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Cathelicidin Peptide Sheep Myeloid Antimicrobial Peptide-29 Prevents Endotoxin-induced Mortality in Rat Models of Septic Shock

Institute of Infectious Diseases and Public Health; Department of General Surgery, I.N.R.C.A. I.R.R.C.S., Università Politecnica delle Marche; Biotechnology Centre, Research Department, I.N.R.C.A. I.R.R.C.S., Ancona; Department of Biomedical Sciences and Technology, University of Udine, Udine; and National Laboratory CIB, Area Science Park, Padriciano, Trieste, Italy

Correspondence and requests for reprints should be addressed to Andrea Giacometti, M.D., Clinica delle Malattie Infettive, c/o Ospedale Regionale, Via Conca, 60020 Torrette AN, Italy. E-mail: anconacmi{at}interfree.it

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- concentrations, and lethality. The in vitro study showed that SMAP-29 completely inhibited the LPS procoagulant activity at approximately 10 µM 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- 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.

Key Words: LPS • cathelicidins • sheep myeloid antimicrobial peptide-29 • septic shock • cationic peptides

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