Summary Background Interleukin-6 (IL-6) is elevated in SARS-CoV-2 infection. IL-6 regulates acute-phase proteins, such as alpha-1 antitrypsin (AAT), a key lung anti-protease. We investigated the protease-anti-protease balance in the circulation and pulmonary compartments in SARS-CoV-2 acute respiratory distress syndrome (ARDS) compared to non-SARS-CoV-2 ARDS (nsARDS) and the effects of tocilizumab (IL-6 receptor antagonist) on anti-protease defence in SARS-CoV-2 infection. Methods Levels and activity of AAT and neutrophil elastase (NE) were measured in plasma, airway tissue and tracheal secretions (TA) of people with SARS-CoV-2 ARDS or nsARDS. AAT and IL-6 levels were evaluated in people with moderate SARS-CoV-2 infection who received standard of care +/- tocilizumab. Findings AAT plasma levels doubled in SARS-CoV-2 ARDS. In lung parenchyma AAT levels were increased, as was the percentage of neutrophils involved in NET formation. A protease-anti-protease imbalance was detected in TA with active NE and no active AAT. The airway anti-protease, secretory leukoprotease inhibitor was decreased in SARS-CoV-2-infected lungs and cleaved in TA. In nsARDS, plasma AAT levels were elevated but TA samples had less AAT cleavage, with no detectable active NE in most samples Induction of AAT in ARDS occurred mainly through IL-6. Tocilizumab down-regulated AAT during SARS-CoV-2 infection. Interpretation There is a protease-anti-protease imbalance in the airways of SARS-CoV-2-ARDS patients. This imbalance is a target for anti-protease therapy.
【저자키워드】 SARS-COV-2 infection, interleukin-6, alpha-1 antitrypsin, Neutrophil elastase, 【초록키워드】 Neutrophils, SARS-CoV-2, Respiratory distress syndrome, ARDS, therapy, acute respiratory distress syndrome, Tocilizumab, IL-6, SARS-COV-2 infection, neutrophil, interleukin-6, lung, Proteins, protease, airway, interleukin, cleavage, Alpha, plasma, target, circulation, inhibitor, moderate, patients, Neutrophil elastase, acute respiratory distress, regulate, lung parenchyma, airways, IL-6 receptor, balance, respiratory distress, receptor antagonist, Standard of care, induction, tissue, SARS-CoV-2 ARDS, secretion, syndrome, ARDS patients, finding, Effect, NET, occurred, involved, investigated, detectable, evaluated, elevated, less, tracheal, Level, cleaved, were measured, down-regulated, IL-6 level, 【제목키워드】 SARS-CoV-2, implication,