title: Activated protein C inhibits local coagulation after intrapulmonary delivery of endotoxin in humans.
abstract: BACKGROUND
  Acute lung injury and pneumonia are associated with pulmonary activation of coagulation and suppression of fibrinolysis, resulting in fibrin deposition in the lung. Activated protein C (APC) has systemic anticoagulant effects in patients with sepsis.
  
  
  OBJECTIVE
  To determine the effect of systemic administration of recombinant human APC on endotoxin-induced hemostatic alterations in the bronchoalveolar space in humans.
  
  
  METHODS
  Healthy humans received intravenous APC (24 microg/kg/hour; n = 8) or vehicle (n = 7); all subjects were administered saline in one lung subsegment and endotoxin (4 ng/kg) into the contralateral lung. Bronchoalveolar lavage was performed 16 hours after saline and endotoxin administration.
  
  
  RESULTS
  Endotoxin induced local activation of coagulation, as reflected by elevated levels of thrombin-antithrombin complexes (1.9 +/- 0.1 ng/ml) and soluble tissue factor (15.0 +/- 0.6 pg/ml) in bronchoalveolar lavage fluid, which was inhibited by APC (1.4 +/- 0.1 ng/ml and 12.3 +/- 0.4 pg/ml, respectively; both p < 0.01). Concurrently, endotoxin suppressed fibrinolysis, as indicated by reduced bronchoalveolar levels of plasminogen activator activity accompanied by elevated levels of plasminogen activator inhibitor type I activity. APC diminished the rise in plasminogen activator inhibitor type I activity (from 3.9 +/- 0.1 to 3.0 +/- 0.2 ng/ml, p = 0.002), while not significantly influencing plasminogen activator activity levels. Endotoxin reduced bronchoalveolar protein C concentrations, which was prevented by APC. Protein C did not influence the endotoxin-induced rise in local soluble thrombomodulin levels.
  
  
  CONCLUSIONS
  APC exerts an anticoagulant effect in the human lung challenged with endotoxin.
authors.affiliation: Department of Medicine, Academic Medical Center, Room G2-130, Meibergdreef 9, 1105AZ Amsterdam, Netherlands. t.vanderpoll@amc.uva.nl
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
authors.forename: Marcel
authors.initials: M
authors.lastname: Levi
authors.forename: Jerry A
authors.initials: JA
authors.lastname: Nick
authors.forename: Edward
authors.initials: E
authors.lastname: Abraham
mesh_terms: D001777:Blood Coagulation / Q000187:drug effects*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004731:Endotoxins; D005342:Fibrinolysis / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D008168:Lung / Q000187:drug effects*; D011014:Pneumonia / Q000139:chemically induced / Q000503:physiopathology; D011486:Protein C / Q000008:administration & dosage* / Q000032:analysis; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000032:analysis
chemical_list: D004731:Endotoxins; D011486:Protein C; D011994:Recombinant Proteins