Oisin 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
Claudie Gabillard-Lefort, 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. Electronic address: mmurphy@rcsi.ie
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
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, rish Centre for Genetic Lung Disease, RCSI Education and Research Centre, Beaumont Hospital, Dublin 9, Dublin, Ireland; Royal College of Surgeons in Ireland, Dublin, Ireland
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

Document Type

Article

Publication Date

3-1-2022

Abstract

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.

FUNDING: NIH Serological Sciences Network, National Heart, Lung, and Blood Institute and National Institute of Diabetes and Digestive and Kidney Diseases.

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