Original Research: Diametric effects of hypoxia on pathophysiology of sickle cell disease in a murine model

Abstract

Hypoxia causes erythrocyte sickling in vitro; however, its role in the pathophysiology of sickle cell disease is poorly understood. We report that hypoxia rapidly decreased oxygen saturation in transgenic sickle cell disease mice, but this effect was immediately buffered by a robust ventilatory response. The initial hypoxemia improved steadily throughout the duration of hypoxia without any detectable acute pulmonary adverse effect. Furthermore, the mice suffered acute anemia that ironically was associated with lowering of both plasma hemoglobin and heme. These results were corroborated by increased plasma haptoglobin and hemopexin levels. Markers of ischemic tissue injury increased spatiotemporally following repeated hypoxia exposures. This variation was supported by organ-specific induction of hypoxia-responsive genes. Our results show that hypoxia exerts diametric effects on sickle cell disease by promoting ischemic injury while enhancing the expression of hemolysis scavenger molecules. This phenomenon may help to understand the disparate clinical syndromes associated with hemolysis and vaso-occlusion in sickle cell disease.

Smooth muscle cytochrome b5 reductase 3 deficiency accelerates pulmonary hypertension development in sickle cell mice

“…Red blood cell hemolysis contributes to anemia of SCD and generates cell-free plasma Hb products that can be elevated in the absence of sufficient Hb and heme-scavenging mechanisms (haptoglobin and hemopexin, respectively), which have been shown to be overwhelmed in patients and animal models with the disease. 50,51 We did not observe a significant difference in plasma Hb levels between the CYB5R3 knockdown and WT groups at either the 3-or 12-week time points. The absence of differences in blood cell counts between the CYB5R3 knockdown and WT groups is consistent with these findings.…”

Experimental intravascular hemolysis induces hemodynamic and pathological pulmonary hypertension: association with accelerated purine metabolism

“…Therefore, we cannot rule out the possibility that hypoxia (due to anemia and emphysematous changes) contributed to the observed pulmonary vascular injury in HAB and SU+HAB treated rats. However, in SCD mice repeatedly exposed to 8% oxygen for 3 h, only a transient drop in SpO2 occurred within the first hour of hypoxia that was associated with a dramatic increase in respiratory rate 43 . In contrast, daily HAB administration did not cause signs of distress, labored breathing, or tachypnea.…”

“…However, in SCD mice repeatedly exposed to 8% oxygen for 3 h, only a transient drop in SpO2 occurred within the first hour of hypoxia that was associated with a dramatic increase in respiratory rate. 43 In contrast, daily HAB administration did not cause signs of distress, labored breathing, or tachypnea. Interestingly, normoxic activation of hypoxic responses (HIF-1α and VEGF) has been reported in SCD patients and linked to development of PH in SCD.…”

Understanding pulse oximetry in hematology patients: Hemoglobinopathies, racial differences, and beyond

“…When HbS polymerizes, the shape of the erythrocyte is distorted into a sickle shape that does not easily flow through tissues 17 . Hypoxia is an established trigger for vasoocclusive crises, causing an increase in sickling and therefore end organ and vascular damage 17,18 . The HbS allele is prevalent in populations in sub‐Saharan Africa and the African diaspora, and many patients with sickle cell disease self‐identify as Black 17 .…”