ULINASTATIN PROTECTS AGAINST LPS-INDUCED ACUTE LUNG INJURY BY ATTENUATING TLR4/NF-KB PATHWAY ACTIVATION AND REDUCING INFLAMMATORY MEDIATORS
ULINASTATIN PROTECTS AGAINST LPS-INDUCED ACUTE LUNG INJURY BY ATTENUATING TLR4/NF-KB PATHWAY ACTIVATION AND REDUCING INFLAMMATORY MEDIATORS
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DOI：
10.1097/shk.0000000000001104
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发表时间：
2018-11-01
期刊：
影响因子：
3.1
通讯作者：
Chai, Yanfen
中科院分区：
文献类型：
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作者：
Cao, Chao;Yin, Chengfen;Chai, Yanfen
急性肺损伤（ALI）及其严重形式急性呼吸窘迫综合征仍然是重症监护病房发病和死亡的主要原因。乌司他丁（UTI）是一种丝氨酸蛋白酶抑制剂，具有抗炎特性，并被认为可调节脂多糖（LPS）诱导的脓毒症；因此，它现在被广泛用于治疗胰腺炎、脓毒症和感染性休克。Toll样受体4（TLR4）是一种重要的LPS信号受体，在先天免疫的激活中起关键作用。本研究的目的是探讨UTI是否通过降低TLR4表达来缓解ALI，并探索所涉及的潜在分子机制。雄性C56BL/6小鼠在气管内滴注LPS前1小时和后6小时静脉注射UTI。人肺上皮（BEAS - 2B）细胞在有或无UTI的情况下与LPS一起孵育。采用酶联免疫吸附测定法检测炎症细胞因子水平。进行蛋白质印迹分析以检测TLR4表达和核因子 - κB（NF - κB）激活的变化。UTI显著保护动物免受LPS诱导的ALI，降低肺湿/干重比、ALI评分、总细胞数、中性粒细胞、巨噬细胞、髓过氧化物酶活性和丙二醛含量，这些都是与肺组织损伤相关的因素。UTI治疗还显著降低了TLR4和其他促炎细胞因子的水平。此外，UTI显著减弱了LPS诱导的肺组织中TLR4蛋白表达和NF - κB激活的增加。同样，UTI显著减弱了LPS刺激的BEAS - 2B细胞中TLR4表达和NF - κB激活。这些发现表明UTI通过减弱TLR4/NF - κB通路的激活来改善LPS诱导的ALI。
Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome, remain the leading causes of morbidity and mortality in intensive care units. Ulinastatin (UTI), a serine protease inhibitor, possesses anti-inflammatory properties and has been suggested to modulate lipopolysaccharide (LPS)-induced sepsis; thus, it is now widely used in the treatment of pancreatitis, sepsis, and septic shock. Toll-like receptor 4 (TLR4), an essential LPS signaling receptor, plays a critical role in the activation of innate immunity. The aim of this study was to investigate whether UTI alleviates ALI by attenuating TLR4 expression and to explore the underlying molecular mechanisms involved. Male C56BL/6 mice were administered UTI intravenously 1 h before and 6 h after exposure to LPS by intratracheal instillation. Human lung epithelial (BEAS-2B) cells were incubated with LPS in the presence or absence of UTI. An enzyme-linked immunosorbent assay was used to detect levels of inflammatory cytokines. Western blot analysis was performed to detect changes in TLR4 expression and nuclear factor-kappa B (NF-kappa B) activation. UTI significantly protected animals from LPS-induced ALI, decreasing the lung wet/dry weight ratio, ALI score, total cells, neutrophils, macrophages, myeloperoxidase activity, and malondialdehyde content, factors associated with lung histological damage. UTI treatment also markedly attenuated levels of TLR4 and other proinflammatory cytokines. Furthermore, UTI significantly attenuated LPS-induced increases in TLR4 protein expression and NF-kappa B activation in lung tissues. Similarly, UTI markedly attenuated TLR4 expression and NF-kappa B activation in LPS-stimulated BEAS-2B cells. These findings indicate that UTI ameliorates LPS-induced ALI by attenuating the TLR4/NF-kappa B pathway activation.