Thalassemias are a heterogeneous group of red blood cell disorders, considered a major cause of morbidity and mortality among genetic diseases. However, there is still no universally available cure for thalassemias. The underlying basis of thalassemia pathology is the premature apoptotic destruction of erythroblasts causing ineffective erythropoiesis. In β-thalassemia, β-globin synthesis is reduced causing α-globin accumulation. Unpaired globin chains, with heme attached to them, accumulate in thalassemic erythroblasts causing oxidative stress and the premature cell death. We hypothesize that in β-thalassemia heme oxygenase (HO) 1 could play a pathogenic role in the development of anemia and ineffective erythropoiesis. To test this hypothesis, we exploited a mouse model of β-thalassemia intermedia, Th3/+ We observed that HO inhibition using tin protoporphyrin IX (SnPP) decreased heme-iron recycling in the liver and ameliorated anemia in the Th3/+ mice. SnPP administration led to a decrease in erythropoietin and increase in hepcidin serum levels, changes that were accompanied by an alleviation of ineffective erythropoiesis in Th3/+ mice. Additionally, the bone marrow from Th3/+ mice treated with SnPP exhibited decreased heme catabolism and diminished iron release as well as reduced apoptosis. Our results indicate that the iron released from heme because of HO activity contributes to the pathophysiology of thalassemia. Therefore, new therapies that suppress heme catabolism may be beneficial in ameliorating the anemia and ineffective erythropoiesis in thalassemias.

中文翻译：

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抑制血红素加氧酶可改善β-地中海贫血小鼠模型中的贫血并减少铁过载

地中海贫血是一组异质性红细胞疾病，被认为是遗传疾病发病率和死亡率的主要原因。然而，仍然没有普遍可用的地贫治疗方法。地贫病理学的潜在基础是成红细胞的过早凋亡破坏，导致无效的红细胞生成。在β-地贫中，β-珠蛋白合成减少导致α-珠蛋白积累。未配对的珠蛋白链，附有血红素，在地贫红细胞中积聚，导致氧化应激和细胞过早死亡。我们假设在 β-地贫血红素加氧酶 (HO) 1 可以在贫血的发展和无效的红细胞生成中发挥致病作用。为了验证这一假设，我们利用了中间型 β-地中海贫血的小鼠模型，Th3/+ 我们观察到使用锡原卟啉 IX (SnPP) 抑制 H2O 减少了肝脏中的血红素铁循环并改善了 Th3/+ 小鼠的贫血。SnPP 给药导致促红细胞生成素减少和铁调素血清水平增加，这些变化伴随着 Th3/+ 小鼠无效红细胞生成的减轻。此外，来自用 SnPP 处理的 Th3/+ 小鼠的骨髓表现出血红素分解代谢减少、铁释放减少以及细胞凋亡减少。我们的结果表明，由于 H2O 活性而从血红素释放的铁有助于地贫的病理生理学。因此，抑制血红素分解代谢的新疗法可能有助于改善地中海贫血症的贫血和无效的红细胞生成。