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

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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