Cathepsin S Contributes to Lung Inflammation in Acute Respiratory Distress Syndrome

Michael C. McKelvey, Anthony A. Abladey, Donna M. Small, Declan F. Doherty, Richard Williams, Aaron Scott, C. Arnold Spek, Keren S. Borensztajn, Leslie Holsinger, Robert Booth, Cecilia M. O'Kane, Daniel F. McAuley, Clifford C. Taggart*, Sinéad Weldon

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)
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Rationale: Although the cysteine protease cathepsin S has been implicated in the pathogenesis of several inflammatory lung diseases, its role has not been examined in the context of acute respiratory distress syndrome, a condition that still lacks specific and effective pharmacological treatments. 

Objectives: To characterize the status of cathepsin S in acute lung inflammation and examine the role of cathepsin S in disease pathogenesis. 

Methods: Human and mouse model BAL fluid samples were analyzed for the presence and activity of cathepsin S and its endogenous inhibitors. Recombinant cathepsin S was instilled directly into the lungs of mice. The effects of cathepsin S knockout and pharmacological inhibition were examined in two models of acute lung injury. Protease-activated receptor-1 antagonism was used to test a possible mechanism for cathepsin S-mediated inflammation. 

Measurements and Main Results: Pulmonary cathepsin S concentrations and activity were elevated in acute respiratory distress syndrome, a phenotype possibly exacerbated by the loss of the endogenous antiprotease cystatin SN. Direct cathepsin S instillation into the lungs induced key pathologies of acute respiratory distress syndrome, including neutrophilia and alveolar leakage. Conversely, in murine models of acute lung injury, genetic knockdown and prophylactic or therapeutic inhibition of cathepsin S reduced neutrophil recruitment and protein leakage. Cathepsin S may partly mediate its pathogenic effects via protease-activated receptor-1, because antagonism of this receptor abrogated cathepsin S-induced airway inflammation. 

Conclusions: Cathepsin S contributes to acute lung injury and may represent a novel therapeutic target for acute respiratory distress syndrome.

Original languageEnglish
Pages (from-to)769-782
Number of pages14
JournalAmerican Journal of Respiratory and Critical Care Medicine
Issue number7
Early online date24 Jan 2022
Publication statusPublished - 01 Apr 2022


  • Critical Care and Intensive Care Medicine
  • Pulmonary and Respiratory Medicine

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine


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