Figure 1. Mechanisms of endothelial dysfunction in influenza virus infection. (A) Endothelial permeability and activation. Elevated levels of pro-inflammatory cytokines/chemokines can directly induce endothelial leak through disruption of cell–cell junctions and may also cause endothelial cells to express elevated levels of adhesion molecules that promote leukocyte recruitment. Neutrophils release neutrophil extracellular traps (NETs), which can damage endothelial cells. There is in vitro evidence that influenza can directly infect lung endothelial cells and cause activation of NFκB, endothelial apoptosis, and loss of junctional proteins. In vivo, only avian H5N1 influenza has been shown to directly infect endothelial cells. (B) Platelet–endothelial interactions. Circulating cytokines/chemokines cause increased expression of platelet-binding receptors. Influenza virus can directly infect lung endothelium and induce endothelial apoptosis exposing the extracellular matrix, which has a high affinity for platelets. Influenza may directly induce platelet activation and activated platelets bind to endothelium. Activated platelets may interact with neutrophils triggering the production of NETs.