Urokinase-Type Plasminogen Activator in Inflammatory Cell Recruitment and Host Defense against Pneumocystis carinii in Mice

Author:

Beck James M.12,Preston Angela M.1,Gyetko Margaret R.12

Affiliation:

1. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-0360,1and

2. Pulmonary Section, Department of Veterans Affairs Medical Center, Ann Arbor, Michigan 48105-23032

Abstract

ABSTRACT Effective host defense against Pneumocystis carinii depends upon the integrated actions of inflammatory cells and mediators in the lungs. Using immunocompetent and immunosuppressed mice, our laboratory has defined inflammatory changes in the lungs in response to P. carinii . However, the essential molecules and mechanisms required for cellular recruitment and for host defense against P. carinii are undefined. We hypothesized that urokinase-type plasminogen activator (uPA), a protease intimately involved in inflammatory cell migration and activation, is required for clearance of P. carinii . To test this hypothesis in vivo, we compared the intensity of P. carinii infection and inflammation in the lungs of mice lacking the uPA gene (uPA knockout mice) and in the lungs of wild-type mice. After intratracheal inoculation with P. carinii organisms, uPA knockout mice developed uniformly heavy P. carinii pneumonia while wild-type mice cleared the P. carinii inoculum. Bronchoalveolar lavage fluid from uPA knockout mice contained significantly smaller numbers of cells than did lavage fluid from wild-type mice. We conclude that deletion of the uPA gene prevents the clearance of P. carinii and reduces inflammatory cell recruitment. Therefore, uPA is an important participant in the network of inflammatory events required for the clearance of P. carinii , confirming an important role for this molecule in pulmonary host defense against opportunistic pathogens.

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Immunology,Microbiology,Parasitology

Reference42 articles.

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