Ibrutinib protects against acute lung injury via inhibiting NLRP3/Caspase-1 in septic mice model.
Ibrutinib protects against acute lung injury via inhibiting NLRP3/Caspase-1 in septic mice model.
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DOI：
10.1016/j.molimm.2022.11.006
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发表时间：
2022-11
影响因子：
3.6
通讯作者：
Huiming Tang;Hui Li;Yang Yang-Yang;Man-li Tang;Zhanfei Li;Xiangjun Bai;Yuchang Wang
中科院分区：
文献类型：
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作者：
Huiming Tang;Hui Li;Yang Yang-Yang;Man-li Tang;Zhanfei Li;Xiangjun Bai;Yuchang Wang
急性肺损伤是重症监护室脓毒症的严重并发症，死亡率高。越来越多的证据表明，Ibrutinib是一种布鲁顿酪氨酸激酶抑制剂，在许多炎症相关疾病中起着关键作用。但其在脓毒症致急性肺损伤中的治疗作用及机制尚不清楚。本研究对雄性C57BL/6 J小鼠进行盲肠结扎穿刺（CLP），建立小鼠脓毒症模型。Ibrutinib （50 mg/kg/d）于CLP前1天灌胃，每天1次，连续3天。第4天，小鼠在CLP诱导前2 h给予一剂依鲁替尼，24 h后给予另一剂。72h对肺组织进行组织病理学检查，ELISA法检测支气管肺泡灌洗液（BALF）中髓过氧化物酶（MPO）、白细胞介素(IL)−6、TNF-α、IL-1β、IL-18水平。Western blotting检测焦亡相关蛋白的表达。结果表明，伊鲁替尼治疗可显著改善小鼠预后，减轻肺组织病理学损伤和炎症反应。此外，伊鲁替尼显著抑制脓毒症小鼠肺组织中焦亡相关蛋白NLRP3、Caspase-1、Gasdermin D （GSDMD）、IL-1β和IL-18的表达。综上所述，我们的研究结果表明，伊鲁替尼对脓毒症小鼠肺损伤具有保护作用，抑制肺组织焦亡的激活，可能是一种潜在的治疗脓毒症肺损伤的方法。
Acute lung injury is a severe complication of sepsis with high mortality in ICU. Increasing evidences have showed that Ibrutinib, a Bruton's Tyrosine kinase inhibitor, plays a critical role in numerous inflammation-related diseases. However, its therapeutic effect and mechanism in sepsis induced acute lung injury remain unclear. In this study, cecal ligation puncture (CLP) was performed on male C57BL/6 J mice to establish a mouse model of sepsis. Ibrutinib (50 mg/kg/d) was administered by gavage 1 day before CLP, once a day, for 3 consecutive days. on the fourth day mice were given one dose of ibrutinib 2 h before CLP induction, and another dose was given 24 h later. Histopathological examination of lung tissues was performed at 72 h. The levels of myeloperoxidase (MPO), interleukin (IL)− 6, TNF-α, IL-1β and IL-18 in bronchoalveolar lavage fluid (BALF) were determined by ELISA. Western blotting was used to detect the expression of pyroptosis related proteins. The results showed that Ibrutinib treatment significantly improved the prognosis of mice and mitigated the lung histopathological injury and inflammatory response. Moreover, Ibrutinib significantly inhibited the expression of pyroptosis related proteins (NLRP3, Caspase-1, Gasdermin D (GSDMD), IL-1β and IL-18) in the lung tissues of sepsis mice. In conclusion, our results suggest that Ibrutinib exerted protective effects against lung injury of septic mice and inhibited the activation of pyroptosis in lung tissue, which may be a potential treatment for sepsis induced lung injury.