急性呼吸窘迫综合征
炎症体
医学
四环素
半胱氨酸蛋白酶1
炎症
弥漫性肺泡损伤
药理学
肺
免疫学
内科学
急性呼吸窘迫
生物
抗生素
微生物学
作者
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
标识
DOI:10.1164/rccm.202005-1916oc
摘要
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).
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