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Development of anti-chemokine therapies and their application to the treatment of imflammatory lung diseases

抗趋化因子疗法的发展及其在炎症性肺部疾病治疗中的应用

基本信息

批准号：
08670678
负责人：
FUJISHIMA Seitaro
金额：
$ 1.41万
依托单位：
KEIO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

项目摘要

To determine the pathogenic roles of chemokines, especially interleukin-8 (IL-8), and to assess a novel therapeutic approach to inflammatory lung diseases, we developed two anti-chemokine therapies and examined their effects in vivo and in vitro. Ferst, we prepared anti-rabbit IL-8 monoclonal antibody and, to study its in vivo effect, we developed a rabbit model of acute respiratory distress syndrome (ARDS). In this model, reexpansion of the collapsed lung induced ARDS-like lung injury, which was associated with locally augmented production of IL-8. Furthermore, pretreatment with anti-IL-8 antibody significantly attenuated lung injury in this model. Since pretreatment with control IgG did not attenuate the lung injury, we concluded that the protective effect of the IL-8 antibody was attributable to its specific neutralizing effect of IL-8. This result also encourage us to proceed the development of anti-IL-8 antibody as a drug fpr various inflammatory lung diseases. We also designed and produced several antisense S-oligos and second generation oligos for IL-8 and examined their effects on the endotoxin-stimulated IL-8 production in MonoMac6 cells. However, none of them did significantly inhibit IL-8 production. This negative results may come from low DNA uptake by monocytic ccells or from the inappropriate three dimensional structure of these oligos. Since artificial additions to antisense DNA molecules occasionally induce nonspecific stimulation of the cells, it is possible to speculate that this nonspecific activation canceled the sequence-specific inhibitory effect of these oligos. With regard to antisense oligos, we concluded that it is necessary to introduce new method for the efficient uptake of oligo DNAs by the cells and to develop new oligos, which efficiently and specifically inhibit mRNA transcription for a certain time.

为了确定趋化因子，特别是白细胞介素-8 （IL-8）的致病作用，并评估炎症性肺病的新治疗方法，我们开发了两种抗趋化因子疗法，并检查了它们在体内和体外的效果。首先制备抗兔IL-8单克隆抗体，建立兔急性呼吸窘迫综合征（ARDS）模型，研究其在体内的作用。在该模型中，塌陷肺的再扩张诱导ards样肺损伤，这与局部IL-8的产生增加有关。此外，抗il -8抗体预处理可显著减轻该模型的肺损伤。由于对照IgG预处理不能减轻肺损伤，我们认为IL-8抗体的保护作用是由于其特异性中和IL-8的作用。这一结果也鼓励我们继续开发抗il -8抗体作为治疗各种炎症性肺部疾病的药物。我们还设计并生产了几种反义s -寡核苷酸和第二代IL-8寡核苷酸，并检测了它们对内毒素刺激的MonoMac6细胞IL-8产生的影响。然而，它们都没有显著抑制IL-8的产生。这种阴性结果可能来自单核细胞的低DNA摄取或这些寡核苷酸不适当的三维结构。由于人工添加到反义DNA分子中偶尔会诱导细胞的非特异性刺激，因此可以推测这种非特异性激活取消了这些寡核苷酸的序列特异性抑制作用。对于反义寡核苷酸，我们认为有必要引入新的方法使细胞有效摄取寡核苷酸，并开发新的寡核苷酸，使其在一定时间内有效和特异性地抑制mRNA转录。