Limitations of a Mouse Model of Sickle Cell Anemia

We aimed to use an established murine model of sickle cell anemia to develop an unambiguous method for testing new therapies, with survival as an end point. Survival rates following various challenges were compared for three different groups of mice: (a) sickle cell mice expressing human hemoglobin-S exclusively (hβs); (b) littermates that expressed both human hemoglobin S and murine β major globin (hβsmβ); and (c) wild-type C57BL/6 mice (wt). Two types of challenge were tested. The first set of studies was based upon recent observations indicating that granulocyte-colony stimulating factor (G-CSF) can precipitate severe complications in patients with sickle cell disease. While hβs mice had higher neutrophil counts than hβsmβ mice at baseline, hβs mice tolerated several different doses and schedules of either human or murine G-CSF without adverse effects. A second type of challenge tested whether sickle cell mice exhibit an enhanced susceptibility to hemoglobin deoxygenation. Acute hemoglobin deoxygenation was accomplished either by a single intraperitoneal injection of sodium bisulfite or by a 1-h exposure to hypoxia. Neither intervention resulted in a significantly different survival rate for hβs mice compared to either hβsmβ or wt mice. Chronic twice-weekly exposures to hypoxia (1 h per exposure) also failed to produce significant differences in survival rates between hβs mice, hβsmβ, and wt mice over a period of 12 weeks. Our results demonstrate that neither G-CSF administration nor hypoxia accentuates survival differences between this model of sickle cell mouse and normal controls.