F
Skerlavaj
Barbara
B
Silvestri
Carmela
C
Saba
Vittorio
V
Zanetti
Margherita
M
Scalise
Giorgio
G
D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D001798:Blood Proteins / Q000378:metabolism / Q000627:therapeutic use*; D054804:Cathelicidins; D004926:Escherichia coli; D015378:Imipenem / Q000627:therapeutic use; D066298:In Vitro Techniques; D008033:Limulus Test; D008070:Lipopolysaccharides / Q000378:metabolism; D008297:Male; D011112:Polymyxin B / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D012756:Sheep; D012772:Shock, Septic / Q000209:etiology / Q000378:metabolism / Q000401:mortality*
D000900:Anti-Bacterial Agents; D001798:Blood Proteins; D054804:Cathelicidins; D008070:Lipopolysaccharides; C403305:SMAP29 protein, Ovis aries; D015378:Imipenem; D011112:Polymyxin B