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Blood, 1 January 2001, Vol. 97, No. 1, pp. 297-304
PHAGOCYTES
Inhibition of neutrophil elastase prevents cathelicidin
activation and impairs clearance of bacteria from wounds
Alexander M. Cole,
Jishu Shi,
Alejandro Ceccarelli,
Yong-Hwan Kim,
Albert Park, and
Tomas Ganz
From the Department of Medicine, University of
California at Los Angeles (UCLA) School of Medicine, Los Angeles, CA.
The host defense roles of neutrophil elastase in a porcine
skin wound chamber model were explored. Analysis of wound fluid by
acid-urea polyacrylamide gel electrophoresis, Western blot, and
bacterial overlay confirmed that the neutrophil-derived protegrins constituted the major stable antimicrobial polypeptide in the wound
fluid. The application to the wound of 0.10 and 0.25 mM N-methoxysuccinyl-alanine-alanine-proline-valine (AAPV) chloromethyl ketone, a specific neutrophil elastase inhibitor (NEI), blocked the
proteolytic activation of protegrins and diminished the associated antimicrobial activity as detected by radial diffusion assay against Staphylococcus epidermidis, Staphylococcus
aureus, Escherichia coli, Pseudomonas
aeruginosa, and Candida albicans or by bacterial gel
overlay against S epidermidis and E
coli. The application of the related cathepsin G
inhibitor (CGI),
benzyloxycarbonyl-glycine-leucine-phenylalanine (ZGLF) chloromethyl
ketone, had no effect. In wound chambers that received
106 colony-forming unit (CFU)/mL of S
epidermidis, the presence of NEI significantly decreased the
24-hour clearance of bacteria from the wound compared to wounds treated
with CGI or solvent only. Neither inhibitor, at 0.10 or 0.25 mM
concentration, affected leukocyte accumulation or degranulation in the
wound chambers. The in vitro microbicidal decrement due to NEI was
restored by an amount of the specific protegrin (PG-1), which was
equivalent to the measured difference of protegrin between control and
inhibited chambers. Administration of 1 µg/mL exogenous PG-1 4 hours
after chamber preparation was sufficient to normalize in vivo
antimicrobial activity. Although pharmacologic NEIs are promising
candidates as anti-inflammatory drugs, they may impair host defense in
part by inhibiting the activation of cathelicidins by neutrophil elastase.
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