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Infection and Immunity, March 1999, p. 1207-1212, Vol. 67, No. 3
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

The Pseudomonas aeruginosa Secretory Product Pyocyanin Inactivates alpha 1 Protease Inhibitor: Implications for the Pathogenesis of Cystic Fibrosis Lung Disease

Bradley E. Britigan,1,2,* Michelle A. Railsback,2 and Charles D. Cox3

Medical Service, VA Medical Center, Iowa City, Iowa 52246,1 and Departments of Internal Medicine2 and Microbiology,3 The University of Iowa College of Medicine, Iowa City, Iowa 52242

Received 10 September 1998/Returned for modification 19 October 1998/Accepted 18 December 1998

alpha 1 Protease inhibitor (alpha 1PI) modulates serine protease activity in the lung. Reactive oxygen species inactivate alpha 1PI, 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 alpha 1PI. When alpha 1PI was exposed to NADH and pyocyanin, a combination that results in superoxide production, alpha 1PI 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 alpha 1PI was also added resulted in a loss of the ability of alpha 1PI 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 alpha 1PI. These data raise the possibility that a direct interaction between reduced pyocyanin and alpha 1PI is involved in the process. Consistent with this possibility, pretreatment of alpha 1PI with the reducing agent beta -mercaptoethanol also inhibited binding of trypsin to alpha 1PI. 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 alpha 1PI to control the local activity of serine proteases.

* Corresponding author. Mailing address: Department of Medicine, The University of Iowa, 200 Hawkins Dr., SW54 GH, Iowa City, IA 52242. Phone: (319) 356-2883. Fax: (319) 356-4600. E-mail: bradley-britigan{at}mail.int-med.uiowa.edu.

Infection and Immunity, March 1999, p. 1207-1212, Vol. 67, No. 3
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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