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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.

我们以前曾报道过，白细胞毒素（Lx），一种环氧化物的亚油酸，激活肺血管内皮一氧化氮合酶和黄嘌呤氧化酶，产生一氧化氮和O-22 β-D2-，分别，潜在的损伤细胞。我们想知道Lx是否可以激活中性粒细胞和肺泡巨噬细胞，炎性吞噬细胞。我们还想知道Lx的环氧二醇是否真的对肺血管内皮细胞产生毒性作用，Lx是一种重要的细胞毒性物质。为了回答这些问题，我们用人中性粒细胞（PMN）、大鼠肺泡巨噬细胞（Mac）、人肺动脉内皮细胞（HPAEC）和中国仓鼠卵巢细胞（CHO）进行了实验。LX和LX-二醇通过百日咳毒素敏感的信号转导引起PMN的强趋化性，而不表达CDIIb或CD 18粘附分子或产生过氧化物。Lx对Mac无激活作用，但对NO和O-22-D2-的产生无明显影响，对TNFα的产生有轻微的促进作用，Lx及其二醇对HPAEC的损伤轻微，但当细胞内谷胱甘肽含量减少时，Lx的细胞毒性更强。另一种环氧化物TSO在CHO中也具有细胞毒性，而TSO诱导的细胞毒性在人可溶性环氧化物水解酶（hsEH）cDNA转染的CHO中减弱。由于TSO-二醇损伤谷胱甘肽缺失hsEH cDNA转染CHO，谷胱甘肽是对抗环氧-二醇诱导的损伤的必需物质。我们目前的研究表明Lx及其二醇的炎症激发作用，并进一步表明谷胱甘肽耗尽的病理状态，如急性肺损伤，包括ARDS，可能会增加Lx和Lx-二醇的细胞毒性。