title: Influenza Virus Infection Induces Platelet-Endothelial Adhesion Which Contributes to Lung Injury.
abstract: Lung injury after influenza infection is characterized by increased permeability of the lung microvasculature, culminating in acute respiratory failure. Platelets interact with activated endothelial cells and have been implicated in the pathogenesis of some forms of acute lung injury. Autopsy studies have revealed pulmonary microthrombi after influenza infection, and epidemiological studies suggest that influenza vaccination is protective against pulmonary thromboembolism; however, the effect of influenza infection on platelet-endothelial interactions is unclear. We demonstrate that endothelial infection with both laboratory and clinical strains of influenza virus increased the adhesion of human platelets to primary human lung microvascular endothelial cells. Platelets adhered to infected cells as well as to neighboring cells, suggesting a paracrine effect. Influenza infection caused the upregulation of von Willebrand factor and ICAM-1, but blocking these receptors did not prevent platelet-endothelial adhesion. Instead, platelet adhesion was inhibited by both RGDS peptide and a blocking antibody to platelet integrin α5β1, implicating endothelial fibronectin. Concordantly, lung histology from infected mice revealed viral dose-dependent colocalization of viral nucleoprotein and the endothelial marker PECAM-1, while platelet adhesion and fibronectin deposition also were observed in the lungs of influenza-infected mice. Inhibition of platelets using acetylsalicylic acid significantly improved survival, a finding confirmed using a second antiplatelet agent. Thus, influenza infection induces platelet-lung endothelial adhesion via fibronectin, contributing to mortality from acute lung injury. The inhibition of platelets may constitute a practical adjunctive strategy to the treatment of severe infections with influenza.IMPORTANCE There is growing appreciation of the involvement of the lung endothelium in the pathogenesis of severe infections with influenza virus. We have recently shown that the virus can infect human lung endothelial cells, but the functional consequences of this infection are unknown (S. M. Armstrong, C. Wang, J. Tigdi, X. Si, C. Dumpit, S. Charles, A. Gamage, T. J. Moraes, and W. L. Lee, PLoS One 7:e47323, 2012, http://dx.doi.org/10.1371/journal.pone.0047323). Here, we show that this infection causes platelets to adhere to the lung endothelium. Importantly, blocking platelets using two distinct antiplatelet drugs improved survival in a mouse model of severe influenza infection. Thus, platelet inhibition may constitute a novel therapeutic strategy to improve the host response to severe infections with influenza.
authors.affiliation: Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Canada Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Sugiyama
authors.affiliation: Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Canada Institute of Medical Science, University of Toronto, Toronto, Canada.
authors.forename: Asela
authors.initials: A
authors.lastname: Gamage
authors.affiliation: Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Canada.
authors.forename: Roman
authors.initials: R
authors.lastname: Zyla
authors.affiliation: Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Canada Institute of Medical Science, University of Toronto, Toronto, Canada.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Armstrong
authors.affiliation: Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Canada.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Advani
authors.affiliation: Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Advani
authors.affiliation: Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Canada.
authors.forename: Changsen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Canada Institute of Medical Science, University of Toronto, Toronto, Canada Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada Division of Respirology and Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Canada leew@smh.ca.
authors.forename: Warren L
authors.initials: WL
authors.lastname: Lee
mesh_terms: D000328:Adult; D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D002448:Cell Adhesion; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000502:physiology*; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000473:pathology; D055370:Lung Injury; D051379:Mice; D009975:Orthomyxoviridae / Q000502:physiology*; D009976:Orthomyxoviridae Infections / Q000473:pathology / Q000821:virology; D016019:Survival Analysis
chemical_list: D005353:Fibronectins