Evaluation of antimicrobial and lipopolysaccharide-neutralizing effects ofa synthetic CAP18 fragment against Pseudomonas aeruginosa in a mouse model

CAP18 (cationic antimicrobial protein; 18 kDa) is a neutrophil-derived prot ein that can bind to and inhibit various activities of lipopolysaccharide ( LPS), The 37 C-terminal amino acids of CAP18 make up the LPS-binding domain . A truncated 32-amino-acid C-terminal fragment of CAP18 had potent activit y against Pseudomonas aeruginosa in vitro. We studied the antimicrobial and LPS-neutralizing effects of this synthetic truncated CAP18 peptide (CAP18( 106-137)) on lung injury in mice infected with cytotoxic P. aeruginosa. To determine its maximal effect, the CAP18(106-137) peptide was mixed with bac teria just prior to tracheal instillation, and lung injury was evaluated by determining the amount of leakage of an alveolar protein tracer (I-125-alb umin) into the circulation and by the quantification of lung edema. The lun g injury caused by the instillation of 5 x 10(5) CFU of P. aeruginosa was s ignificantly reduced by the concomitant instillation of CAP18(106-137). How ever, the administration of CAP18(106-137) alone, without bacteria, induced lung edema, suggesting that it has some toxicity. Also, the peptide did no t significantly reduce the number of bacteria that had been simultaneously instilled, nor did it significantly improve the survival of the infected mi ce. The addition of CAP18(106-137) to aztreonam along with the bacteria did decrease the level of antibiotic-induced release of inflammatory mediators including tumor necrosis factor alpha, interleukin-6 and nitric oxide and also improved the survival of the mice. Therefore, more investigations are needed to confirm the toxicities and the therapeutic benefits of CAP18(106- 137) as an adjunctive therapy to antibiotics in the treatment of infections caused by gram-negative bacteria.