Pathophysiology and Treatment of Beta-Thalassemia: Investigations of Heme Oxygenase 1 and Its Inhibitors
Notice bibliographique
Résumé
Abstract Thalassemias are a heterogeneous group of red blood cell disorders ranging from a clinically severe phenotype requiring life-saving transfusions (thalassemia major) to a relatively moderate symptomatic disorder, sometimes requiring transfusions (thalassemia intermedia). Thalassemia minor, the least severe form of the disorder, is characterized by minimal to mild symptoms. Though considered a major cause of morbidity and mortality worldwide, there is still no universally available cure for thalassemia major. The reason for this is, at least in part, due to the lack of full understanding of pathophysiology of thalassemia. The underlying basis of thalassemia pathology is the premature apoptotic destruction of erythroblasts causing ineffective erythropoeisis. Normally, the assembly of adult hemoglobin (consisting of a tetramer of two α- and two β-globin chains) features a very tight coordination of α- and β-globin chain synthesis. However, in β-thalassemia, β-globin synthesis is diminished causing α-globin accumulation; while in α-thalassemia the opposite scenario occurs. Unpaired globin chains that accumulate in thalassemic erythroblasts are bound to heme. In addition, in β-thalassemia an erythroid specific protease destroys excess α-globin chains, likely leading to the generation of a pool of "free" heme in erythroblasts. "Unshielded" heme is toxic, but this toxicity will likely be augmented, if heme oxygenase 1 (HO-1) can release iron from heme. So far, virtually no information about the expression of HO-1 in erythroblasts has been produced. However, we have recently provided unequivocal evidence that this enzyme is present in several model erythroid cells1. Based on this novel and important finding, we hypothesize that in β-thalassemic erythroblasts HO-1-mediated release of iron from heme is the major culprit responsible for cellular damage. To test this hypothesis, we exploited the mouse model of β-thalassemia known as th3/th3. Our data indicates that HO-1 expression is increased in the liver, spleen and kidney of β-thalassemic mice compared to wild-type mice. Importantly, we observed that erythropoietin-mediated erythroid differentiation of fetal liver (FL) cells isolated from β-thalassemic fetuses have increased levels of HO-1 at mRNA and protein levels as well as a decrease in phosphorylated eIF2-α levels. Ferritin levels were increased in β-thalassemic FL cells suggesting increased heme catabolism and iron release. To investigate the contribution of HO-1 to the pathology associated with β-thalassemia, wild-type and thalassemic (th3/+) mice were injected with 40 µmoles/kg/d of tin-protoporphyrin IX (SnPP, HO-1 inhibitor) during a 4-week period, 3 times a week. Our results show that β-thalassemic mice injected with SnPP display a decrease in the spleen index, hemoglobin levels, red blood cell counts, reticulocyte counts and liver iron content when compared to PBS injected β-thalassemic mice. Additionally, HO-1 inhibition reduced ineffective erytropoiesis in β-thalassemia mice. Our results indicate that β-thalassemic erythroblasts have inappropriately high levels of "free" heme that is continuously degraded by HO-1. Further research is needed to determine whether iron liberated from heme by HO-1 is directly responsible for the damage of β-thalassemic erythroblasts. 1Garcia-Santos D, et al. Heme oxygenase 1 is expressed in murine erythroid cells where it controls the level of regulatory heme. Blood 123 (14): 2269-77, 2014. Disclosures No relevant conflicts of interest to declare.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».