| Research Abstract |
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
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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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