| Co-Investigator(Kenkyū-buntansha) |
OHTA Kazuhide Kanazawa University, Kanazawa University Hospital, Lecturer, 医学部附属病院, 講師 (20283129)
KASAHARA Yoshihito Kanazawa University, Graduate School of Medical Science, Associate Professor, 大学院・医学系研究科, 助教授 (30204366)
YACHIE Akihiro Kanazawa University, Faculty of Medicine, Professor, 医学部, 教授 (40210281)
SAIKAWA Yutaka Kanazawa University, Kanazawa University Hospital, Lecturer, 医学部附属病院, 講師 (60283107)
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| Research Abstract |
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
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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
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