title: Sickle cell disease of transgenic SAD mice.
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.
authors.affiliation: Institut de Recherches Cliniques de Montréal, Faculté de Médecine de L'Université de Montréal, Québec, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Trudel
authors.forename: M E
authors.initials: ME
authors.lastname: De Paepe
authors.forename: N
authors.initials: N
authors.lastname: Chrétien
authors.forename: N
authors.initials: N
authors.lastname: Saadane
authors.forename: J
authors.initials: J
authors.lastname: Jacmain
authors.forename: M
authors.initials: M
authors.lastname: Sorette
authors.forename: T
authors.initials: T
authors.lastname: Hoang
authors.forename: Y
authors.initials: Y
authors.lastname: Beuzard
mesh_terms: D000755:Anemia, Sickle Cell / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D000986:Antisickling Agents / Q000494:pharmacology; D001547:Benzaldehydes / Q000494:pharmacology; D004195:Disease Models, Animal; D004913:Erythrocytes, Abnormal / Q000473:pathology; D004920:Erythropoiesis; D000860:Hypoxia / Q000473:pathology; D008136:Longevity; D008168:Lung / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008833:Microcirculation; D013154:Spleen / Q000473:pathology
chemical_list: D000986:Antisickling Agents; D001547:Benzaldehydes; C039599:5-(2-formyl-3-hydroxyphenoxy)pentanoic acid