Influenza virus damages the alveolar barrier by disrupting epithelial cell tight junctions

Abstract

A major cause of respiratory failure during influenza A virus (IAV) infection is damage to the epithelial-endothelial barrier of the pulmonary alveolus. Damage to this barrier results in flooding of the alveolar lumen with proteinaceous oedema fluid, erythrocytes and inflammatory cells. To date, the exact roles of pulmonary epithelial and endothelial cells in this process remain unclear.Here, we used an in vitro co-culture model to understand how IAV damages the pulmonary epithelialendothelial barrier. Human epithelial cells were seeded on the upper half of a transwell membrane while human endothelial cells were seeded on the lower half. These cells were then grown in co-culture and IAV was added to the upper chamber.We showed that the addition of IAV (H1N1 and H5N1 subtypes) resulted in significant barrier damage. Interestingly, we found that, while endothelial cells mounted a pro-inflammatory/pro-coagulant response to a viral infection in the adjacent epithelial cells, damage to the alveolar epithelial-endothelial barrier occurred independently of endothelial cells. Rather, barrier damage was associated with disruption of tight junctions amongst epithelial cells, and specifically with loss of tight junction protein claudin-4.Taken together, these data suggest that maintaining epithelial cell integrity is key in reducing pulmonary oedema during IAV infection. @ERSpublications Influenza A virus damages tight junctions, and specifically claudin-4, of respiratory epithelial cells

The differentiated airway epithelium infected by influenza viruses maintains the barrier function despite a dramatic loss of ciliated cells

“…A recent study reported IAV infection interrupts the tight junction formation in an in vitro alveolar culture model comprising immortalized epithelial cells25. In our study, however, the well differentiated tracheal and bronchial epithelia retain their barrier function.…”

Galectin-1 inhibition attenuates profibrotic signaling in hypoxia-induced pulmonary fibrosis

“…To determine the effect of hypoxia as a profibrotic injury to distinct lung epithelial cells, four different cell types derived from proximal and distal lung epithelium were exposed to hypoxia. These include NuLi-1 cells: primary bronchial epithelial cells; H441 cells: derived from bronchoalveolar acinar region, which maintains alveolar and club cell-like features that exhibit features of AEC2s; 26 A549 cells: originating from AEC2s; and primary murine AEC2s. Hypoxia increased mRNA levels of a host of profibrotic genes, including PDGFB (platelet-derived growth factor B), TGF-β , TNF-α (tumor necrosis factor- α ), EDN1 (endothelin-1), and PAI-1 (plasminogen activator inhibitor-1) (Figures 1d–g) in each cell type.…”

“…Therefore, the possibility exists that other hypoxia-associated signaling pathways such as Notch, Hedgehog, and Wnt signaling may participate in progression of PF. 26,50,51 While AE-IPF remains a major cause of mortality in IPF patients, patients with previous histories of lung infections and injury may also be prone to developing PF due to sustained hypoxia signaling in the lung. Therefore, we propose galectin-1 as an important mediator of profibrotic events in the lung and a viable therapeutic target in patients suffering from fibrotic lung diseases, including IPF.…”

Influenza Virus and Glycemic Variability in Diabetes: A Killer Combination?

“…Endothelial cells, whilst not the primary target of influenza virus in humans, play an important role in disease pathogenesis (Teijaro et al, 2011; Short et al, 2013, 2014, 2016). During severe influenza virus infection, pulmonary endothelial cells produce cytokines which drive pulmonary lesions and mortality (Teijaro et al, 2011).…”