title: Endogenous α2-antiplasmin is protective during severe gram-negative sepsis (melioidosis).
abstract: BACKGROUND
  α2-Antiplasmin (A2AP) is a major inhibitor of fibrinolysis by virtue of its capacity to inhibit plasmin. Although the fibrinolytic system is strongly affected by infection, the functional role of A2AP in the host response to sepsis is unknown.
  
  
  OBJECTIVE
  To study the role of A2AP in melioidosis, a common form of community-acquired sepsis in Southeast Asia and Northern Australia caused by the gram-negative bacterium Burkholderia pseudomallei.
  
  
  METHODS
  In a single-center observational study A2AP was measured in patients with culture-proven septic melioidosis. Wild-type and A2AP-deficient (A2AP(-/-)) mice were intranasally infected with B. pseudomallei to induce severe pneumosepsis (melioidosis). Parameters of inflammation and coagulation were measured, and survival studies were performed.
  
  
  RESULTS
  Patients with melioidosis showed elevated A2AP plasma levels. Likewise, A2AP levels in plasma and lung homogenates were elevated in mice infected with B. pseudomallei. A2AP-deficient (A2AP(-/-)) mice had a strongly disturbed host response during experimental melioidosis as reflected by enhanced bacterial growth at the primary site of infection accompanied by increased dissemination to distant organs. In addition, A2AP(-/-) mice showed more severe lung pathology and injury together with an increased accumulation of neutrophils and higher cytokine levels in lung tissue. A2AP deficiency further was associated with exaggerated systemic inflammation and coagulation, increased distant organ injury, and enhanced lethality.
  
  
  CONCLUSIONS
  This study is the first to identify A2AP as a protective mediator during gram-negative (pneumo)sepsis by limiting bacterial growth, inflammation, tissue injury, and coagulation.
authors.affiliation: 1 Center of Experimental and Molecular Medicine (CEMM).
authors.forename: Liesbeth M
authors.initials: LM
authors.lastname: Kager
authors.forename: Tassili A
authors.initials: TA
authors.lastname: Weehuizen
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: Arjen M
authors.initials: AM
authors.lastname: Dondorp
authors.forename: Cornelis
authors.initials: C
authors.lastname: van 't Veer
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D058491:Bacterial Load; D016957:Burkholderia pseudomallei; D005260:Female; D005342:Fibrinolysis / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000276:immunology / Q000503:physiopathology; D008168:Lung / Q000473:pathology; D008297:Male; D008554:Melioidosis / Q000097:blood* / Q000276:immunology / Q000382:microbiology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008875:Middle Aged; D018805:Sepsis / Q000097:blood* / Q000276:immunology / Q000382:microbiology / Q000503:physiopathology; D055815:Young Adult; D000979:alpha-2-Antiplasmin / Q000032:analysis* / Q000502:physiology
chemical_list: D000979:alpha-2-Antiplasmin