Molecular biological study of leukotoxin and its diol-induced cell activation and injury -experimental model of ARDS-

白细胞毒素及其二醇诱导的细胞活化和损伤的分子生物学研究-ARDS实验模型-

基本信息

批准号：
10670536
负责人：
ISHIZAKI Takeshi
金额：
$ 1.86万
依托单位：
Fukui Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

We previously reported that leukotoxin (Lx), an epoxide of linolate, which activated pulmonary vascular endothelial nitric oxide synthase and xanthine oxidase, producing nitric oxide and OィイD22ィエD2-respectively, potentially injured cells. We wondered whether Lx could activate neutrophils and alveolar macrophage, inflammatory phagocytic cells. We also wondered whether epoxide-diol of Lx, a Lx-diol which was reported to be an important cellular toxic substance, realy exert its toxicity in pulmonary vascular endothelial cells. To answer these questions we tested the experiments using human neutrophils (PMN), rat alveolar macrophage (Mac), human pulmonary artery endothelial cell (HPAEC) and chinese hamster ovary cell (CHO). Lx and Lx-diol caused potent chemotaxis of PMN via pertussis toxin-sensitive signal transduction without expression of CDIIb or CD18 adhesion molecules or production of peroxides. Lx, however, did not activate Mac in terms of production of nitric oxide or OィイD22ィエD2- with slight enhanced production of TNFα.Lx and its diol caused slight injury of HPAEC, however, when cell glutathione contents were depleted Lx exerted more potent cytotoxicity. TSO, another epoxide, also exerted cytotoxicity in CHO whereas TSO-induced cytotoxicity was attenuated in human soluble epoxide hydrolase (hsEH) cDNA transfected CHO. Since TSO-diol injured glutathione-depleted hsEH cDNA transfected CHO, glutathione was an essential substance against epoxide-diol-induced injury. Our current study suggests inflammation provoking effects of Lx and its diol and further suggests glutathione-depleted pathological state such an acute lung injury including ARDS may augment cytotoxicity of Lx and Lx-diol.

我们先前曾报道过，Liukotoxin（LX），一种环氧化物的环氧化物，它激活了肺血管内皮一氧化氮合酶和黄嘌呤氧化物，可产生一氧化氮和OII D22探索，并可能受到损伤。我们还想知道LX是否可以激活中性粒细胞和肺泡巨噬细胞，炎症性吞噬细胞。我们还想知道，LX的环氧二醇是一种LX-二醇，据报道是一个重要的细胞，可以回答这些问题，我们使用人类嗜中性粒细胞（PMN），大鼠肺泡巨噬细胞（MAC），人肺动脉内皮细胞（HPAEC）和中国的hamster hamster hamster hamster Ovary Ovary Ovary Ovare Ovare Ovare Ovare Ovare Ovare Ovare Ovare（Cho）测试了实验。 LX和LX-DIO通过百日咳毒素敏感的信号转导引起PMN的潜在趋化性，而无需表达CDIIB或CD18粘附分子或过氧化物的产生。然而，LX并未在一氧化氮或OI D22-的产生中激活MAC，而TNFα.lx的产生略有增强，而其DIOL及其二醇引起了HPAEC的轻微损伤，但是，当细胞谷胱甘肽含量耗尽时，LX导出了LX Export Export Export Export lx Export formant lx Export。 TSO是另一种环氧，也在CHO中执行了细胞毒性，而TSO诱导的细胞毒性在人类固体环氧化物水解酶（HSEH）cDNA转染的CHO中减弱。由于TSO二醇损伤耗尽的HSEH cDNA转染了CHO，因此谷胱甘肽是针对环氧二醇诱导的损伤的必不可少的物质。我们目前的研究表明，LX及其二醇的炎症引起的作用，并进一步表明，谷胱甘肽缺乏的病理状态，包括ARDS在内的急性肺损伤可能会增强LX和LX二醇的细胞毒性。