Protease-anti-protease compartmentalization in SARS-CoV-2 ARDS: Therapeutic implications

Area of Science:

• Pulmonary Medicine
• Immunology
• Infectious Diseases

Background:

• Interleukin-6 (IL-6) is elevated in SARS-CoV-2 infection and regulates acute-phase proteins like alpha-1 antitrypsin (AAT).
• AAT is a crucial lung anti-protease, and its balance with proteases is vital for lung health.

Purpose of the Study:

• To investigate the protease-anti-protease balance in SARS-CoV-2 acute respiratory distress syndrome (ARDS) compared to non-SARS-CoV-2 ARDS (nsARDS).
• To evaluate the effect of tocilizumab, an IL-6 receptor antagonist, on anti-protease defense in SARS-CoV-2 infection.

Main Methods:

• Measured AAT and neutrophil elastase (NE) levels and activity in plasma, airway tissue, and tracheal secretions (TA) from SARS-CoV-2 ARDS and nsARDS patients.
• Assessed AAT and IL-6 levels in moderate SARS-CoV-2 infection patients treated with standard care +/- tocilizumab.

Main Results:

• SARS-CoV-2 ARDS showed doubled plasma AAT levels and increased AAT in lung parenchyma.
• A protease-anti-protease imbalance was found in TA, with active NE and inactive AAT.
• Tocilizumab treatment down-regulated AAT levels during SARS-CoV-2 infection, suggesting IL-6's role in AAT induction.

Conclusions:

• A significant protease-anti-protease imbalance exists in the airways of SARS-CoV-2 ARDS patients.
• This airway imbalance represents a potential therapeutic target for anti-protease treatments in severe COVID-19.