Division of Pulmonary Diseases, State Key Laboratory of Biotherapy, and Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, China; Department of Intensive Care Unit, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
Institute of Digestive Surgery, State Key Laboratory of Biotherapy of China, West China Hospital of Sichuan University, Chengdu, China.
Eur J Pharmacol. 2022 Jul 5;926:175047. doi: 10.1016/j.ejphar.2022.175047. Epub 2022 May 21.
There is a dearth of effective pharmacotherapies for sepsis-induced acute lung injury/acute respiratory distress syndrome (ALI/ARDS) to which oxidative stress and excessive inflammation are major contributors. We hypothesized that fudosteine, a cysteine derivative, may protect against sepsis-induced ALI/ARDS given its anti-oxidant capacity. This study aimed to investigate the effects and mechanisms of fudosteine in a mouse model of sepsis-induced ALI. Sepsis was induced by cecal ligation and puncture (CLP). The intragastrical administration of fudosteine (25 mg/kg, 50 mg/kg, and 100 mg/kg) dose-dependently decreased proinflammatory cytokine levels in bronchoalveolar lavage fluid (BALF) and serum and reduced BALF/serum albumin and lung wet/dry weight ratios in septic mice. The lung injury score was significantly lowered by fudosteine [e.g., 0.18 ± 0.03 (100 mg/kg) vs. 0.42 ± 0.03 (CLP), P < 0.0001]. Fudosteine also reduced the biomarkers of lung epithelial injury in BALF and markedly improved oxidative stress indicators in lung tissues [e.g., malondialdehyde: 337.70 ± 23.78 (100 mg/kg) vs. 686.40 ± 28.36 (CLP) nmol/mg protein, P < 0.0001]. Lung tissue transcriptomics analyses revealed suppressed inflammatory responses and oxidative stress with fudosteine and the involvement of the inflammasome and pyroptosis pathways. Western blot analyses indicated that fudosteine inhibited the sepsis-induced activation of gasdermin D (GSDMD) and caspase-1 and the upregulation of thioredoxin-interacting protein (TXNIP), nucleotide-binding domain, leucine-rich repeat-containing receptor, pyrin domain-containing-3 (NLRP3), and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC). Fudosteine therefore protects against sepsis-induced ALI in mice, and the inhibition of pyroptosis via the TXNIP/NLRP3/GSDMD pathway may be an underlying mechanism.
目前针对脓毒症引起的急性肺损伤/急性呼吸窘迫综合征（ALI/ARDS），缺乏有效的药物治疗方法，而氧化应激和过度炎症是其主要原因。我们假设半胱氨酸衍生物福多司坦可能通过其抗氧化能力来预防脓毒症引起的 ALI/ARDS。本研究旨在探讨福多司坦在脓毒症诱导的 ALI 小鼠模型中的作用和机制。通过盲肠结扎和穿孔（CLP）诱导脓毒症。福多司坦（25mg/kg、50mg/kg 和 100mg/kg）的胃内给药剂量依赖性地降低了脓毒症小鼠支气管肺泡灌洗液（BALF）和血清中的促炎细胞因子水平，并降低了 BALF/血清白蛋白和肺湿/干重比。福多司坦显著降低了肺损伤评分[例如，0.18±0.03（100mg/kg）vs. 0.42±0.03（CLP），P<0.0001]。福多司坦还降低了 BALF 中肺上皮损伤的生物标志物，并显著改善了肺组织中的氧化应激指标[例如，丙二醛：337.70±23.78（100mg/kg）vs. 686.40±28.36（CLP）nmol/mg 蛋白，P<0.0001]。肺组织转录组学分析显示，福多司坦抑制了炎症反应和氧化应激，涉及炎症小体和细胞焦亡途径。Western blot 分析表明，福多司坦抑制了脓毒症诱导的 gasdermin D（GSDMD）和 caspase-1 的激活以及硫氧还蛋白相互作用蛋白（TXNIP）、核苷酸结合域、富含亮氨酸重复受体、pyrin 域包含 3（NLRP3）和含有半胱氨酸募集域的凋亡相关斑点样蛋白（ASC）的上调。因此，福多司坦可预防小鼠脓毒症引起的 ALI，通过 TXNIP/NLRP3/GSDMD 途径抑制细胞焦亡可能是其潜在机制。
