Published ahead of print on October 16, 2003, doi:10.1164/rccm.200307-971OC
Am. J. Respir. Crit. Care Med., Volume 169, Number 2, January 2004, 187-194
A more recent version of this article appeared on January 15, 2004
Submitted on July 25, 2003
Accepted on October 15, 2003
Cathelicidin peptide SMAP-29 Prevents Endotoxin-Induced Mortality in Rat Models of Septic Shock
ANDREA GIACOMETTI1*, OSCAR CIRIONI1, ROBERTO GHISELLI2, FEDERICO MOCCHEGIANI2, GIUSEPPINA D'AMATO1, RAFFAELLA CIRCO3, FIORENZA ORLANDO4, BARBARA SKERLAVAJ3, CARMELA SILVESTRI1, VITTORIO SABA2, MARGHERITA ZANETTI5, and GIORGIO SCALISE1
1 Institute of Infectious Diseases and Public Health, Universita Politecnica delle Marche, Ancona, Italy,
2 Department of General Surgery, I.N.R.C.A. I.R.R.C.S., Universita Politecnica delle Marche, Ancona, Italy,
3 Department Biomedical Sciences and Technology, Universita of Udine, Udine, Italy,
4 Biotechnology Centre, Research Department, I.N.R.C.A. I.R.R.C.S., Ancona, Italy,
5 Department Biomedical Sciences and Technology, Universita of Udine, Udine, Italy; National Laboratory CIB, Area Science Park, Padriciano, Trieste, Italy
* To whom correspondence should be addressed. E-mail: anconacmi{at}interfree.it.
The present study was designed to investigate the antiendotoxin activity and therapeutic efficacy of 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: i) rats were injected intraperitoneally with 1 mg Escherichia coli 0111:B4 LPS; ii) intra-abdominal 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. Main outcome measures were: bacterial growth in abdominal exudate and plasma, endotoxin and TNF-A concentrations in plasma, 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 to controls. SMAP-29 achieved a substantial decrease in the plasma concentrations of endotoxin and TNF--A 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. SMAP29, because of its double anti-endotoxin and antimicrobial activities, could be an interesting compound for the treatment of septic shock.
Key words: Lipopolysaccharide, Cathelicidins, SMAP-29, Septic shock, Cationic Peptides
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