State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin 300353, People's Republic of China; Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin 300457, People's Republic of China.
Tianjin Jikun Technology Co., Ltd., Tianjin 301700, People's Republic of China.
Int Immunopharmacol. 2022 Oct;111:109138. doi: 10.1016/j.intimp.2022.109138. Epub 2022 Aug 13.
Acute lung injury (ALI) is a disease characterized by pulmonary diffusion dysfunction and its exacerbation stage is acute respiratory distress syndrome (ARDS), which may develop to multiple organ failure and seriously threatens human health. ALI has high mortality rates and few effective treatments, thus effective protection measures for ALI are becoming increasingly important. Macrophages play a key regulatory role in the pathogenesis of ALI, and the degree of macrophage polarization is closely related to the severity and prognosis of ALI. In this study, we evaluated the effects of Zanubrutinib (ZB), a BTK small molecule inhibitor approved by the FDA for the treatment of cell lymphoma, on macrophage polarization and acute lung injury. In the in vivo study, we constructed a mouse model of Lipopolysaccharide (LPS)-induced acute lung injury and found that ZB could improve the acute injury of mouse lungs by inhibiting the secretion of proinflammatory factors and promoting the secretion of anti-inflammatory factors, reduce the number of inflammatory cells in alveolar lavage fluid, and then alleviate the inflammatory response. In vivo and in vitro studies have shown that ZB could inhibit the M1 macrophage polarization and promote the M2 macrophage polarization. Subsequent mechanistic studies revealed that ZB could inhibit the macrophage M1 polarization via targeting BTK activation and inhibiting JAK2/STAT1 and TLR4/MyD88/NF-κB signaling pathways, and promote the macrophage M2 polarization by promoting the activation of STAT6 and PI3K / Akt signaling pathways. In summary, ZB has shown therapeutic effect in LPS-induced acute lung injury in mice, which provides a potential candidate drug to treat acute lung injury.
急性肺损伤（ALI）是一种以肺弥散功能障碍为特征的疾病，其加重期为急性呼吸窘迫综合征（ARDS），可能发展为多器官衰竭，严重威胁人类健康。ALI 死亡率高，治疗方法有限，因此，寻找有效的 ALI 保护措施变得越来越重要。巨噬细胞在 ALI 的发病机制中起关键的调节作用，巨噬细胞极化的程度与 ALI 的严重程度和预后密切相关。在本研究中，我们评估了 FDA 批准用于治疗细胞淋巴瘤的 BTK 小分子抑制剂泽布替尼（ZB）对巨噬细胞极化和急性肺损伤的影响。在体内研究中，我们构建了脂多糖（LPS）诱导的急性肺损伤小鼠模型，发现 ZB 通过抑制促炎因子的分泌和促进抗炎因子的分泌来改善小鼠肺部的急性损伤，减少肺泡灌洗液中炎症细胞的数量，从而减轻炎症反应。体内和体外研究均表明，ZB 可以抑制 M1 型巨噬细胞极化，促进 M2 型巨噬细胞极化。随后的机制研究表明，ZB 可以通过靶向 BTK 激活并抑制 JAK2/STAT1 和 TLR4/MyD88/NF-κB 信号通路来抑制巨噬细胞 M1 极化，通过促进 STAT6 和 PI3K/Akt 信号通路的激活来促进巨噬细胞 M2 极化。总之，ZB 对 LPS 诱导的急性肺损伤小鼠具有治疗作用，为治疗急性肺损伤提供了一种潜在的候选药物。
