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Inhibition of Caspase-1 with Tetracycline Ameliorates Acute Lung Injury.

RATIONALE
Acute respiratory distress syndrome (ARDS) is a heterogeneous syndrome with mortality up to 40%. Precision medicine approaches targeting patients based on their molecular phenotypes of ARDS might help to identify effective pharmacotherapies. The inflammasome-caspase-1 pathway contributes to the development of ARDS via IL-1β and IL-18 production. Recent studies indicate that tetracycline can be used to treat inflammatory diseases mediated by IL-1β and IL-18 while the molecular mechanism by which tetracycline inhibits inflammasome-caspase-1 signaling remains unknown.


OBJECTIVES
To identify patients with ARDS characterized by IL-1β and IL-18 expression and investigate the ability of tetracycline to inhibit inflammasome-caspase-1 signaling in ARDS.


METHODS
IL-1β and IL-18 levels were quantified in bronchoalveolar lavage fluid (BALF) from patients with ARDS. Tetracycline's effect on lung injury and inflammation were assessed in two mouse models of direct (pulmonary) acute lung injury (ALI) and on IL-1β and IL-18 production by alveolar leucocytes from patients with direct ARDS ex vivo. Murine macrophages were used to further characterize the effect of tetracycline on the inflammasome-caspase-1 pathway.


MEASUREMENTS AND MAIN RESULTS
BALF levels of IL-1β and IL-18 are significantly higher in patients with direct than those with indirect (non-pulmonary) ARDS. In experimental ALI, tetracycline significantly diminished lung injury and pulmonary inflammation by selectively inhibiting caspase-1-dependent IL-1β and IL-18 production leading to improved survival. Tetracycline also reduced the production of IL-1β and IL-18 by alveolar leucocytes from patients with direct ARDS.


CONCLUSIONS
Tetracycline may be effective in the treatment of direct ARDS in patients with elevated caspase-1 activity.