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Am J Physiol Lung Cell Mol Physiol 289: L875-L882, 2005; doi:10.1152/ajplung.00103.2005
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Thioredoxin and dihydrolipoic acid inhibit elastase activity in cystic fibrosis sputum

Rees L. Lee,1,3 Raymond C. Rancourt,1 Greg del Val,2 Kami Pack,1 Churee Pardee,3 Frank J. Accurso,3 and Carl W. White1

1Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado; 2Jealott's Hill International Research Center, Bracknell, United Kingdom; and 3Mike McMorris Cystic Fibrosis Center, University of Colorado Health Sciences Center, Denver, Colorado

Submitted 4 March 2005 ; accepted in final form 13 June 2005

Excessive neutrophil elastase activity within airways of cystic fibrosis (CF) patients results in progressive lung damage. Disruption of disulfide bonds on elastase by reducing agents may modify its enzymatic activity. Three naturally occurring dithiol reducing systems were examined for their effects on elastase activity: 1) Escherichia coli thioredoxin (Trx) system, 2) recombinant human thioredoxin (rhTrx) system, and 3) dihydrolipoic acid (DHLA). The Trx systems consisted of Trx, Trx reductase, and NADPH. As shown by spectrophotometric assay of elastase activity, the two Trx systems and DHLA inhibited purified human neutrophil elastase as well as the elastolytic activity present in the soluble phase (sol) of CF sputum. Removal of any of the three Trx system constituents prevented inhibition. Compared with the monothiols N-acetylcysteine and reduced glutathione, the dithiols displayed greater elastase inhibition. To streamline Trx as an investigational tool, a stable reduced form of rhTrx was synthesized and used as a single component. Reduced rhTrx inhibited purified elastase and CF sputum sol elastase without NADPH or Trx reductase. Because Trx and DHLA have mucolytic effects, we investigated changes in elastase activity after mucolytic treatment. Unprocessed CF sputum was directly treated with reduced rhTrx, the Trx system, DHLA, or DNase. The Trx system and DHLA did not increase elastase activity, whereas reduced rhTrx treatment increased sol elastase activity by 60%. By contrast, the elastase activity after DNase treatment increased by 190%. The ability of Trx and DHLA to limit elastase activity combined with their mucolytic effects makes these compounds potential therapies for CF.

thioctic acid; serine protease; lipoic acid; human thioredoxin; mucolytic


Address for reprint requests and other correspondence: C. W. White, National Jewish Medical and Research Center, Dept. of Pediatrics, Rm. J318, 1400 Jackson St., Denver, CO 80206 (e-mail: whitec{at}njc.org)






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