The suppressive effects of Mer inhibition on inflammatory responses in the pathogenesis of LPS-induced ALI/ARDS
The suppressive effects of Mer inhibition on inflammatory responses in the pathogenesis of LPS-induced ALI/ARDS
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DOI：
10.1126/scisignal.abd2533
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发表时间：
2022-03-08
影响因子：
7.3
通讯作者：
Ikezoe, Takayuki
中科院分区：
文献类型：
--
作者：
Fukatsu, Masahiko;Ohkawara, Hiroshi;Ikezoe, Takayuki
脓毒症引起的急性肺损伤(ALI)/急性呼吸窘迫综合征（ARDS）的发病机制尚未完全阐明。生长阻滞特异性6 （Gas6）通过与TAM家族的受体酪氨酸激酶Tyro3、Axl和Mer相互作用，具有显著的止血和减轻炎症的作用。在这里，我们发现严重脓毒症或脓毒性ALI/ARDS患者的血浆中Gas6和可溶性Mer浓度高于正常健康供者。为了确定Gas6-Mer轴是否在ALI/ARDS发病机制中起关键作用，我们研究了静脉注射选择性Mer抑制剂UNC2250对吸入LPS小鼠模型中脂多糖（LPS）诱导的ALI的影响。在lps诱导的ALI小鼠中，UNC2250显著抑制中性粒细胞和单核细胞向肺的浸润，增加Gas6和Mer蛋白的数量，严重的肺损伤，增加活性氧（ROS）的数量。在人肺主动脉内皮细胞中，LPS诱导内皮型一氧化氮合酶、血栓调节蛋白和血管内皮-钙粘蛋白的含量降低，而UNC2250可阻断这一过程。在人嗜中性粒细胞样细胞系HL-60细胞和小鼠单核/巨噬细胞系RAW264.7细胞中，UNC2250还抑制了lps依赖性的细胞增殖增加和细胞凋亡增强。这些数据为Mer抑制剂UNC2250作为治疗ALI/ARDS炎症反应的治疗试剂的潜在多重有益作用提供了见解。
The pathogenesis of sepsis-induced acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) has not yet been fully elucidated. Growth arrest-specific 6 (Gas6) has marked effects on hemostasis and reduces inflammation through its interaction with receptor tyrosine kinases of the TAM family: Tyro3, Axl, and Mer. Here, we found that plasma concentrations of Gas6 and soluble Mer were greater in patients with severe sepsis or septic ALI/ARDS compared with those in normal healthy donors. To determine whether the Gas6-Mer axis was critical in the pathogenesis of ALI/ARDS, we investigated the effects of intravenous administration of the selective Mer inhibitor UNC2250 on lipopolysaccharide (LPS)-induced ALI in mouse models subjected to inhalation of LPS. UNC2250 markedly inhibited the infiltration into the lungs of neutrophils and monocytes with increased amounts of Gas6 and Mer proteins, severe lung damage, and increased amounts of reactive oxygen species (ROS) in LPS-induced ALI in mice. In human pulmonary aortic endothelial cells, LPS induced decreases in the amounts of endothelial nitric oxide synthase, thrombomodulin, and vascular endothelial-cadherin, which was blocked by treatment with UNC2250. UNC2250 also inhibited the LPS-dependent increases in cell proliferation and enhanced apoptosis in HL-60 cells, a human neutrophil-like cell line, and RAW264.7 cells, a mouse monocyte/macrophage cell line. These data provide insights into the potential multiple beneficial effects of the Mer inhibitor UNC2250 as a therapeutic reagent to treat inflammatory responses in ALI/ARDS.