Supplemental Digital Content is available in the text. Objective: SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection is a major cause of morbidity and mortality, often as a result of acute respiratory distress syndrome. Respiratory failure is characterized by a hyperinflammatory immune response, lung vascular injury, and edema formation. The potential for immunomodulatory therapy to prevent lung vascular injury and edema formation is not well understood. Approach and Results: We show that SARS-CoV-2 infection in humanized K18-hACE-2 mice activated inflammatory NLRP3 (NLR family pyrin domain containing 3)–caspase-1 pyroptotic signaling in lungs, release of IL (interleukin)-1β, and downregulation of the lung endothelial adherens junction protein VE (vascular endothelial)-cadherin. Primary human lung microvascular endothelial cells were susceptible to SARS-CoV-2 infection and displayed pyroptosis-like injury. We observed profound lung vascular injury post–SARS-CoV-2 infection and resultant protein-rich lung edema formation. Selective blockade of IL-1 receptor signaling by IL-1RA (IL-1 receptor antagonist) anakinra prevented downregulation of VE-cadherin, as well as accompanying lung vascular hyperpermeability. IL-1RA also significantly increased survival. Conclusions: These results provide insights into the central role of NLRP3–caspase-1 pyroptotic innate immune signaling and loss of lung endothelial adherens junctions in the mechanism of acute respiratory distress syndrome induced by SARS-CoV-2. Our data show that treatment with IL-1RA during activation of inflammasome provides the ideal scenario for preventing lung vascular injury and respiratory failure in coronavirus disease 2019 (COVID-19).
【저자키워드】 SARS-CoV-2, interleukin-1, edema, pyroptosis, vascular system injur, ies, 【초록키워드】 COVID-19, Treatment, coronavirus disease, Respiratory distress syndrome, Coronavirus disease 2019, coronavirus, immune response, Respiratory failure, Anakinra, acute respiratory distress syndrome, SARS-COV-2 infection, Infection, lung, severe acute respiratory syndrome Coronavirus, Protein, survival, mice, endothelial cells, Lungs, human lung, morbidity, edema, pyroptosis, Digital, morbidity and mortality, Inflammasome, receptor, respiratory, VE-cadherin, mechanism, IL-1, caspase, immunomodulatory therapy, acute respiratory distress, NLRP3, NLR, Endothelial cell, Signaling, innate immune, Inflammatory, Injury, respiratory distress, receptor antagonist, Digital Content, Vascular injury, acute respiratory syndrome, Vascular, junctions, domain, syndrome, IL-1ra, downregulation, blockade, content, cadherin, text, IL-1 receptor antagonist, lung edema, lung endothelial, Hyperinflammatory, humanized, susceptible, Prevent, junction, significantly increased, characterized, provide, activated, prevented, activation of inflammasome, receptor signaling, 【제목키워드】 leakage,