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Protease-anti-protease compartmentalization in SARSCoV-2 ARDS: therapeutic implications

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journal contribution
posted on 28.03.2022, 14:09 by Oisin McelvaneyOisin Mcelvaney, Takanori Asakura, Suzanne L Meinig, Jose L Torres-Castillo, Robert S Hagan, Claudie Gabillard, Mark MurphyMark Murphy, Leigh B Thorne, Alain Borczuk, Emer ReevesEmer Reeves, Ross E Zumwalt, Yu Mikami, Tomas CarrollTomas Carroll, Kenichi Okuda, Grace HoganGrace Hogan, Oliver McElvaneyOliver McElvaney, Jennifer ClarkeJennifer Clarke, Natalie McEvoyNatalie McEvoy, Patrick W. Mallon, Cormac McCarthy, Gerard CurleyGerard Curley, Matthew C Wolfgang, Richard C Boucher, Noel G McElvaneyNoel G McElvaney
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

Health Research Board (HRB) Ireland Impact award 2021

Alpha 1 Foundation (US)

NIH Serological Sciences Network, grant U54CA260543-01

NIH National Heart, Lung, and Blood Institute (NHLBI) grants UH3 HL123645, R01 HL136961, and P01 HL108808

NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant P30 DK065988

History

Comments

The original article is available at https://www.sciencedirect.com/

Published Citation

McElvaney OF, et al. Protease-anti-protease compartmentalization in SARS-CoV-2 ARDS: therapeutic implications. EBioMedicine. 2022;77:103894.

Publication Date

21 February 2022

PubMed ID

35217407

Department/Unit

  • Beaumont Hospital
  • Medicine
  • Anaesthetics and Critical Care

Publisher

Elsevier B.V.

Version

  • Published Version (Version of Record)