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

Margaret R. Gyetko, Gwo Hsiao Chen, Roderick A. McDonald, Richard Goodman, Gary B. Huffnagle, Camille C. Wilkinson, Jennifer A. Fuller, Galen B. Toews

Research output: Contribution to journalArticle

164 Scopus citations

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/CDl8+ cells compared with uPA+/+ controls (P < 0.007); 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.

Original languageEnglish (US)
Pages (from-to)1818-1826
Number of pages9
JournalJournal of Clinical Investigation
Volume97
Issue number8
DOIs
StatePublished - Apr 15 1996

Keywords

  • Cellular recruitment
  • Fungal pathogens
  • Lung inflammation
  • Plasminogen activators
  • Transgenic mice

ASJC Scopus subject areas

  • Medicine(all)

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    Gyetko, M. R., Chen, G. H., McDonald, R. A., Goodman, R., Huffnagle, G. B., Wilkinson, C. C., Fuller, J. A., & Toews, G. B. (1996). Urokinase is required for the pulmonary inflammatory response to Cryptococcus neoformans: A murine transgenic model. Journal of Clinical Investigation, 97(8), 1818-1826. https://doi.org/10.1172/JCI118611