The Pseudomonas aeruginosa secretory product pyocyanin inactivates α1 protease inhibitor

Implications for the pathogenesis of cystic fibrosis lung disease

Bradley E Britigan, Michelle A. Railsback, Charles D. Cox

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

α1 Protease inhibitor (α1PI) modulates serine protease activity in the lung. Reactive oxygen species inactivate α1PI, and this process has been implicated in the pathogenesis of a variety of forms of lung injury. An imbalance of protease-antiprotease activity is also detected in the airways of patients with cystic fibrosis-associated lung disease who are infected with Pseudomonas aeruginosa. P. aeruginosa secretes pyocyanin, which, through its ability to redox cycle, induces cells to generate reactive oxygen species. We tested the hypothesis that redox cycling of pyocyanin could lead to inactivation of α1PI. When α1PI was exposed to NADH and pyocyanin, a combination that results in superoxide production, α1PI lost its ability to form an inhibitory complex with both porcine pancreatic elastase (PPE) and trypsin. Similarly, addition of pyocyanin to cultures of human airway epithelial cells to which α1PI was also added resulted in a loss of the ability of α1PI to form a complex with PPE or trypsin. Neither superoxide dismutase, catalase, nor dimethylthiourea nor depletion of the media of O2 to prevent formation of reactive oxygen species blocked pyocyanin-mediated inactivation of α1PI. These data raise the possibility that a direct interaction between reduced pyocyanin and α1PI is involved in the process. Consistent with this possibility, pretreatment of α1PI with the reducing agent β-mercaptoethanol also inhibited binding of trypsin to α1PI. These data suggest that pyocyanin could contribute to lung injury in the P. aeruginosa-infected airway of cystic fibrosis patients by decreasing the ability of α1PI to control the local activity of serine proteases.

Original languageEnglish (US)
Pages (from-to)1207-1212
Number of pages6
JournalInfection and Immunity
Volume67
Issue number3
StatePublished - Jan 1 1999

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Pyocyanine
Protease Inhibitors
Cystic Fibrosis
Pseudomonas aeruginosa
Lung Diseases
Trypsin
Reactive Oxygen Species
Serine Proteinase Inhibitors
Pancreatic Elastase
Lung Injury
Oxidation-Reduction
Swine
Mercaptoethanol
Reducing Agents
Serine Proteases
Superoxides
NAD

ASJC Scopus subject areas

  • Immunology

Cite this

The Pseudomonas aeruginosa secretory product pyocyanin inactivates α1 protease inhibitor : Implications for the pathogenesis of cystic fibrosis lung disease. / Britigan, Bradley E; Railsback, Michelle A.; Cox, Charles D.

In: Infection and Immunity, Vol. 67, No. 3, 01.01.1999, p. 1207-1212.

Research output: Contribution to journalArticle

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