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Research Article Free access | 10.1172/JCI118611

Urokinase is required for the pulmonary inflammatory response to Cryptococcus neoformans. A murine transgenic model.

M R Gyetko, G H Chen, R A McDonald, R Goodman, G B Huffnagle, C C Wilkinson, J A Fuller, and G B Toews

Department of Internal Medicine, Ann Arbor Veterans Affairs Medical Center and University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.

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Department of Internal Medicine, Ann Arbor Veterans Affairs Medical Center and University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.

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Department of Internal Medicine, Ann Arbor Veterans Affairs Medical Center and University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.

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Department of Internal Medicine, Ann Arbor Veterans Affairs Medical Center and University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.

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Department of Internal Medicine, Ann Arbor Veterans Affairs Medical Center and University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.

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Department of Internal Medicine, Ann Arbor Veterans Affairs Medical Center and University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.

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Department of Internal Medicine, Ann Arbor Veterans Affairs Medical Center and University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.

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Department of Internal Medicine, Ann Arbor Veterans Affairs Medical Center and University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.

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Published April 15, 1996 - More info

Published in Volume 97, Issue 8 on April 15, 1996
J Clin Invest. 1996;97(8):1818–1826. https://doi.org/10.1172/JCI118611.
© 1996 The American Society for Clinical Investigation
Published April 15, 1996 - Version history
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Abstract

Urokinase (uPA) is hypothesized to provide proteolytic activity enabling inflammatory cells to traverse tissues during recruitment, and it is implicated as a cytokine modulator. Definitive evaluation of these hypotheses in vivo has previously been impossible because uPA could not completely and irreversibly be eliminated. This limitation has been overcome through the development of uPA-deficient transgenic mice (uPA-/-). Using these mice, we evaluated the importance of uPA in the pulmonary inflammatory response to Cryptococcus neoformans (strain 52D). C. neoformans was inoculated into uPA-/- and control mice (uPA+/+), and cell recruitment to the lungs was quantitated. The number of CFU in lung, spleen and brain was determined to assess clearance, and survival curves were generated. By day 21 after inoculation, uPA-/- mice had markedly fewer pulmonary inflammatory (CD45+), CD4+, and CD11b/CD18+ cells compared with uPA+/+ controls (P<0.0007); pulmonary CFUs in the uPA-/- mice continued to increase, whereas CFUs diminished in uPA+/+ mice(P<0.005). In survival studies, only 3/19 uPA+/+ mice died, whereas 15/19 uPA-/- mice died (p<0.001). We have demonstrated that uPA is required for a pulmonary inflammatory response to C. neoformans. Lack of uPA results in inadequate cellular recruitment, uncontrolled infection, and death.

Version history
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