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Endogenous Tissue-Type Plasminogen Activator Is Protective during Escherichia coli-Induced Abdominal Sepsis in Mice¹

Rosemarijn Renckens^2,*,, Joris J. T. H. Roelofs, Sandrine Florquin, Alex F. de Vos^*,, Jennie M. Pater^*,, H. Roger Lijnen, Peter Carmeliet^¶, Cornelis van ’t Veer^*, and Tom van der Poll^*,

^* Center of Infection and Immunity Amsterdam, Laboratory of Experimental Internal Medicine, and Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Center for Molecular and Vascular Biology and ^¶ Center for Transgene Technology and Gene Therapy, University of Leuven, Leuven, Belgium

Sepsis is associated with enhanced production of tissue-type plasminogen activator (tPA). We investigated the function of endogenous tPA in the immune responses to Escherichia coli-induced abdominal sepsis using tPA gene-deficient (tPA^–/–) and normal wild-type (WT) mice. tPA^–/– mice demonstrated an impaired defense against E. coli peritonitis as indicated by higher bacterial loads at the primary site of the infection, enhanced dissemination, and reduced survival. The protective function of tPA was independent of plasmin since plasminogen gene-deficient (Plg^–/–) mice were indistinguishable from WT mice. Relative to WT mice, tPA^–/– mice demonstrated similar neutrophil counts in the peritoneal cavity despite much higher bacterial loads and higher local concentrations of neutrophil attracting chemokines, suggesting a reduced migratory response. In line, tPA^–/– mice demonstrated a reduced thioglycolate-induced neutrophil influx into the peritoneal cavity and i.p. injection of WT mice with a replication-defective adenoviral vector expressing tPA caused an enhanced cell migration to the peritoneal cavity during E. coli peritonitis. These findings identify a novel protective function of tPA in abdominal sepsis caused by E. coli that seems independent of its role in the generation of plasmin.

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