Institute of Pharmacology, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 311400, China.
Department of Pulmonology and Endoscopy Center, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang 310052, China.
Bioorg Med Chem. 2021 Jan 15;30:115954. doi: 10.1016/j.bmc.2020.115954. Epub 2020 Dec 15.
Acute respiratory distress syndrome/chronic obstructive pulmonary disease (ARDS/COPD) is a diffuse inflammatory injury of the lung that is characterized by respiratory distress and vascular leakage and is caused by various factors. Although the treatment strategy for ARDS/COPD continues to be improved, it still lacks effective drugs. MCC950 is a potent and selective inhibitor ofthe nucleotide-binding oligomerization domain-like-receptor family pyrin domain-containing 3 (NLRP3) inflammasome. However, there have been no reports on the effects of MCC950 on lipopolysaccharide (LPS)-induced lung inflammation in mice. The objective of the present study was to evaluate the effects of MCC950 (given either intranasally or intraperitoneally) on inhibiting LPS-induced lung inflammation in mice. Acute lung inflammation was induced by intratracheal administration of LPS in ICR mice. The results showed that MCC950 at 50 mg/kg efficiently suppressed neutrophil lymphocytes (p < 0.001) and macrophage accumulation (p < 0.01) in bronchoalveolar lavage fluid (BALF) in LPS-instilled mice. In addition, hematoxylin and eosin (H&E) staining revealed that MCC950 at 50 mg/kg significantly inhibited pathological progress in the lung tissues (p < 0.01). Furthermore, treatment with MCC950 substantially reduced mRNA expression of IL-1β, IL-8, TGF-β1, and MMP-9 and also reduced protein levels of IL-1β, IL-18 and caspase-1 at 24 h after LPS instillation. The results of the present study indicate that MCC950 effectively inhibits LPS-induced lung inflammation in vivo, which can be considered for clinical translation.
急性呼吸窘迫综合征/慢性阻塞性肺疾病（ARDS/COPD）是一种弥漫性肺部炎症性损伤，其特征是呼吸窘迫和血管渗漏，由各种因素引起。尽管 ARDS/COPD 的治疗策略不断得到改善，但仍然缺乏有效的药物。MCC950 是一种有效的核苷酸结合寡聚化结构域样受体家族吡喃结构域包含蛋白 3（NLRP3）炎症小体的选择性抑制剂。然而，目前尚无关于 MCC950 对脂多糖（LPS）诱导的小鼠肺部炎症影响的报道。本研究旨在评估 MCC950（经鼻内或腹腔内给予）对抑制 LPS 诱导的小鼠肺部炎症的作用。通过气管内给予 LPS 诱导 ICR 小鼠急性肺炎症。结果表明，MCC950 50mg/kg 可有效抑制 LPS 诱导的小鼠支气管肺泡灌洗液（BALF）中性粒细胞淋巴细胞（p<0.001）和巨噬细胞积聚（p<0.01）。此外，苏木精和伊红（H&E）染色显示，MCC950 50mg/kg 可显著抑制肺组织的病理进展（p<0.01）。此外，MCC950 治疗可显著降低 LPS 诱导后 24 小时 IL-1β、IL-8、TGF-β1 和 MMP-9 的 mRNA 表达，并降低 IL-1β、IL-18 和半胱天冬酶-1 的蛋白水平。本研究结果表明，MCC950 可有效抑制 LPS 诱导的小鼠肺部炎症，可考虑用于临床转化。
