The role of neutrophils and macrophages in influenza-induced ARDS
(A) Neutrophils can damage the epithelial–endothelial barrier in influenza virus infection via the production of reactive oxygen species (i). In response to influenza virus infection, neutrophils also produce cytokines (ii), which can then indirectly damage the epithelial–endothelial barrier. The production of NETs (iii) can also damage epithelial and endothelial cells. The inset shows NETs (arrowheads) in large blood vessels of a mouse after in-vivo infection with influenza virus (haematoxylin and eosin stain). (B) Macrophages can damage the epithelial–endothelial barrier directly by influenza-induced expression of TRAIL, which interacts with DR5 (iv) to cause epithelial cell apoptosis. TRAIL expression is triggered by interferon β. In response to influenza virus, macrophages also produce various cytokines (v) that can indirectly damage the epithelial–endothelial barrier. The inset shows a macrophage (arrowhead) interacting with an alveolar epithelial cell in human lung tissue, 24 h after ex-vivo infection with influenza A H5N1 virus (haematoxylin and eosin stain, reduced by 33% from ×500). Finally, influenza A induces macrophages to mediate the production of NO (vi) and the subsequent formation of peroxynitrite, which can damage the epithelial–endothelial barrier. In both (A) and (B) epithelial cells represent both type 1 and type 2 pneumocytes. Newly recruited macrophages are depicted in dark pink, and resident alveolar macrophages are depicted in green. Accumulation of proteinaceous fluid in the alveolus is shown in pink. ARDS=acute respiratory distress syndrome. BM=basement membrane. ROS=reactive oxygen species. ROS=reactive oxygen species. NET=neutrophil extracellular trap. TNF=tumour necrosis factor. NO=nitric oxide. DR5=death receptor 5. TRAIL=tumour-necrosis-factor-related apoptosis-inducing ligand. Inset of part iii reproduced from Narasaraju and colleagues90 by permission of Elsevier.