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Cathepsin S Contributes to Lung Inflammation in Acute Respiratory Distress Syndrome.

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
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 bronchoalveolar lavage 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 levels 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, as 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.