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

严重的感染和休克综合征往往伴随着强烈的机体反应，称为巨噬细胞激活综合征，以单核细胞活化、高细胞因子血症、循环衰竭和多器官功能障碍为特征。为了预防病原体暴露造成的这些有害后果，身体防御系统不仅要提供有效的抗原特异性免疫反应，而且要有严格控制的炎症调控系统。以往的报道表明，巨噬细胞在各种炎症性疾病中渗透到各个器官，参与器官损伤的发病。但同时，HO-1及其相关产物是由单核/巨噬细胞产生的调节过度炎症反应的一组关键分子。我们先前的研究表明，在循环的单核细胞…中，HO-1的产生是迅速诱导的在氧化应激和HO-1缺乏的情况下，更多的细胞与终生持续的炎症有关。这些发现表明，在体内各种炎症性疾病中，单核细胞在控制炎症水平方面发挥着关键作用。此外，流行病学研究表明，HO-1基因启动子区GT重复序列的长度与多种炎症性疾病的发生密切相关。这些研究表明，诱导型HO-1基因启动子区域的GT重复序列水平控制着由一定的氧化应激引发的炎症反应的强度。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在各种炎症性疾病的发病机制中的作用。在这些发现的基础上，进一步开展研究，以开发一种新的治疗方法来对抗过度炎症，通过在体内调节HO-1的产生，本研究表明循环中的单核细胞是体内和体外产生HO-1的主要来源。激活的单核细胞产生HO-1与急性炎症时单核细胞的表型变化有关。HO-1的产生优先观察到在特定的单核细胞亚群中，这表明通过调控这一特殊单核细胞亚群的数量和功能来指导抗炎治疗的发展是可能的。较少

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