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Sickle cell disease of transgenic SAD mice
M Trudel1, M E De Paepe, N Chrétien
1Institut de Recherches Cliniques de Montréal, Faculté de Médecine de L'Université de Montréal, Québec, Canada.
Insights
Transgenic SAD mice exhibit sickle cell disease-like pathology, including vaso-occlusion and organ damage. These mice are sensitive to hypoxia but can be protected by antisickling agents, offering a model for disease research.
Area of Science:
- Hematology
- Genetics
- Pathology
Background:
- Sickle cell disease is a genetic blood disorder characterized by abnormal hemoglobin.
- Transgenic mouse models are crucial for studying disease mechanisms and testing therapies.
Purpose of the Study:
- To characterize the in vivo cellular defects and pathological changes in transgenic SAD mice.
- To evaluate the effect of acute hypoxia on SAD mice and their response to antisickling agents.
Main Methods:
- Generation of transgenic SAD mice with modified human sickle hemoglobin (HbSAD).
- Assessment of in vivo pathology, including microvascular occlusion and organ damage.
- Evaluation of hypoxic stress response and efficacy of an antisickling agent (BW12C79).
Main Results:
- SAD mice displayed generalized congestion, microvascular occlusions, and organ infarctions.
- Chronic lesions included splenomegaly (83%) and renal glomerulopathy (75%).
- Mean lifespan was reduced by 40%; mice succumbed to hypoxia-induced vaso-occlusion, preventable by BW12C79.
Conclusions:
- Transgenic SAD and beta-thal/SAD mice develop a pathophysiology mirroring human sickle cell disease.
- This model is valuable for studying sickle cell disease progression and evaluating antisickling agents.
Abstract:
Erythrocyte sickling on deoxygenation in vitro occurs in transgenic SAD mice, hemizygous for a modified human sickle hemoglobin, HbSAD [alpha 2 beta 2S(beta 6val)Antilles (beta 23 lle)D- Punjab (beta 121Gln)] (SAD-1, 19% HbSAD; beta-thal/SAD-1, 26% HbSAD). The present study examines the cellular defects in vivo and pathologic changes observed in SAD-1 mice at atmospheric oxygenation as well as the effect of acute hypoxia. The transgenic mice showed generalized congestion and microvascular occlusions, occasionally with thrombosis and infarctions of lung, kidneys, penis, and myocardium. The most prevalent chronic organ lesions were congestive splenomegaly (83% of animals) and renal glomerulopathy, which affected 75% of animals by 10 months of age. Further, SAD mice have a mean lifespan that was reduced by 40% when compared with nontransgenic littermates. Premature death of SAD mice was associated with acute vasoocclusive events or severe renal disease. SAD mice developed lethal vasoocclusive processes when exposed to reduced pO2 conditions, whereas control mice survived normally. The sensitivity to hypoxia appears to depend on the cellular level of HbSAD, because death occurred at pO2 of 42 mmHg for SAD mice and 49 mmHg for beta-thal/SAD. Administration 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 developed a pathophysiology that strongly resembles human sickle cell disease. Moreover, this animal model allows studies on the effect of antisickling agents.