SICKLE-CELL DISEASE OF TRANSGENIC SAD MICE

Erythrocyte sickling on deoxygenation in vitro occurs in transgenic SA D mice, hemizygous for a modified human sickle hemoglobin, HbSAD [alph a(2) beta(2)(S(beta 6val)Antilles{beta 23IIe)D-Punjab{beta 121Gln)] (S AD-1, 19% HbSAD; beta-thal/SAD-1, 26% HbSAD). The present study examin es the cellular defects in vivo and pathologic changes observed in SAD -1 mice at atmospheric oxygenation as well as the effect of acute hypo xia. The transgenic mice showed generalized congestion and microvascul ar occlusions, occasionally with thrombosis and infarctions of lung, k idneys, penis, and myocardium. The most prevalent chronic organ lesion s were congestive splenomegaly (83% of animals) and renal glomerulopat hy, which affected 75% of animals by 10 months of age. Further, SAD mi ce have a mean lifespan that was reduced by 40% when compared with non transgenic littermates. Premature death of SAD mice was associated wit h acute vasoocclusive events or severe renal disease. SAD mice develop ed lethal vasoocclusive processes when exposed to reduced pO(2) condit ions. whereas control mice survived normally. The sensitivity to hypox ia appears to depend on the cellular level of H6SAD, because death occ urred at pO(2) of 42 mmHg for SAD mice and 49 mmHg for beta-thal/AD. A dministration of an antisickling agent that increases oxygen affinity (BW12C79) protected SAD and beta-thal/SAD mice from the lethal hypoxic stress. In conclusion, the transgenic SAD and beta-thal/SAD mice deve loped a pathophysiology that strongly resembles human sickle cell dise ase. Moreover, this animal model allows studies on the effect of antis ickling agents. (C) 1994 by The American Society of Hematology.