title: Endogenous tissue-type plasminogen activator impairs host defense during severe experimental Gram-negative sepsis (melioidosis)*.
abstract: OBJECTIVE
  Melioidosis is a frequent cause of severe sepsis in Southeast Asia caused by the gram-negative bacterium Burkholderia pseudomallei. Patients with melioidosis have elevated circulating levels of tissue-type plasminogen activator, an important regulator of fibrinolysis. In this study, we aimed to investigate the role of tissue-type plasminogen activator during melioidosis.
  
  
  METHODS
  Animal study.
  
  
  METHODS
  University research laboratory.
  
  
  METHODS
  Wild-type and tissue-type plasminogen activator-deficient C57BL/6 mice.
  
  
  METHODS
  Mice were intranasally infected with viable Burkholderia pseudomallei and killed after 24, 48, or 72 hrs for harvesting of lungs, liver, and blood. Additionally, survival studies were performed.
  
  
  RESULTS
  Experimentally induced melioidosis was associated with elevated levels of tissue-type plasminogen activator in lungs of infected wild-type mice. During infection with Burkholderia pseudomallei, tissue-type plasminogen activator-deficient mice were protected when compared to wild-type mice as demonstrated by a strongly decreased mortality (62% vs. 100% amongst wild-type mice, p < .0001), together with decreased pulmonary bacterial loads, less severe histopathological scores, and decreased fibrinolysis. These results were accompanied with an early increase in cytokine levels in tissue-type plasminogen activator-deficient mice.
  
  
  CONCLUSIONS
  During severe gram-negative sepsis caused by Burkholderia pseudomallei, endogenous tissue-type plasminogen activator has harmful effects with respect to survival and pulmonary bacterial growth. These effects are related to tissue-type plasminogen activator-associated plasmin-induced fibrinolysis and/or a tissue-type plasminogen activator-associated decrease in proinflammatory cytokine production.
authors.affiliation: Center for Infection and Immunity Amsterdam, Amsterdam, The Netherlands. l.m.kager@amc.uva.nl
authors.forename: Liesbeth M
authors.initials: LM
authors.lastname: Kager
authors.forename: W Joost
authors.initials: WJ
authors.lastname: Wiersinga
authors.forename: Joris J T H
authors.initials: JJ
authors.lastname: Roelofs
authors.forename: Joost C M
authors.initials: JC
authors.lastname: Meijers
authors.forename: Marcel
authors.initials: M
authors.lastname: Levi
authors.forename: Cornelis
authors.initials: C
authors.lastname: Van't Veer
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
mesh_terms: D000818:Animals; D058491:Bacterial Load; D001769:Blood; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D005338:Fibrin Fibrinogen Degradation Products; D005342:Fibrinolysis; D008099:Liver / Q000382:microbiology; D008168:Lung / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008297:Male; D008554:Melioidosis / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010959:Tissue Plasminogen Activator / Q000172:deficiency / Q000378:metabolism*; D015854:Up-Regulation; D014568:Urokinase-Type Plasminogen Activator
chemical_list: D016207:Cytokines; D005338:Fibrin Fibrinogen Degradation Products; C036309:fibrin fragment D; C030568:fibrinogen fragment X; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator