Activated protein C ameliorates coagulopathy but does not influence outcome in lethal H1N1 influenza: a controlled laboratory study.
BACKGROUND
Influenza accounts for 5 to 10% of community-acquired pneumonias and is a major cause of mortality. Sterile and bacterial lung injuries are associated with procoagulant and inflammatory derangements in the lungs. Activated protein C (APC) is an anticoagulant with anti-inflammatory properties that exert beneficial effects in models of lung injury. We determined the impact of lethal influenza A (H1N1) infection on systemic and pulmonary coagulation and inflammation, and the effect of recombinant mouse (rm-) APC here on.


METHODS
Male C57BL/6 mice were intranasally infected with a lethal dose of a mouse adapted influenza A (H1N1) strain. Treatment with rm-APC (125 microg intraperitoneally every eight hours for a maximum of three days) or vehicle was initiated 24 hours after infection. Mice were euthanized 48 or 96 hours after infection, or observed for up to nine days.


RESULTS
Lethal H1N1 influenza resulted in systemic and pulmonary activation of coagulation, as reflected by elevated plasma and lung levels of thrombin-antithrombin complexes and fibrin degradation products. These procoagulant changes were accompanied by inhibition of the fibrinolytic response due to enhanced release of plasminogen activator inhibitor type-1. Rm-APC strongly inhibited coagulation activation in both plasma and lungs, and partially reversed the inhibition of fibrinolysis. Rm-APC temporarily reduced pulmonary viral loads, but did not impact on lung inflammation or survival.


CONCLUSIONS
Lethal influenza induces procoagulant and antifibrinolytic changes in the lung which can be partially prevented by rm-APC treatment.
Schouten
Marcel
M
Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Meibergdreef 9, Room G2-130, Amsterdam, The Netherlands. m.schouten@amc.uva.nl
Sluijs
Koenraad F van der
KF
Gerlitz
Bruce
B
Grinnell
Brian W
BW
Roelofs
Joris J T H
JJ
Levi
Marcel M
MM
van 't Veer
Cornelis
C
van der Poll
Tom
T
D000818:Animals; D000925:Anticoagulants / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects*; D015536:Down-Regulation / Q000235:genetics; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000472:pathogenicity*; D008168:Lung / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009976:Orthomyxoviridae Infections / Q000097:blood* / Q000503:physiopathology; D011486:Protein C / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D011994:Recombinant Proteins; D019562:Viral Load
D000925:Anticoagulants; D011486:Protein C; D011994:Recombinant Proteins
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