02094nas a2200325   4500000000100000000000100001008004100002260001500043653001300058653003000071653002200101653001100123653000900134653001500143653002000158653001800178653001800196653001500214100002100229700001700250700001600267700002500283700002800308700002100336245010800357300001100465490000700476520127100483022001401754       2021                            d  c2021-06-0410aCOVID-1910aCytokine Release Syndrome10aEndothelial Cells10aHumans10aLung10aSARS-CoV-210aalveolar models10ainterleukin-610aorgan-on-chip10avasculitis1 aVivek V. Thacker1 aKunal Sharma1 aNeeraj Dhar1 aGian-Filippo Mancini1 aJessica Sordet-Dessimoz1 aJohn D. McKinney00aRapid endotheliitis and vascular damage characterize SARS-CoV-2 infection in a human lung-on-chip model  ae527440 v223 aSevere cases of SARS-CoV-2 infection are characterized by hypercoagulopathies and systemic endotheliitis of the lung microvasculature. The dynamics of vascular damage, and whether it is a direct consequence of endothelial infection or an indirect consequence of an immune cell-mediated cytokine storm remain unknown. Using a vascularized lung-on-chip model, we find that infection of alveolar epithelial cells leads to limited apical release of virions, consistent with reports of monoculture infection. However, viral RNA and proteins are rapidly detected in underlying endothelial cells, which are themselves refractory to apical infection in monocultures. Although endothelial infection is unproductive, it leads to the formation of cell clusters with low CD31 expression, a progressive loss of barrier integrity and a pro-coagulatory microenvironment. Viral RNA persists in individual cells generating an inflammatory response, which is transient in epithelial cells but persistent in endothelial cells and typified by IL-6 secretion even in the absence of immune cells. Inhibition of IL-6 signalling with tocilizumab reduces but does not prevent loss of barrier integrity. SARS-CoV-2-mediated endothelial cell damage thus occurs independently of cytokine storm.  a1469-3178