Therapeutic application of NO scavenger and NO donor for endotoxin shock
Therapeutic application of NO scavenger and NO donor for endotoxin shock
批准号:
09557127
负责人:
MAEDA Hiroshi
金额:
$7.23万
依托单位:
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
项目状态:
已结题
起止时间:
1997 至 1999
中文摘要
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。在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,αI D21 I D 2-protease inhibitor(αI D 21 I D 2-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-nitrosylatedαI D 21 D 2-PI(S-NO-αI D 21 D 2 PI)。S-NO-αI D21 ii D2 PI 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-αI D21 ii D2 PI 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-αI D 21 I D 2 PI,may lead to further clinical application of S-NO-αI D 21 ii D 2 PI for treatment of various inflammatory and infectious diseases including endotoxin shock.Less:Less
英文摘要
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
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赤池孝章、前田浩: "「細胞工学」特集:多機能分子NOによる生体制御と病態(森正敬,井上正康編)"(株)秀潤社(東京)(in press). (2000)
Takaaki Akaike、Hiroshi Maeda:“‘细胞工程’专题:多功能分子 NO 的生物控制和病理学(由 Masataka Mori 和 Masayasu Inoue 编辑)” Shujunsha Co., Ltd.(东京)(2000 年出版)。 )
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D.C. Hooper, et al.: "Prevention of experimental allergic encephalitis by targeting nitric oxide and peroxynitrite: Implications for the treatment of multiple sclerosis."Proc. Natl. Acad. Sci. U.S.A.. 94. 2528-2533 (1997)
D.C. Hooper 等人:“通过一氧化氮和过氧亚硝酸盐预防实验性过敏性脑炎:对治疗多发性硬化症的影响”。
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H.Maeda 等人:“感染和癌症中的激肽释放酶激肽”免疫药理学。
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