TY - JOUR
T1 - Platelet activation and aggregation promote lung inflammation and influenza virus pathogenesis
AU - Lê, Vuong Ba
AU - Schneider, Jochen G.
AU - Boergeling, Yvonne
AU - Berri, Fatma
AU - Ducatez, Mariette
AU - Guerin, Jean Luc
AU - Adrian, Iris
AU - Errazuriz-Cerda, Elisabeth
AU - Frasquilho, Sonia
AU - Antunes, Laurent
AU - Lina, Bruno
AU - Bordet, Jean Claude
AU - Jandrot-Perrus, Martine
AU - Ludwig, Stephan
AU - Riteau, Bé Atrice
N1 - Publisher Copyright:
Copyright © 2015 by the American Thoracic Society.
PY - 2015/4/1
Y1 - 2015/4/1
N2 - Rationale: The hallmark of severe influenza virus infection is excessive inflammation of the lungs. Platelets are activated during influenza, but their role in influenza virus pathogenesis and inflammatory responses is unknown. Objectives: To determine the role of platelets during influenza A virus infections and propose new therapeutics against influenza. Methods: We used targeted gene deletion approaches and pharmacologic interventions to investigate the role of platelets during influenza virus infection in mice. Measurements and Main Results: Lungs of infected mice were massively infiltrated by aggregates of activated platelets. Platelet activation promoted influenza A virus pathogenesis. Activating protease-activated receptor 4, a platelet receptor for thrombin that is crucial for platelet activation, exacerbated influenza-induced acute lung injury and death. In contrast, deficiency in the major platelet receptor glycoprotein IIIa protected mice from death caused by influenza viruses, and treating the mice with a specific glycoprotein IIb/IIIa antagonist, eptifibatide, had the same effect. Interestingly, mice treated with other antiplatelet compounds (antagonists of protease-activated receptor 4, MRS 2179, and clopidogrel) were also protected from severe lung injury and lethal infections induced by several influenza strains. Conclusions: The intricate relationship between hemostasis and inflammation has major consequences in influenza virus pathogenesis, and antiplatelet drugs might be explored to develop new antiinflammatory treatment against influenza virus infections.
AB - Rationale: The hallmark of severe influenza virus infection is excessive inflammation of the lungs. Platelets are activated during influenza, but their role in influenza virus pathogenesis and inflammatory responses is unknown. Objectives: To determine the role of platelets during influenza A virus infections and propose new therapeutics against influenza. Methods: We used targeted gene deletion approaches and pharmacologic interventions to investigate the role of platelets during influenza virus infection in mice. Measurements and Main Results: Lungs of infected mice were massively infiltrated by aggregates of activated platelets. Platelet activation promoted influenza A virus pathogenesis. Activating protease-activated receptor 4, a platelet receptor for thrombin that is crucial for platelet activation, exacerbated influenza-induced acute lung injury and death. In contrast, deficiency in the major platelet receptor glycoprotein IIIa protected mice from death caused by influenza viruses, and treating the mice with a specific glycoprotein IIb/IIIa antagonist, eptifibatide, had the same effect. Interestingly, mice treated with other antiplatelet compounds (antagonists of protease-activated receptor 4, MRS 2179, and clopidogrel) were also protected from severe lung injury and lethal infections induced by several influenza strains. Conclusions: The intricate relationship between hemostasis and inflammation has major consequences in influenza virus pathogenesis, and antiplatelet drugs might be explored to develop new antiinflammatory treatment against influenza virus infections.
KW - Flu pathogenesis
KW - Lung injury
KW - Novel drugs
KW - Platelets
KW - Pneumonia
UR - http://www.scopus.com/inward/record.url?scp=84926682268&partnerID=8YFLogxK
U2 - 10.1164/rccm.201406-1031OC
DO - 10.1164/rccm.201406-1031OC
M3 - Article
C2 - 25664391
AN - SCOPUS:84926682268
SN - 1073-449X
VL - 191
SP - 804
EP - 819
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
IS - 7
ER -