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Endogenous tissue-type plasminogen activator impairs host defense during severe experimental Gram-negative sepsis

Liesbeth M Kager1, W Joost Wiersinga, Joris J T H Roelofs

  • 1Center for Infection and Immunity Amsterdam, Amsterdam, The Netherlands. l.m.kager@amc.uva.nl

Critical Care Medicine
|May 9, 2012
PubMed
Abstract

Insights

Tissue-type plasminogen activator (t-PA) worsens outcomes in melioidosis, a severe sepsis caused by Burkholderia pseudomallei. Deficiency in t-PA improved survival and reduced bacterial load in mice, highlighting its detrimental role.

Area of Science:

  • Infectious Diseases
  • Bacteriology
  • Immunology

Background:

  • Melioidosis, a severe sepsis caused by Burkholderia pseudomallei, is prevalent in Southeast Asia.
  • Elevated levels of tissue-type plasminogen activator (t-PA), a fibrinolysis regulator, are observed in melioidosis patients.

Purpose of the Study:

  • To investigate the role of endogenous tissue-type plasminogen activator (t-PA) in the pathogenesis of melioidosis.

Main Methods:

  • An animal study using wild-type and t-PA-deficient C57BL/6 mice intranasally infected with Burkholderia pseudomallei.
  • Assessment of survival, pulmonary bacterial loads, histopathology, fibrinolysis, and cytokine levels at 24, 48, and 72 hours post-infection.

Main Results:

  • Melioidosis induced elevated t-PA in wild-type mice lungs.
  • t-PA-deficient mice exhibited significantly decreased mortality (62% vs. 100%), reduced bacterial burden, less severe lung pathology, and diminished fibrinolysis compared to wild-type mice.
  • Early increases in cytokine levels were noted in t-PA-deficient mice.

Conclusions:

  • Endogenous t-PA has detrimental effects on survival and bacterial growth during severe Burkholderia pseudomallei sepsis.
  • These harmful effects are linked to t-PA-mediated fibrinolysis and potentially reduced pro-inflammatory cytokine production.

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