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Inhibition of Caspase-1 with Tetracycline Ameliorates Acute Lung Injury

Peukert, Konrad; Fox, Mario; Schulz, Susanne; Feuerborn, Caroline; Frede, Stilla; Putensen, Christian; Wrigge, Hermann; Kümmerer, Beate Mareike; David, Sascha; Seeliger, Benjamin; Welte, Tobias; Latz, Eicke; Klinman, Dennis; Wilhelm, Christoph; Steinhagen, Folkert; Bode, Christian (2021). Inhibition of Caspase-1 with Tetracycline Ameliorates Acute Lung Injury. American Journal of Respiratory and Critical Care Medicine, 204(1):53-63.

Abstract

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.

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Intensive Care Medicine
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:1 July 2021
Deposited On:15 Apr 2021 13:01
Last Modified:25 Oct 2024 01:39
Publisher:American Thoracic Society
ISSN:1073-449X
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1164/rccm.202005-1916OC
PubMed ID:33760701
Full text not available from this repository.

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