Potential Therapeutic Role of Cationic Peptides in Three Experimental Models of Septic Shock

Abstract

The therapeutic efficacies of buforin II, indolicidin, and KFFKFFKFF were investigated in three rat models of septic shock: (i) rats injected intraperitoneally with 10 g of Escherichia coli O111:B4 lipopolysaccharide, (ii) rats given an intraperitoneal injection of 2 ؋ 10 10 CFU of Escherichia coli ATCC 25922, and (iii) rats in which intra-abdominal sepsis was induced via cecal ligation and single puncture. All animals were randomized to receive parenterally isotonic sodium chloride solution, 1 mg of buforin II per kg of body weight, 1 mg of indolicidin per kg, 1 mg of KFFKFFKFF per kg, and 20 mg of imipenem per kg. The main outcome measures were bacterial growth in abdominal exudate and plasma, endotoxin and tumor necrosis factor alpha (TNF-␣) concentrations in plasma, and lethality. Treatment with all peptides resulted in significant reductions in plasma endotoxin and TNF-␣ concentrations compared with those resulting from the imipenem and saline treatments. On the other hand, imipenem treatment significantly reduced the levels of bacterial growth compared with the reductions achieved with the peptide and saline treatments. All compounds reduced the rates of death compared to that for the controls. Although the peptides demonstrated lower levels of antimicrobial activity than imipenem, they exhibited the dual properties of antimicrobial and antiendotoxin agents.Severe sepsis and septic shock are major causes of morbidity and mortality in neutropenic individuals, hospitalized patients, and all immunocompromised subjects (3, 26, 28). The lipopolysaccharides (LPSs) associated with the cell membranes of gram-negative bacteria, known as endotoxin, activate host effector cells through stimulation of receptors on their surfaces (13). These target cells secrete large quantities of inflammatory cytokines, such as tumor necrosis factor (TNF), interleukin-1 (IL-1), IL-6, IL-8, platelet-activating factor, arachidonic acid metabolites, erythropoietin, and endothelin (1,2,13,17,27). LPS is composed of an O-polysaccharide chain, a core sugar, and a lipophilic fatty acid, lipid A (1, 13). Lipid A produces the signal responsible for the induction of cytokine genes. Many methods have been used to treat septic shock, including treatments with monoclonal antibodies to endotoxin, IL-1 receptor antagonists, and antioxidants and various anti-inflammatory therapies, but no treatment has produced clinically effective results (1-3, 13, 17, 26-28).Antimicrobial peptides are positively charged molecules isolated from a wide variety of animals and plants. Among these compounds, buforin II (which is isolated from the stomach of an Asian toad named Bufo bufo gargarizans), indolicidin (a 13-residue peptide isolated from cytoplasmic granules of bovine neutrophils), and KFFKFFKFF (a novel synthetic cationic peptide) have broad-spectrum antibacterial activities and outer membrane permeability-increasing properties (5,19,25). In addition, cationic peptides have received increasing attention in recent years as they also possess antiendotoxin acti...

Bactericidal and Antiendotoxic Properties of Short Cationic Peptides Derived from a Snake Venom Lys49 Phospholipase A2

“…The modest protection from lethality observed in both models, with preincubation and by independent administration, encourages the performance of further studies with delayed administration of peptides to evaluate their actual performance in established cases of endotoxemia or sepsis. It was recently shown that the results derived from septic shock models based on LPS injection are very similar to those derived from other experimental models, such as cecal ligation and puncture, which better reflect the conditions observed in patients with sepsis (12). This suggests that pEM-2 (D) could also be assessed in such models, for example.…”

Microdialysis Study of Imipenem Distribution in the Intraperitoneal Fluid of Rats with or without Experimental Peritonitis

“…The well-known experimental model of peritonitis by cecal ligation and puncture (5,25) used in the present study was easily reproduced, with increased lactate concentrations, as well as characteristic clinical symptoms (tissue necrosis and a nauseating smell), attesting to peritonitis. Several intraperitoneal microdialysis studies of rats have been reported, but all were conducted by the same group (2,10,11,12).…”

Clavanin bacterial sepsis control using a novel methacrylate nanocarrier

“…Since no polymeric nanoparticles containing antimicrobial peptides have been evaluated against sepsis until now, only a few studies were found in the literature. Giacometti et al 53 showed that intravenous doses of the antimicrobial peptides buforin II (1 mg⋅kg ), an antimicrobial peptide, against E. coli septic shock in rat model. In that study, the author showed 73.3% survival in comparison to 67% obtained by using 60 mg⋅kg -1 of piperacillin, a beta-lactam antibiotic.…”

“…In that study, the author showed 73.3% survival in comparison to 67% obtained by using 60 mg⋅kg -1 of piperacillin, a beta-lactam antibiotic. In Giacometti et al 53 and Cirioni et al 54 free peptides were used to control sepsis infection, at peptide concentrations above 1 mg⋅kg . Data here reported show the antibiotic activity against a bacterial mix containing S. aureus, K. pneumoniae, P. aeruginosa, and E. coli using 1.2 µg⋅kg -1 of nanostructured clavanin A.…”