Protease-anti-protease compartmentalization in SARS-CoV-2 ARDS: Therapeutic implications
Oisin F. McElvaney,
Takanori Asakura,
Suzanne L. Meinig,
Jose L. Torres-Castillo,
Robert S. Hagan,
Claudie Gabillard,
Mark P. Murphy,
Leigh B. Thorne,
Alain Borczuk,
Emer P. Reeves,
Ross E. Zumwalt,
Yu Mikami,
Tomas P. Carroll,
Kenichi Okuda,
Grace Hogan,
Oliver J. McElvaney,
Jennifer Clarke,
Natalie L. McEvoy,
Patrick W. Mallon,
Cormac McCarthy,
Ger Curley,
Matthew C. Wolfgang,
Richard C. Boucher,
Noel G. McElvaney
Affiliations
Oisin F. McElvaney
Irish Centre for Genetic Lung Disease, RCSI Education and Research Centre, Beaumont Hospital, Dublin 9, Dublin, Ireland; Royal College of Surgeons in Ireland, Dublin, Ireland
Takanori Asakura
Marsico Lung Institute/Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Suzanne L. Meinig
Marsico Lung Institute/Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Jose L. Torres-Castillo
Division of Pulmonary Diseases and Critical Care Medicine, Department of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
Robert S. Hagan
Marsico Lung Institute/Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Division of Pulmonary Diseases and Critical Care Medicine, Department of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
Claudie Gabillard
Irish Centre for Genetic Lung Disease, RCSI Education and Research Centre, Beaumont Hospital, Dublin 9, Dublin, Ireland; Royal College of Surgeons in Ireland, Dublin, Ireland
Mark P. Murphy
Irish Centre for Genetic Lung Disease, RCSI Education and Research Centre, Beaumont Hospital, Dublin 9, Dublin, Ireland; Royal College of Surgeons in Ireland, Dublin, Ireland; Corresponding author at: Irish Centre for Genetic Lung Disease, RCSI Education and Research Centre, Beaumont Hospital, Dublin 9, Dublin, Ireland.
Leigh B. Thorne
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Alain Borczuk
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
Emer P. Reeves
Irish Centre for Genetic Lung Disease, RCSI Education and Research Centre, Beaumont Hospital, Dublin 9, Dublin, Ireland; Royal College of Surgeons in Ireland, Dublin, Ireland
Ross E. Zumwalt
Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM, USA
Yu Mikami
Marsico Lung Institute/Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Tomas P. Carroll
Irish Centre for Genetic Lung Disease, RCSI Education and Research Centre, Beaumont Hospital, Dublin 9, Dublin, Ireland; Royal College of Surgeons in Ireland, Dublin, Ireland; Alpha-1 Foundation, Ireland
Kenichi Okuda
Marsico Lung Institute/Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Grace Hogan
Royal College of Surgeons in Ireland, Dublin, Ireland
Oliver J. McElvaney
Irish Centre for Genetic Lung Disease, RCSI Education and Research Centre, Beaumont Hospital, Dublin 9, Dublin, Ireland; Royal College of Surgeons in Ireland, Dublin, Ireland
Jennifer Clarke
Department of Anaesthesia and Critical Care, Beaumont Hospital, Dublin, Ireland; Royal College of Surgeons in Ireland, Dublin, Ireland
Natalie L. McEvoy
Department of Anaesthesia and Critical Care, Beaumont Hospital, Dublin, Ireland; Royal College of Surgeons in Ireland, Dublin, Ireland
Patrick W. Mallon
Department of Infectious Diseases, St Vincent's University Hospital, Dublin, Ireland; Centre for Experimental Pathogen Host Research (CEPHR), University College Dublin, Dublin, Ireland
Cormac McCarthy
Department of Respiratory Medicine, St Vincent's University Hospital, Dublin, Ireland; School of Medicine, University College Dublin, Dublin, Ireland
Ger Curley
Department of Anaesthesia and Critical Care, Beaumont Hospital, Dublin, Ireland; Royal College of Surgeons in Ireland, Dublin, Ireland
Matthew C. Wolfgang
Marsico Lung Institute/Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Richard C. Boucher
Marsico Lung Institute/Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Noel G. McElvaney
Irish Centre for Genetic Lung Disease, RCSI Education and Research Centre, Beaumont Hospital, Dublin 9, Dublin, Ireland; Royal College of Surgeons in Ireland, Dublin, Ireland
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 samplesInduction 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.
