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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

基本信息

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

项目摘要

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）的过量产生有助于各种疾病的发病机制。例如，在内毒素休克中，低血压伴外周血管阻力降低现在已知是通过NO的过量产生介导的。在这种情况下，似乎合理的是，抑制NO的产生或清除NO将导致PTIO的治疗效果，PTIO是我们以前开发的一种NO清除剂，对抗内毒素休克。事实上，PTIO可以挽救处于病理状态的模型动物。然而，发现PTIO在生物系统中不一定稳定，特别是当静脉内给予动物时。在本研究中，为了克服PTIO的这一缺点，我们首先成功地制备了脂质体包裹的PTIO，其可以作为特异性NO清除剂用于治疗NO相关疾病，包括内毒素休克。相反，现在认识到NO在器官功能中的作用是 ...更多信息 10个具有保护和伤害效果的双重效果。据报道，NO的这些相反功能也适用于内毒素休克。因此，我们进一步发明了一种新的和有效的NO供体，以观察NO在休克发病机制中的细胞保护作用。为此目的，α-亚硝基D21亚硝基D2-蛋白酶抑制剂（α-NO-α-亚硝基D21亚硝基D2-PI）是人血浆中最丰富的丝氨酸蛋白酶抑制剂，被称为重要的防御导向急性期蛋白，在生理条件下S-亚硝基化，产生100% S-亚硝基化α-亚硝基D21亚硝基D2-PI（S-NO-α-亚硝基D21亚硝基D2-PI）。由此获得的S-NO-α β D21 β D2 PI具有多种药理学功能，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。此外，S-NO-α-D21-D2 PI在大鼠肝脏缺血再灌注损伤中显示出有效的抗中性粒细胞和抗氧化活性是相当重要的。S-NO-α β-D_（21）β-D_（21）β-D_（21）PI具有独特的生物学活性，有望在临床上进一步应用于包括内毒素休克在内的各种炎症和感染性疾病的治疗。少