Influenza virus-cytokine-protease cycle in the pathogenesis of vascular hyperpermeability in severe influenza.
BACKGROUND
Severe influenza is characterized by cytokine storm and multiorgan failure with edema. The aim of this study was to define the impact of the cytokine storm on the pathogenesis of vascular hyperpermeability in severe influenza.


METHODS
Weanling mice were infected with influenza A WSN/33(H1N1) virus. The levels of proinflammatory cytokines, tumor necrosis factor (TNF) alpha, interleukin (IL) 6, IL-1beta, and trypsin were analyzed in the lung, brain, heart, and cultured human umbilical vein endothelial cells. The effects of transcriptional inhibitors on cytokine and trypsin expressions and viral replication were determined.


RESULTS
Influenza A virus infection resulted in significant increases in TNF-alpha, IL-6, IL-1beta, viral hemagglutinin-processing protease trypsin levels, and viral replication with vascular hyperpermeability in lung and brain in the first 6 days of infection. Trypsin upregulation was suppressed by transcriptional inhibition of cytokines in vivo and by anti-cytokine antibodies in endothelial cells. Calcium mobilization and loss of tight junction constituent, zonula occludens-1, associated with cytokine- and trypsin-induced endothelial hyperpermeability were inhibited by a protease-activated receptor-2 antagonist and a trypsin inhibitor.


CONCLUSIONS
The influenza virus-cytokine-protease cycle is one of the key mechanisms of vascular hyperpermeability in severe influenza.
Wang
Siye
S
Division of Enzyme Chemistry, Institute for Enzyme Research, The University of Tokushima, Tokushima, Japan.
Le
Trong Quang
TQ
Kurihara
Naoki
N
Chida
Junji
J
Cisse
Youssouf
Y
Yano
Mihiro
M
Kido
Hiroshi
H
D000818:Animals; D001923:Brain Chemistry; D002199:Capillary Permeability; D002478:Cells, Cultured; D016207:Cytokines / Q000032:analysis / Q000276:immunology*; D042783:Endothelial Cells / Q000737:chemistry; D005260:Female; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology* / Q000472:pathogenicity*; D008168:Lung / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000737:chemistry; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000473:pathology*; D010447:Peptide Hydrolases / Q000032:analysis / Q000378:metabolism*
D016207:Cytokines; D010447:Peptide Hydrolases