Cathepsin S as a mediator of acute lung inflammation

Free and active cathepsin S (CTSS) is a known feature of chronic inflammatory lung conditions such as cystic fibrosis. However, a role for this potent protease in acute lung inflammation, such as that seen in the Acute Respiratory Distress Syndrome (ARDS), has not previously been demonstrated. ARDS is characterised by the flooding of the alveoli with leukocytes and protein-rich oedema. Importantly, there are no effective pharmacological treatments for ARDS. We hypothesise that CTSS plays a role in the pathogenesis of ARDS, namely the recruitment of neutrophils to the lung and subsequent tissue damage, and therefore represents a viable therapeutic target. CTSS levels and activity are significantly elevated in bronchoalveolar lavage fluid (BALF) from ARDS patients compared to healthy volunteer BALF. This finding was recapitulated in an endotoxin-mediated murine model of acute lung injury. In this model, genetic and pharmacological knockdown of CTSS significantly decreased BALF total cell and neutrophil counts. CTSS inhibitor-treated mice also showed decreased protein leakage in to the alveolar space, significantly lowered lung weight/body weight ratios and decreased overall weight loss post-injury. These findings suggest a role for CTSS in acute lung inflammation and highlight the potential of CTSS inhibition in mitigating key pathologies of ARDS.