Analyses of pathophysiological functions of prostaglandin E synthases as a potential target for novel anti-inflammatory drugs

前列腺素E合酶作为新型抗炎药物潜在靶点的病理生理功能分析

基本信息

批准号：
18390033
负责人：
MURAKAMI Makoto
金额：
$ 11.21万
依托单位：
Tokyo Metropolitan Organization for Medical Research
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390033/
关键词：
PGE_2 PGE_2 synthase knockout mouse cancer inflammation arachidonic acid metabolism cyclooxygenase phospholipase A_2

项目摘要

In this study, we examined the pathophysiological roles of PGE_2 synthase (mPGES-1), a terminal PGE_2-biosynthetic enzyme in the arachidonic acid metabolism, using mPGES-1 knockout mice.1. mPGES-1 and cancer : Luwis lung carcinoma (LLC) cells stably overexpressing mPGES-1 proliferated more rapidly in vitro and, when implanted into C57BL/6 mice, formed larger and more subcutaneous tumors and lung metastatic foci than did parental cells. Conversely, mPGES-knockdown LLC cells produced smaller and fewer tumors in implanted mice mPGES-1-null mice implanted with LLC cells showed resistance to tumor growth and metastasis associated with reduced angiogenesis compared with replicate wild-type mice Moreover, azoxymethanie-induced colon carcinogenesis was markedly reduced in mPGES-1-null mice relative to that in wild-type mice These results indicate that mPGES-1 expressed in tumor cells as well as in host tissues participates in tumorigenesis.2. mPGES-1 and inflammation : In carageenan- and thioglycolate-induced peritonitis models, leukocyte infiltration was markedly mitigated in mPGES-1-deficient mice as compared with that m control mice.3. mPGES-1 and bone : mPGES-1 deficiency was associated with impaired fracture healing, but not with bone loss or osteoarthritis, in mouse models of skeletal disorders.4. mPGES-1 and colitis : Dextran sulfate-induced colitis (a model of inflammatory bowel disease), as evaluated by intestinal histology, bleeding and cytokine expression, was significantly exacerbated in mPGES-1 knockout mice compared with control mice.Thus, novel drugs that could inhibit mPGES-1 would be useful for treatments of cancer and inflammation, yet they might have some adverse effects on bone and gastrointestinal tract.

在这项研究中，我们使用MPGES-1基因敲除小鼠研究了PGE_2合酶（MPGES-1）的病理生理作用，PGE_2合酶（MPGES-1）（一种末端PGE_2-生物合成酶在花生四烯酸代谢中。1。 MPGES-1和癌症：Luwis肺癌（LLC）细胞稳定地过表达MPGES-1的细胞在体外更快地增殖，并且当植入C57BL/6小鼠中时，形成比植物细胞形成更大的皮下肿瘤和更大的皮下肿瘤和肺转移灶。相反，在植入的小鼠MPGES-1-NULL小鼠中植入LLC细胞的MPGES-KENOCKDOWN LLC细胞在植入的小鼠中产生较小和较少的肿瘤，与复制性野生型小鼠相比，与血管生成相比，与血管生成减少相关的肿瘤生长和转移的耐药性相对于野生型小鼠的MPGES-1-NULL小鼠在MPGES-1-NULL小鼠中显着降低，这些结果表明，在肿瘤细胞和宿主组织中表达的MPGES-1参与肿瘤发生。2。 MPGES-1和炎症：与该M对照小鼠相比，在MPGES-1缺陷型小鼠中明显缓解白细胞浸润的白细胞浸润。 MPGES-1和骨：MPGES-1缺乏症与骨骼疾病的小鼠模型中的骨折愈合受损，但与骨质流失或骨关节炎有关。4。 MPGES-1和结肠炎：硫酸葡萄糖诱导的结肠炎（一种通过肠道组织学，出血和细胞因子表达评估的炎性肠病模型）在MPGES-1基因敲除小鼠中显着加剧。与对照小鼠相比。可能抑制MPGES-1对于癌症和炎症的治疗很有用，但它们可能会对骨骼和胃肠道有一些不利影响。