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

血红素加氧酶(HO)是一种限速酶，它在血红素的卟啉环上添加一个氧分子，从而催化血红素氧化成胆绿素/胆红素、游离铁和一氧化碳(CO)。通过产生这些代谢物，HO作为抵抗各种氧化应激的防御因子在人类中发挥着至关重要的作用。第一例人HO-1缺乏症是由Ychie等人报道的。艾尔。1999年在我们的实验室里。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，遗传上存在父亲等位基因外显子3的双碱基缺失和母亲等位基因外显子2的缺失，并通过Alu-Alu重组介导的基因组外显子缺失(1730bp)。(2)单核细胞和内皮细胞功能障碍明显。(2)外周持续应激引起全身炎症反应过度，凝血/…明显异常更多的纤溶系统，最终导致免疫和凝血系统的衰竭。(3)单核细胞形态异常，表面分子明显减少，单核细胞吞噬功能明显受损。此外，CD16+，CCR2-单核细胞亚群在包括细菌和病毒感染在内的急性感染期间显示出选择性地扩增，该亚群优先产生HO-1mRNA。儿童肺动脉高压时肺泡巨噬细胞产生HO-1与CD1G3表面分子的过度表达有关。(4)HO-1缺乏者进行性肾小管间质损害显著。在各种肾活检标本和体外实验中，HO-LIN近端肾小管上皮细胞的产量均高于系膜细胞。最近，通过尿沉渣的MA分析，研究了尿路细胞产生HO-1和评估肾小管-肠损伤。对HO-I缺乏的详细分析可能为了解全身性炎症性疾病的发病机制和开发一种新的治疗方法提供有价值的工具。较少

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