Activated protein C ameliorates coagulopathy but does not influence outcome in lethal H1N1 influenza: a controlled laboratory study

Introduction 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 prope...

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Vydáno v:	Critical care (London, England) Ročník 14; číslo 2; s. R65
Hlavní autoři:	Schouten, Marcel, van der Sluijs, Koenraad F, Gerlitz, Bruce, Grinnell, Brian W, Roelofs, Joris JTH, Levi, Marcel M, van 't Veer, Cornelis, Poll, Tom van der
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London BioMed Central 14.04.2010 BioMed Central Ltd National Library of Medicine - MEDLINE Abstracts
Témata:	Animals Anticoagulants - antagonists & inhibitors Anticoagulants - metabolism Anticoagulants - therapeutic use Blood clotting disorders Blood Coagulation - drug effects Critical Care Medicine Dosage and administration Down-Regulation - genetics Drug therapy Emergency Medicine Influenza A Virus, H1N1 Subtype - genetics Influenza A Virus, H1N1 Subtype - pathogenicity Intensive Lung - drug effects Lung - immunology Male Medicine Medicine & Public Health Mice Mice, Inbred C57BL Models, Animal Orthomyxoviridae Infections - blood Orthomyxoviridae Infections - physiopathology Patient outcomes Protein C Protein C - antagonists & inhibitors Protein C - genetics Protein C - metabolism Protein C - therapeutic use Recombinant Proteins Respiratory intensive care Swine influenza Viral Load Netherlands Lung Homogenate Plasminogen Activator Activity Fibrin Degradation Product Influenza Lung Inflammation
ISSN:	1364-8535, 1466-609X, 1364-8535, 1466-609X
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Shrnutí:	Introduction 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 hereon. 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 μg 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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 content type line 14 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	1364-8535 1466-609X 1364-8535 1466-609X
DOI:	10.1186/cc8964