TY - JOUR
T1 - Activated protein C inhibits local coagulation after intrapulmonary delivery of endotoxin in humans
AU - van der Poll, Tom
AU - Levi, Marcel
AU - Nick, Jerry A.
AU - Abraham, Edward
PY - 2005
Y1 - 2005
N2 - Rationale: 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 μ g/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. Measurements and Main Results: Endotoxin induced local activation of coagulation, as reflected by elevated levels of thrombin-antithrombin complexes (1.9 &PLUSMN; 0.1 ng/ml) and soluble tissue factor (15.0 &PLUSMN; 0.6 pg/ml) in bronchoalveolar lavage fluid, which was inhibited by APC (1.4 &PLUSMN; 0.1 ng/ml and 12.3 &PLUSMN; 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 &PLUSMN; 0.1 to 3.0 &PLUSMN; 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. Conclusion: APC exerts an anticoagulant effect in the human lung challenged with endotoxin
AB - Rationale: 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 μ g/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. Measurements and Main Results: Endotoxin induced local activation of coagulation, as reflected by elevated levels of thrombin-antithrombin complexes (1.9 &PLUSMN; 0.1 ng/ml) and soluble tissue factor (15.0 &PLUSMN; 0.6 pg/ml) in bronchoalveolar lavage fluid, which was inhibited by APC (1.4 &PLUSMN; 0.1 ng/ml and 12.3 &PLUSMN; 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 &PLUSMN; 0.1 to 3.0 &PLUSMN; 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. Conclusion: APC exerts an anticoagulant effect in the human lung challenged with endotoxin
U2 - https://doi.org/10.1164/rccm.200411-1483OC
DO - https://doi.org/10.1164/rccm.200411-1483OC
M3 - Article
C2 - 15750041
SN - 1073-449X
VL - 171
SP - 1125
EP - 1128
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 10
ER -