BML-111 attenuates acute lung injury in endotoxemic mice.
BML-111 attenuates acute lung injury in endotoxemic mice.
复制标题
DOI：
10.1016/j.jss.2015.09.005
复制
发表时间：
2016-02
期刊：
影响因子：
--
通讯作者：
Min Tang;Lin Chen;Bo Li;Yaxin Wang;Sheng-nan Li;Aiqing Wen;S. Yao;Y. Shang
中科院分区：
文献类型：
--
作者：
Min Tang;Lin Chen;Bo Li;Yaxin Wang;Sheng-nan Li;Aiqing Wen;S. Yao;Y. Shang
背景：BML-111是一种脂氧素受体激动剂，在多种肺损伤模型中具有保护作用。方法采用C57BL/6小鼠和人脐静脉内皮细胞(HUVECs)，观察BML-111对小鼠肺损伤的影响。雄性C57BL/6小鼠腹腔注射生理盐水、BML-111和/或脂氧素受体拮抗剂Boc-2。然后，给予脂多糖(LPS)或生理盐水。肺损伤通过肺组织和支气管肺泡灌洗液中中性粒细胞浸润、肺内皮细胞通透性和炎性细胞因子的病理组织学检查来评估。HUVEC在与内毒素孵育24小时前加入或不加入BML-111，BOC-2也被检测为一种新的BML-111抑制剂。Transwell法检测血管内皮细胞通透性。结果BML-111能显著提高小鼠存活率，减轻体重减轻，减轻肺组织病理改变，抑制中性粒细胞浸润和促炎细胞因子的产生，减轻血管内皮细胞的高通透性。BML-111可上调脂多糖诱导的肺组织和血管内皮细胞连接蛋白的表达。此外，BML-111还抑制Akt、ERK1/2和p38 MAPK信号通路的激活。结论BML-111通过上调连接蛋白的表达，减轻内毒素血症小鼠的肺损伤，减轻内皮细胞的高通透性。
BackgroundBML-111 is a lipoxin receptor agonist that has protective effects in various lung injury models. We tried to elucidate whether BML-111 could mitigate lung injury in a mouse model of endotoxemia and endothelial hyperpermeabilityin vitro.MethodsThe effect of BML-111 on lung injury was evaluated using C57BL/6 mice and human umbilical vein endothelial cells (HUVECs). Male C57BL/6 mice were intraperitoneally injected with normal saline, BML-111, and/or the lipoxin receptor antagonist Boc-2. Then, either lipopolysaccharide (LPS) or normal saline was given intraperitoneally. Lung injury was assessed by a pathohistologic examination for neutrophil infiltration, pulmonary endothelial permeability, and inflammatory cytokines in lung tissue and bronchoalveolar lavage fluid. HUVECs were treated with or without BML-111 before incubation with LPS for 24 h. Boc-2 was also tested as a novel inhibitor of BML-111. A Transwell assay was used to evaluate the permeability of HUVECs. Junction protein expression was also assessed.ResultsBML-111 significantly improved the mouse survival rate, reduced body weight loss, attenuated the pulmonary pathologic changes, inhibited neutrophil infiltration and proinflammatory cytokine production, and mitigated endothelial hyperpermeability. The decreased expression of junction proteins induced by LPS in lung tissue and endothelial cells were upregulated by BML-111. In addition, BML-111 inhibited the activation of the Akt, ERK1/2, and p38 MAPK signaling pathways. However, the beneficial effects of BML-111 were abolished by Boc-2.ConclusionsBML-111 attenuated lung injury in endotoxemic mice and mitigated endothelial hyperpermeability by upregulating the expression of junction proteins.