Department of Anesthesiology and Intensive Care Medicine.
Department of Anesthesiology, Intensive Care and Emergency Medicine, Pain Therapy, Bergmannstrost Hospital Halle, Halle, Germany.
Am J Respir Crit Care Med. 2021 Jul 1;204(1):53-63. doi: 10.1164/rccm.202005-1916OC.
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. 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. 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 . Murine macrophages were used to further characterize the effect of tetracycline on the inflammasome-caspase-1 pathway. 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. 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).
急性呼吸窘迫综合征 (ARDS) 是一种异质性综合征，死亡率高达 40%。基于 ARDS 患者的分子表型对患者进行精准医学治疗的方法可能有助于确定有效的药物治疗方法。炎性小体-半胱天冬酶-1 途径通过白细胞介素-1β 和白细胞介素-18 的产生导致 ARDS 的发生。最近的研究表明，四环素可用于治疗由白细胞介素-1β 和白细胞介素-18 介导的炎症性疾病，尽管四环素抑制炎性小体-半胱天冬酶-1 信号传导的分子机制尚不清楚。本研究旨在鉴定以白细胞介素-1β 和白细胞介素-18 表达为特征的 ARDS 患者，并研究四环素抑制 ARDS 中炎性小体-半胱天冬酶-1 信号的能力。通过 ARDS 患者的 BAL 液中定量白细胞介素-1β 和白细胞介素-18 的浓度。通过直接 ARDS 患者的肺泡白细胞评估四环素对肺损伤和炎症的影响，通过直接 ARDS 患者的肺泡白细胞评估四环素对白细胞介素-1β 和白细胞介素-18 产生的影响。进一步用鼠巨噬细胞来描述四环素对炎性小体-半胱天冬酶-1 途径的影响。与间接（非肺部）ARDS 患者相比，直接 ARDS 患者的 BAL 液中白细胞介素-1β 和白细胞介素-18 的浓度明显更高。在实验性急性肺损伤中，四环素通过选择性抑制半胱天冬酶-1 依赖性白细胞介素-1β 和白细胞介素-18 的产生，显著减轻肺损伤和肺部炎症，从而提高存活率。四环素还降低了直接 ARDS 患者肺泡白细胞中白细胞介素-1β 和白细胞介素-18 的产生。四环素可能对活性升高的 caspase-1 的直接 ARDS 患者的治疗有效。在 www.clinicaltrials.gov（NCT04079426）上注册了临床试验。
