Hasegawa S, Rodgers G P, Dwyer N, Noguchi C T, Blanchette-Mackie E J, Uyesaka N, Schechter A N, Fibach E
Laboratory of Chemical Biology, NIDDK, National Institutes of Health, Bethesda, MD 20892-1822, USA.
Exp Hematol. 1998 Apr;26(4):314-9.
The pathophysiology of sickle cell anemia is primarily explained in terms of the oxygen-dependent polymerization of sickle hemoglobin (HbS) followed by sickling of erythrocytes. Since the rate and extent of HbS polymerization depend on its intracellular concentration, it has been generally assumed that sickling occurs primarily in mature erythrocytes with their high intracellular hemoglobin concentration. In the present study, we investigated the propensity of nucleated erythroid precursors to undergo sickling; both cultured and fresh marrow-derived erythroid precursors from patients with homozygous sickle cell anemia were studied. The results revealed that upon deoxygenation cultured erythroblasts underwent characteristic morphological deformation in the form of fine, fragile, elongated spicules. Ultrastructural analysis demonstrated highly organized and tightly aligned hemoglobin fibers in the protruded regions. Bone marrow cells examined under partial or complete deoxygenated conditions displayed similar morphological changes. When cultured SS erythroid precursors were exposed to hydroxyurea or butyrate, drugs that may increase fetal hemoglobin (HbF) and inhibit intracellular polymerization, a significant decrease was observed in the propensity of these precursors to undergo sickling, accompanied by a three- to fivefold increase in HbF. These results suggest that, in addition to mature erythrocytes, nucleated erythroid precursors in the bone marrow have the capacity to undergo characteristic sickling as a result of HbS polymerization and may be involved in several aspects of the pathophysiology of sickle cell anemia. Treatment with HbF-stimulating drugs may benefit patients with this disease by inhibiting polymerization-induced sickling of erythroid precursors in the marrow as well as mature erythrocytes in the peripheral blood.
镰状细胞贫血的病理生理学主要通过镰状血红蛋白（HbS）的氧依赖性聚合作用来解释，随后红细胞发生镰变。由于HbS聚合的速率和程度取决于其细胞内浓度，因此一般认为镰变主要发生在细胞内血红蛋白浓度较高的成熟红细胞中。在本研究中，我们调查了有核红细胞前体发生镰变的倾向；对来自纯合镰状细胞贫血患者的培养和新鲜骨髓来源的红细胞前体均进行了研究。结果显示，在脱氧后，培养的成红细胞会发生特征性的形态变形，表现为细小、脆弱、细长的针状突起。超微结构分析表明，在突出区域有高度有序且紧密排列的血红蛋白纤维。在部分或完全脱氧条件下检查的骨髓细胞也显示出类似的形态变化。当将培养的镰状细胞贫血（SS）红细胞前体暴露于可能增加胎儿血红蛋白（HbF）并抑制细胞内聚合的羟基脲或丁酸盐时，观察到这些前体发生镰变的倾向显著降低，同时HbF增加了三到五倍。这些结果表明，除了成熟红细胞外，骨髓中有核红细胞前体也有能力因HbS聚合而发生特征性镰变，并且可能参与镰状细胞贫血病理生理学的多个方面。用刺激HbF的药物进行治疗可能通过抑制骨髓中红细胞前体以及外周血中成熟红细胞的聚合诱导镰变，从而使患有这种疾病的患者受益。
