Research on regulatory mechanism of inflammation by HO-1 and development of novel anti-inflammatory threrapy

HO-1炎症调节机制研究及新型抗炎治疗药物开发

• 批准号: 14570729
• 负责人: YACHIE Akihiro
• 金额: $ 2.5万
• 依托单位: KANAZAWA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570729/
• 关键词: heme oxygenase-1; monocyte; oxidative stress; inflammation; anti-inflammatory therapy; 単球:monocyte; ヘムオキシゲナーゼ1:HO-1; 炎症:inflammation; 川崎病:MCLS; インフルエンザ:influenza

Savere infection and shock syndromes are often associated with intense body reactions called macrophage activation syndrome, characteried by monocyte activation, hypercytokinemia, circulatory failure and multiple organ dysfunction.To prevent these deleterious consequenoes upon pathogen exposure, the body defense system has to be supplied not only with effective antigen-specific immune response, but at the same time with tightly controlled regulatory system of inflammation.Previous reports indicated that macrophages infiltrate into various organs in various inflammatory illnesses and they contribute to the pathogenesis of organ injury.But at the same time, it is suggested that mecrophages themselves play roles in counteracting inflammation locally.Heme oxygenase-1(HO-1) and its related products are the groups of key molecules produced by monocytes/macrophages to regulate excessive inflammatory reactions.We have previously shown that HO-1 production is rapidly induced in circulating mono … More cytes upon oxidative stress and a patient with HO-1 deficiency was associated with sustained inflammation throughout his life.These findings suggesed that monocytes play cardinal roles in controlling the level of inflammation during various inflammatory illnesses in vivo. In addition, GT repeat polymorphism within the promoter region of HO-1 gene is associated with the levels of induced HO-1 activity.Furthermore, epidemiological studies have shown that there exist strong correlation between the length of GT repeats and the incidence of multiple of inflammatory illnesses.These studies indicate that the levels of inducible HO-1 controls the intensity of inflammatory reaction elicited upon certain oxidative stresses.In this study regulatory mechanism of HO-1 production by circulating monocytes was analyzed and tried to darify the role of HO-1 in the pathogenesis of various inflammatory disorders.Based on these findings, further studies were performed to develop a novel therapeutic approach to counteract excessive inflammation, by modulating HO-1 production in vivo.It was shown in this study that circulating monocytes are the major producer of HO-1 both in vivo andin vitro.HO-1 production by activated monocytes was associated with phenotypical changes in monocytes during acute inflammation.HO-1 production was preferentially observed within a particular subpopulation of monocytes, indicating that it is possible to direct the development of anti-inflammatory therapy by manipulating the numbers and functions of This particular subpopulation of monocytes. Less

严重感染和休克综合征常伴有强烈的机体反应，称为巨噬细胞活化综合征，其特征为单核细胞活化、高细胞素血症、循环衰竭和多器官功能障碍。为了防止病原体暴露后的这些有害后果，身体防御系统不仅必须提供有效的抗原特异性免疫反应，同时还必须提供严格控制的炎症调节系统。以往的报道表明，巨噬细胞在各种炎症性疾病中浸润到各种器官，并参与器官损伤的发病机制。但同时，也提示巨噬细胞自身在局部对抗炎症中发挥作用。血红素加氧酶-1（Heme oxygenase-1, HO-1）及其相关产物是单核/巨噬细胞调节过度炎症反应的关键分子群。我们之前的研究表明，在循环单核细胞中，氧化应激会迅速诱导HO-1的产生，并且HO-1缺乏症患者一生中都会持续炎症。这些发现表明，单核细胞在体内各种炎症性疾病的炎症水平控制中起着重要作用。此外，HO-1基因启动子区域内的GT重复多态性与诱导的HO-1活性水平有关。此外，流行病学研究表明，GT重复序列的长度与多种炎症性疾病的发病率之间存在很强的相关性。这些研究表明，诱导HO-1的水平控制了某些氧化应激引起的炎症反应的强度。本研究分析了循环单核细胞产生HO-1的调控机制，试图阐明HO-1在各种炎性疾病发病机制中的作用。基于这些发现，我们进行了进一步的研究，以开发一种新的治疗方法，通过调节体内HO-1的产生来对抗过度炎症。本研究表明，在体内和体外循环单核细胞是HO-1的主要生产者。激活的单核细胞产生HO-1与急性炎症期间单核细胞的表型变化有关。HO-1的产生在特定的单核细胞亚群中被优先观察到，这表明有可能通过操纵这一特定单核细胞亚群的数量和功能来指导抗炎治疗的发展。少

项目成果

谷内江 昭宏: "ヘムオキシゲナーゼ1欠損症から学ぶもの"日本小児科学会雑誌. 106. 1380-1389 (2002)

Akihiro Yauchie：“我们可以从血红素加氧酶 1 缺乏症中学到什么”日本儿科学会杂志 106. 1380-1389 (2002)。

Yachie A, et al.: "Human heme oxygenas (HO)-1 deficienc and the oxidative injury of vascular endothelia cells."Kluwer Academic/Plenum Publishers, New York. 10 (2002)

Yachie A 等人：“人血红素氧合 (HO)-1 缺乏和血管内皮细胞的氧化损伤。”Kluwer Academy/Plenum Publishers，纽约。

Hori R, et al.: "Gene transfection of H25A mutant heme oxygenase-1 protects cells against hydroperoxide induce cytotoxicity."J.Biol.Chem.. 277. 10712-10718 (2002)

Hori R 等人：“H25A 突变血红素加氧酶-1 的基因转染可保护细胞免受氢过氧化物诱导的细胞毒性。”J.Biol.Chem.. 277. 10712-10718 (2002)

Yang Y, et al.: "Selective protection of renal epithelial cells by hem oxygenase(HO)-1 during stress-induced injury."Kidney Int.. 64. 1302-1309 (2003)

Yang Y 等人：“应激诱导损伤期间血红素加氧酶 (HO)-1 对肾上皮细胞的选择性保护。”Kidney Int.. 64. 1302-1309 (2003)

Balla J, et al.: "Haem, haem oxygenase and ferritin in vascular endothelial cell injury."Nephron Dial Transplant. Suppl 5. v8-v12 (2003)

Balla J 等人：“血管内皮细胞损伤中的血红素、血红素加氧酶和铁蛋白。”肾单位拨号移植。