Therapeutic trial of inflammatory response by suppressing inflammatory mediators.

通过抑制炎症介质来治疗炎症反应的试验。

基本信息

批准号：
05670199
负责人：
OHKAWARA Susumu
金额：
$ 1.28万
依托单位：
KUMAMOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1994
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05670199/
关键词：
INFLAMMATION LEUKOCYTE INFILTRATION TISSURY INJURY IL-1beta TNFalpha IL-1ra NEUTROPHIL THERAPY 組織破壊 IL-1 IL-1ra TNFα LPS エンドトキシン尿酸結晶 TNF

项目摘要

We developed rabbit recombinant IL-1beta and IL-1ra, as well as antibodies against these cytokines. Using these materials and anti-rabbit TNFalpha, we investigated the role of IL-1 and TNFalpha in the pathogenesis of LPS-arthritis in rabbits. In the LPS-induced arthritis leukocyte infiltration peaked at 9 hrs while destruction of caltilagepeaked at 24 hrs of the inflammation. When 10mug of IL-1ra was injected simulataneously with LPS,the resulting neutrophil infiltration was inhibited by 70% during a whole observation period until 48 hrs and destruction of caltilage was completely prevented. Anti-TNFalpha(100mug) antibody also inhibited neutrophil infiltration by 70% and completely prevented destruction of caltilage. A combination of these two inhibitory substances produced furher suppression of neutrophil-infiltration by more than 90% and complete abrogation of caltilage-destruction. In the LPS-arthritis, production of IL-1 peaked at 6hr and its amount was 196.7 pg/joint and the most of the produced IL-1 was beta in form. Production of TNFalpha peaked at 2hr and its amount was 12.5 ng/joints.To investigate the role of neutrophils in the destruction of caltilate, we made neutropenic rabbits using i.v. nitrogen mustard. LPS induced no caltilage destruction and no production of IL-1beta in the neutropenic rabbits, while production of TNF-alpha was unchanges incomparison with non-leukopenic rabbits. Injection of IL-1beta (187 pg) into the leukopenic rabbits did not result in destruciton of caltilage. Thus, both TNFalpha and IL-1beta is the key mediators for induction of LPS-stimulated arthritis. But, these cytokines are not directly responsible for tissue damage. Next, we investigated a production which may involved in the destruction of caltilage and we found that neutrophilderived superoxide anion and elastase is responsible for destruction of caltilage in this inflammation.

我们开发了兔重组IL-1BETA和IL-1RA，以及针对这些细胞因子的抗体。使用这些材料和抗兔TNFALPHA，我们研究了IL-1和TNFALPHA在兔子中LPS关节炎发病机理中的作用。在LPS诱导的关节炎中，白细胞浸润在9小时的峰值上达到峰值，而在炎症的24小时内破坏了Caltialagepeakepeakepepa。当向LPS模拟注射10兆IL-1RA时，在整个观察期间，抑制了70％的中性粒细胞浸润，直到48小时并完全阻止了Caltialage的破坏。抗TNFALPHA（100mug）抗体也抑制了嗜中性粒细胞的浸润70％，并完全阻止了Caltilage的破坏。这两种抑制性物质的结合产生了急性抑制中性粒细胞浸润的抑制，并完全消除了钙化量的抑制作用。在LPS关节炎中，IL-1的产生在6小时达到峰值，其量为196.7 pg/关节，而生产的IL-1大部分是beta形式。 Tnfalpha的产生在2小时达到峰值，其量为12.5 ng/intims。为了研究中性粒细胞在Caltilate破坏中的作用，我们使用i.v.进行了中性粒细胞减少兔。氮芥末。 LPS在中性粒细胞减少兔中没有引起无钙的破坏，也没有产生IL-1Beta，而TNF-Alpha的产生与非白细胞减少兔子没有改变。将IL-1Beta（187 pg）注入白细胞减少兔子并没有导致caltialage的破坏。因此，TNFalpha和IL-1Beta都是诱导LPS刺激的关节炎的关键介体。但是，这些细胞因子并不直接负责组织损伤。接下来，我们调查了可能涉及钙化破坏的生产，我们发现嗜中性粒细胞的超氧化物阴离子和弹性蛋白酶在这种炎症中造成了钙钙的破坏。