Sustained treatment of sickle cell mice with haptoglobin increases HO‐1 and H‐ferritin expression and decreases iron deposition in the kidney without improvement in kidney function

Abstract

There is growing evidence that extracellular haemoglobin and haem mediate inflammatory and oxidative damage in sickle cell disease. Haptoglobin (Hp), the scavenger for free haemoglobin, is depleted in most patients with sickle cell disease due to chronic haemolysis. Although single infusions of Hp can ameliorate vaso-occlusion in mouse models of sickle cell disease, prior studies have not examined the therapeutic benefits of more chronic Hp dosing on sickle cell disease manifestations. In the present study, we explored the effect of Hp treatment over a three-month period in sickle mice at two dosing regimens: the first at a moderate dose of 200 mg/kg thrice weekly and the second at a higher dose of 400 mg /kg thrice weekly. We found that only the higher dosing regimen resulted in increased haem-oxygenase-1 and heavy chain ferritin (H-ferritin) expression and decreased iron deposition in the kidney. Despite the decreased kidney iron deposition following Hp treatment, there was no significant improvement in kidney function. However, there was a nearly significant trend towards decreased liver infarction.

Haptoglobin and hemopexin inhibit vaso-occlusion and inflammation in murine sickle cell disease: Role of heme oxygenase-1 induction

“…These data suggest that kidney filtration in the Townes-SS mice may be partially compromised and allow Hp-Hb complexes access to Hp receptors on the proximal tubules of the cortex. A previous study by Shi et al supports our current observation that Hp supplementation increases HO-1 expression in the kidneys of Townes-SS mice [ 56 ].…”

Impairment of Nitric Oxide Pathway by Intravascular Hemolysis Plays a Major Role in Mice Esophageal Hypercontractility: Reversion by Soluble Guanylyl Cyclase Stimulator

“…In hemolytic anemia, accumulation of excess iron can occur in certain organs due to increased hemoglobin catabolism (Shi et al, 2016). Considering that free iron participates in the generation of reactive oxygen species (Winterbourn, 1995), we evaluated the effects of treatment with two iron-chelating…”

Case series supporting heme detoxification via therapeutic plasma exchange in acute multiorgan failure syndrome resistant to red blood cell exchange in sickle cell disease

“…30,31 Exogenous Hp and Hx therapy preserves vascular nitric oxide signaling and ameliorates disease pathophysiology, [32][33][34][35] including in SCD mouse models. [4][5][6][7][8]15,[36][37][38] The chronic hemolysis of SCD continuously releases Hb into the plasma, 39,40 resulting in steady-state depletion of Hp in 50% to 90% and of Hx in 10% to 30% of patients. 3,41,42 Brazilian children with steady-state SS disease (n 5 173) had mean plasma Hp and Hx levels of 8 and 14% of healthy AA control children, respectively, and SC children (n 5 93) likewise had levels of 16 and 39%, respectively.…”