Heme oxygenase-1 deficiency and failure of human defense mechanisms against generalized chronic inflammation

血红素加氧酶-1 缺乏和人体针对全身慢性炎症的防御机制失败

• 批准号: 17390298
• 负责人: KOIZUMI Shoichi
• 金额: $ 10.41万
• 依托单位: Kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390298/
• 关键词: Heme omenase; Inflammation; Coagulation; fibrinolvsis system; Monnsvts; Endothelial cell; Vasculitis; CD163; Renal tubular enitherial cell; ヘムオキシゲナーゼ1; ヘム; 炎症防御; ヒトHO-1欠損症; HO; HO-1

Heme oxygenase (HO) is the rate-limiting enzyme that adds an oxygen molecule to the porphyrin ring of heme, thereby catalyzing the oxidation of heme to biliverdin/ bilirubin, free iron, and carbon monoxide (CO). By producing these metabolites, HO plays a crucial role in humans as a defense factor against a variety of oxidative stresses. The first case of human HO - 1 deficiency was reported by Yachie, et. Al. in our laboratory in 1999. A series of clinical and laboratory investigation of the patient with HO-1 deficiency revealed that (1) The boy completely lacked HO-1, genetically having a two-base-pair deletion in exon 3 of the paternal allele of the gene and a deletion of exon 2 of the maternal allele with genomic exon-deletion (1,730bp) mediated by Alu-Alu, recombination. (2) Dysfunction of both monocytes and endothelial cells was remarkably demonstrated. (2) External continuous stresses triggered excessive systemic inflammatory reactions and marked abnormalities of the coagulation/ … More fibrinolysis system, resulting finally in exhaustion of immune and coagulation system. (3) Morphological abnormality of monocytes and significant reduction of their surface molecules resulted in a markedly impaired phagocytosis of monocytes. Furthermore, the selective expansion of a CD16+++, CCR2- subpopulation of monocytes that preferentially produced HO-1 mRNA was shown during the acute phase of infections including both bacterial and viral infections. HO-1 production by alveolar macrophages in childhood pulmonary hypertension correlated with overexpression of CD1G3 surface molecules was also demonstrated. (4) Progressive renal tubulointerstitial injury was remarkable in the patient with HO-1 deficiency. Enhanced production of HO-lin proximal tubular epithelial cells as compared with mesangial cells was shown in variety of renal biopsy specimen as well as in vitro experiment. Recently HO-1 production by urinary tract cells and evaluation of tubulointestinal injury of the kidney was investigated by MA analysis of urinary sediments. Detailed analysis of HO-I deficiency may offer a valuable tool to understand the pathogenesis of and to develop a novel therapeutic approach to systemic inflammatory illnesses. Less

血红素氧化酶（HO）是限制速率的酶，可在血红素的卟啉环中添加氧分子，从而催化血红素到双脂蛋白/胆红素，游离铁和一氧化碳（CO）的氧化。通过产生这些代谢产物，HO在人类中起着至关重要的作用，是针对多种氧化应激的防御因素。 Yachie等报道了人类HO -1缺陷的第一个病例。 al。在1999年我们的实验室中。对HO-1缺乏症患者的一系列临床和实验室研究表明，（1）男孩完全缺乏HO-1，通常在基因的家属等位基因的外显子3中具有两种基本对的缺失，而载体等位基因2的外显子删除的Genomic Exon-Deletion-Deletion-Delet-Delet-Delet-Delet-Deletrue（1,1,730bp）均具有。 （2）明显证明了单核细胞和内皮细胞的功能障碍。 （2）外部连续应力引发了过度的全身性炎症反应，并引发了凝结的异常/……更多的纤维蛋白溶解系统，最终导致免疫和凝结系统耗尽。 （3）单核细胞的形态异常及其表面分子的显着降低导致单核细胞的吞噬作用显着受损。此外，在包括细菌和病毒感染在内的急性感染期间，显示了CD16 +++的选择性扩展，CCR2的单核细胞的CCR2亚群。还证明了肺泡巨噬细胞在儿童肺动脉高压中与CD1G3表面分子的过表达相关的HO-1。 （4）HO-1缺乏症患者的进行性肾结构性造成损伤是显着的。与肾小球细胞相比，在各种肾脏活检标本以及体外实验中显示了HO-LIN近端结节上皮细胞的产生。最近，通过尿液沉积物分析研究了尿路细胞的HO-1产生和肾脏肾小管损伤的评估。 HO-I缺乏症的详细分析可能提供了一种有价值的工具，可以理解并开发出一种新型的系统性炎症性疾病治疗方法。较少的

项目成果

HO-1 production by urinary tract cells and evaluation of tubulointerstitial injury of the kidney: immunohistochemical and EIA analysis of urinary sediments.

尿路细胞产生 HO-1 和肾小管间质损伤的评估：尿沉渣的免疫组织化学和 EIA 分析。

• 发表时间: 2007
• 作者: Yachie A;Yokoyama T;Yuno T;Ohta K;Koizumi S.
• 通讯作者: Koizumi S.

Corticosteroid enhances heme oxygenase-I production by circulating monocytes by up-regulating hemoglobin scavenger receptor and amplifying the receptor-mediated uptake of hemoblobin-haptoglobin complex

皮质类固醇通过上调血红蛋白清道夫受体并放大受体介导的血红蛋白-触珠蛋白复合物的摄取，从而通过循环单核细胞增强血红素加氧酶-I的产生

• 发表时间: 2007
• 期刊: Biochem Biophys Res Commun 358(2)
• 作者: Yamazaki;H.;Ohta;K.;Tsukiji;H.;Toma;T.;Hashida;Y.;Ishizaki;A.;Saito,. T;Arai;S.;Koizumi;S.;Yachie;A
• 通讯作者: A

Selective expansion of CD16high CCR2- subpopulation of circulating monocytes with preferential production of haem oxygenase (H0)-1 in response to acute inflammation

选择性扩增循环单核细胞 CD16high CCR2 亚群，优先产生血红素加氧酶 (H0)-1 以应对急性炎症

• 发表时间: 2005
• 期刊: Clinical and Experimental Immunology 142
• 作者: Mizuno;K.;Toma;T.;Tsukiji;H.;Okamoto;H.;Yamazaki;H.;Ohta;K.;Ohta;K.;Kasahara;Y.;Koizumi;S.;Yachie;A
• 通讯作者: A

気道炎症制御とヘムオキシゲナーゼ、CO

气道炎症控制和血红素加氧酶，CO

• 发表时间: 2005
• 期刊: アレルギー・免疫 12
• 作者: Hitomi K;Yamasaki O;Asagoe K;Iwatsuki K( et al.;谷内江昭宏
• 通讯作者: 谷内江昭宏

観察、発見、挑戦の小児医学・小児医療-ヘムオキシゲナーゼ(HO)-1欠症発見からセレンディピティを学ぶ

儿科医学和儿科医学的观察、发现和挑战——从血红素加氧酶 (HO)-1 缺乏症的发现中学习意外发现

• 发表时间: 2006
• 期刊: 日本小児科学会雑誌 110・8
• 作者: Yamazaki H; Ohta K; Tsukiji H; Toma T; Hashida Y; Ishizaki A; Saito T; Arai S; Koizumi S; Yachie A;小泉晶一
• 通讯作者: 小泉晶一