Open AccessInhibition of Caspase-1 with Tetracycline Ameliorates Acute Lung Injury
Author(s) -
Konrad Peukert,
Mario Fox,
Susanne Schulz,
C. Feuerborn,
Stilla Frede,
Christian Putensen,
Hermann Wrigge,
Beate M. Kümmerer,
Sascha David,
Benjamin Seeliger,
Tobias Welte,
Eicke Latz,
Dennis M. Klinman,
Christoph Wilhelm,
Folkert Steinhagen,
Christian Bode
Publication year - 2021
Publication title -
american journal of respiratory and critical care medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.272
H-Index - 374
eISSN - 1535-4970
pISSN - 1073-449X
DOI - 10.1164/rccm.202005-1916oc
Subject(s) - ards , inflammasome , medicine , tetracycline , lung , caspase 1 , inflammation , diffuse alveolar damage , immunology , pharmacology , acute respiratory distress , biology , antibiotics , microbiology and biotechnology
Rationale: Acute respiratory distress syndrome (ARDS) is a heterogeneous syndrome with a mortality of up to 40%. Precision medicine approaches targeting patients on the basis of 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, although 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 concentrations were quantified in BAL fluid from patients with ARDS. Tetracycline's effects on lung injury and inflammation were assessed in two mouse models of direct (pulmonary) acute lung injury, and its effects on IL-1β and IL-18 production were assessed by alveolar leukocytes 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: BAL fluid concentrations of IL-1β and IL-18 are significantly higher in patients with direct ARDS than those with indirect (nonpulmonary) ARDS. In experimental acute lung injury, 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 leukocytes from patients with direct ARDS. Conclusions: Tetracycline may be effective in the treatment of direct ARDS in patients with elevated caspase-1 activity. Clinical Trial registered with www.clinicaltrials.gov (NCT04079426).