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

Savere感染和休克综合征通常与称为巨噬细胞活化综合征的强烈身体反应有关，其特征是单核细胞活化、高细胞因子血症、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应答，但与此同时，炎症的调节系统受到严格控制。以往的报道表明，在各种炎症性疾病中，巨噬细胞浸润到各种器官中，并参与器官损伤的发病机制。但与此同时，血红素氧合酶-1（HO-1）及其相关产物是单核/巨噬细胞产生的调节过度炎症反应的关键分子。我们以前的研究表明，在循环单核/巨噬细胞中，HO-1的产生是快速诱导的， 关于我们 HO-1缺乏的患者与终生持续的炎症有关，这些发现证实了单核细胞在体内各种炎症性疾病中控制炎症水平的主要作用。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活性水平相关。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生率存在很强的相关性，这些研究表明，诱导型HO-本研究分析了循环单核细胞产生HO-1的调节机制，并试图阐明HO-1在氧化应激中的作用。基于这些发现，进行了进一步的研究以开发新的治疗方法来对抗过度炎症，通过调节体内HO-1的产生，本研究表明，循环单核细胞是体内和体外HO-1的主要产生者。HO-1的产生与急性炎症过程中单核细胞的表型变化有关，HO-1的产生主要发生在特定的单核细胞亚群中，这表明有可能通过操纵该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

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