Multilateral-physiological and functional evidences of the heme oxygenase-1 (HO-1) enzyme : learning from the first case with human HO-1deficiency

报告首例人类血红素加氧酶-1(HO-1)缺乏症。患者是一名6岁的男孩，类似于HO-1基因敲除小鼠，表现出严重的生长迟缓、贫血、肾脏和肝脏组织中的铁沉积，以及对高烧应激相关损伤的易感性。(1)基因组分析显示，男孩完全缺乏HO-1，母亲的等位基因外显子2缺失，父亲的等位基因外显子3缺失。进一步的分析揭示了该病例中由Alu-Alu重组介导的基因组外显子缺失(L，730bp)的结构证据。(2)男孩表现出单核细胞形态异常，其表面分子CD11b、CD14、CD16和CD36显著减少，导致单核细胞吞噬功能明显受损。我们在两个活体模型系统中研究了单核细胞HO-1产生的重要性。在急性发热性疾病中，单核细胞被激活，同时…升高更多的HO-1产量。此外，我们还检测了儿童肺动脉高压时肺泡巨噬细胞产生HO-1的情况，显示HO-1的水平与肺动脉高压的程度有良好的相关性。(3)本病例连续三次活检标本显示肾小球系膜毛细血管壁厚的改变。肾小管间质损伤进行性加重，肾小管扩张和/或萎缩，间质纤维化和炎性细胞浸润。电子显微镜检查显示广泛的内皮细胞脱离和内皮下的不明物质沉积。此外，我们比较了原代培养的人肾小球系膜细胞(HMCs)和近端肾小管上皮细胞(HTECs)在体外对HO-1的表达模式和对应激诱导的细胞毒性的反应。与HMCS相比，hTECs对氧化应激更敏感，对HO-1表达的依赖性更强。(4)HO-1基因转染ECV304细胞后，HO-1表达水平最低。HO-1高表达的细胞比HO-1低表达的细胞表现出更多的细胞死亡增加，这表明HO-1的高表达并不总是预防应激诱导损伤的良好预后因素。从这些基于HO-1缺乏的首例人类病例的数据，新的证据表明HO-1酶的多方面生理功能。较少

The first-described case of human heme oxygenase-1 (HO-1) deficiency is presented. The patient, a 6-year-old boy, similar to HO-1 knockout mice, exhibited severe growth retardation, anemia, iron deposition in renal and hepatic tissue, and vulnerability to stress-related injury with high fever.(1) The genomic analysis revealed that the boy completely lacked HO-1, having a deletion of exon 2 of the maternal allele and a two-base-pair deletion in exon 3 of the paternal allele of the gene. Further analysis revealed structural evidence of genomic exon-deletion (l,730bp) mediated by Alu-Alu recombination in this case.(2) The boy exhibited morphological abnormality of monocytes and significant reduction of their surface molecules including CD11b, CD 14, CD16 and CD36, resulting in a markedly impaired phagocytosis of monocytes. We investigated the importance of monocyte HO-1 production in two in vivo model systems. In acute febrile illnesses monocytes are activated with simultaneous increase o … More f HO-1 production. In addition, we also examined HO-1 production by alveolar macrophages in childhood pulmonary hypertension, showing well correlation of the level of HO-1 with the degree of pulmonary hypertension.(3) Renal mesangial change in glomerular capillary-wall thickness was shown in the three consecutive biopsy specimens in this case. Tubulointerstitial injury, with tubular dilatation and/or atrophy, interstitial fibrosis, and inflammatory cell infiltration advanced progressively. Electron microscopic examination showed widespread endothelial detachment and subendothelial deposits of an unidentifiable material. Furthermore, we compared the patterns of HO-1 expression and the responses to stress-induced cytotoxicity by primary cultured human mesangial cells (hMCs) and proximal tubular epithelial cells (hTECs) in vitro. The hTECs were shown to be more susceptible to oxidative stress and significantly more dependent on HO-1 expression than the hMCs.(4) We transfected HO-1 gene to die ECV304 cells with a minimal level of HO-1 expression. The high HO-1-expressed cells showed more increase of cell death by H2O2 than die low HO-1-expressed one, indicating that the high expression of HO-1 was not always a good prognostic factor for prevention of stress-induced injuries.From these data based on the first human case of HO-1 deficiency, multilateral physiological functions of die HO-1 enzyme were newly evidenced. Less