Therapeutic application of NO scavenger and NO donor for endotoxin shock

NO清除剂和NO供体在内毒素休克的治疗中的应用

• 批准号: 09557127
• 负责人: MAEDA Hiroshi
• 金额: $ 7.23万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09557127/
• 关键词: endotoxin; NO; NO scavenger; nitrosothiol; cytoprotection; anti-apoptosis; anti-oxidant

It is now well conceivable that overproduction of nitric oxide (NO) contributes to the pathogenesis of various diseases. In endotoxic shock, for example, hypotension with decreased peripheral vascular resistance is now known to be mediated through excessive production of NO. In this context, it seems reasonable that inhibition of NO production or scavenging of NO will result in therapeutic effect of PTIO, an NO scavenger we developed previously, against endotoxin shock. In fact, PTIO can rescue such model animals in pathological condition. It is, however, found that PTIO was not necessarily stable in biological systems particularly when administered intravenously to the animals. In the present study, to overcome this drawback of PTIO, we first successfully prepared liposome-encapsulated PTIO, which can be applicable as a specific NO scavenger for the treatment of NO-related diseases including endotoxin shock. In contrast, it is now recognized that the role of NO in organ function is of … More ten dual with protective and injurious effects. These opposing functions of NO are also reported for endotoxin shock. We thus further invented a novel and potent NO donor to see the cytoprotective effect of NO in shock pathogenesis. For this purpose, αィイD21ィエD2-protease inhibitor (αィイD21ィエD2-PI), which is the most abundant serine protease inhibitor in human plasma known as an important defense-oriented acute phase protein, is S-nitrosylated under physiological conditions, yielding 100% S-nitrosylatedαィイD21ィエD2-PI (S-NO-αィイD21ィエD2PI). S-NO-αィイD21ィエD2PI thus obtained has multiple pharmacological functions, including potent antimicrobial activity and inhibition of cell apoptosis, and sustaining blood flow and organ functions. Also, it is of considerable importance that S-NO-αィイD21ィエD2PI shows a potent anti-neutrophil and anti-oxidant activities during ischemia-reperfusion injuries in rat livers. The present evidence, concerning the unique biological activities of S-NO-αィイD21ィエD2PI, may lead to further clinical application of S-NO-αィイD21ィエD2PI for treatment of various inflammatory and infectious diseases including endotoxin shock. Less

现在可以想象，一氧化氮（NO）的过量产生会导致各种疾病的发病机制，例如，现在已知外周血管阻力降低的低血压是通过一氧化氮的过量产生而介导的。抑制NO产生或清除NO会导致我们之前开发的NO清除剂PTIO对抗内毒素休克的治疗效果似乎是合理的。事实上，PTIO可以挽救这种病理模型动物。然而，我们发现PTIO在生物系统中不一定稳定，特别是当静脉注射给动物时，为了克服PTIO的这一障碍，我们首先成功地制备了可应用的脂质体封装的PTIO。作为一种特定的 NO 清除剂，用于治疗包括内毒素休克在内的 NO 相关疾病。相比之下，NO 在器官功能中的作用具有双重作用，具有保护性和损伤性作用。还因此，我们进一步发明了一种新型有效的 NO 供体，以观察 NO 在休克发病机制中的细胞保护作用，为此，αD21D2-蛋白酶抑制剂（αD21D2-PI）是人类中最丰富的丝氨酸蛋白酶抑制剂。血浆被称为重要的防御型急性期蛋白，在生理条件下被 S-亚硝基化，产率 100% S-亚硝基化αD21D2-PI（S-NO-αD21D2PI）因此具有多种药理功能，包括有效的抗菌活性和抑制细胞凋亡，以及维持血流和器官功能。 S-NO-αD21D2PI 显示出有效的抗中性粒细胞和抗氧化剂大鼠肝脏缺血再灌注损伤期间的活性 目前的证据表明，S-NO-αD21D2PI 具有独特的生物活性，可能会导致 S-NO-αD21D2PI 进一步临床应用，用于治疗包括内毒素休克在内的各种炎症和感染性疾病。较少的

项目成果

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