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 3-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.
Subject(s)
Anemia, Sickle Cell/metabolism , Apoferritins/metabolism , Haptoglobins/pharmacology , Iron/metabolism , Kidney Diseases/metabolism , Kidney Diseases/pathology , Anemia, Sickle Cell/complications , Anemia, Sickle Cell/drug therapy , Anemia, Sickle Cell/genetics , Animals , Apoferritins/genetics , Blood Cell Count , Disease Models, Animal , Female , Gene Expression , Haptoglobins/administration & dosage , Haptoglobins/adverse effects , Haptoglobins/pharmacokinetics , Heme Oxygenase-1/genetics , Heme Oxygenase-1/metabolism , Kidney Diseases/etiology , Kidney Diseases/physiopathology , Male , Mice , Mice, Transgenic , Treatment OutcomeABSTRACT
Haptoglobin is a hemoglobin-binding acute-phase protein which possesses anti-inflammatory and antioxidative properties. In this study, we investigated changes in protein expression of rat haptoglobin under diabetes-related inflammatory and oxidative stress conditions induced by an i.p. injection of streptozotocin. The progress of diabetes during an 8-week follow-up period was associated with the increased presence of haptoglobin in the serum and in the liver. This increase was most prominent during the first 2 weeks after which it started to decline. Temporary changes in haptoglobin expression strongly correlated with the serum levels of TNF-α and IL-6. Lower haptoglobin expression at the fourth week and thereafter correlated with a decrease in TNF-α concentration and changes in the TNF-α/IL-6 ratio. Based on the decrease of GSH/GSSG ratio and antioxidant enzyme activities in the liver until the end of fourth week, it was concluded that the liver was exposed to oxidative stress and injury which in the presence of the abovementioned inflammatory mediators lead to different haptoglobin expression profiles at different stages of diabetes. An inverse correlation was observed between the haptoglobin and free iron serum levels in diabetic rats. The higher levels of haptoglobin during the first 2 weeks were accompanied by a lower level of free iron. In view of the established function of haptoglobin, we discuss its possible role in decreasing oxidative stress during the early stage of diabetes (AU)
Subject(s)
Animals , Haptoglobins/pharmacokinetics , Diabetes Mellitus/physiopathology , Inflammation/physiopathology , Oxidative Stress , Disease Models, Animal , Protective Agents/pharmacokinetics , Antioxidants/pharmacokineticsABSTRACT
AIMS: Infusion of purified haptoglobin (Hp) functions as an effective hemoglobin (Hb) scavenging therapeutic in animal models of hemolysis to prevent cardiovascular and renal injury. Epidemiologic studies demonstrate the phenotype heterogeneity of human Hp proteins and suggest differing vascular protective potential imparted by the dimeric Hp1-1 and the polymeric Hp2-2. RESULTS: In vitro experiments and in vivo studies in guinea pigs were performed to evaluate phenotype-specific differences in Hp therapeutics. We found no differences between the two phenotypes in Hb binding and intravascular compartmentalization of Hb in vivo. Both Hp1-1 and Hp2-2 attenuate Hb-induced blood pressure response and renal iron deposition. These findings were consistent with equal prevention of Hb endothelial translocation. The modulation of oxidative Hb reactions by the two Hp phenotypes was not found to be different. Both phenotypes stabilize the ferryl (Fe(4+)) Hb transition state, provide heme retention within the complex, and prevent Hb-driven low-density lipoprotein (LDL) peroxidation. Hb-mediated peroxidation of LDL resulted in endothelial toxicity, which was equally blocked by the addition of Hp1-1 and Hp2-2. INNOVATION AND CONCLUSION: The present data do not provide support for the concept that phenotype-specific Hp therapeutics offer differential efficacy in mitigating acute Hb toxicity.
Subject(s)
Haptoglobins/chemistry , Hemoglobins/metabolism , Animals , Guinea Pigs , Haptoglobins/pharmacokinetics , Haptoglobins/therapeutic use , Human Umbilical Vein Endothelial Cells , Humans , Hydrogen Peroxide/chemistry , Hydrogen Peroxide/metabolism , Lipid Peroxidation/drug effects , Lipoproteins, LDL/metabolism , MaleABSTRACT
Local dysregulation of iron metabolism is suggested to contribute to atherosclerotic lesion development through hemoglobin scavenging pathways. We evaluated the effects of CD163-mediated uptake of hemoglobin-haptoglobin (HbHp) complexes on surface CD163 and intracellular heme oxygenase-1 expression and the secretion of pro- and antiinflammatory cytokines by macrophages. We found that increased availability of HbHp complexes triggers the upregulation of surface CD163, and also results in a dose-dependent secretion of IL-6 and IL-10.
Subject(s)
Antigens, CD/metabolism , Antigens, Differentiation, Myelomonocytic/metabolism , Haptoglobins/pharmacokinetics , Hemoglobins/pharmacokinetics , Interleukins/metabolism , Macrophages/metabolism , Monocytes/metabolism , Receptors, Cell Surface/metabolism , Flow Cytometry , Gene Expression/drug effects , Gene Expression/genetics , Haptoglobins/pharmacology , Heme Oxygenase-1/genetics , Heme Oxygenase-1/metabolism , Hemoglobins/pharmacology , Humans , Interleukin-10/metabolism , Interleukin-6/metabolism , Macrophages/drug effects , Monocytes/drug effects , RNA, Messenger/genetics , RNA, Messenger/metabolismABSTRACT
The serum concentration of haptoglobin was measured in 51 cows with toxic puerperal metritis which were being treated with one of three different antimicrobial regimens. The mean concentration of haptoglobin was 19.0 mg/dl on the day that the treatments began and declined steadily during the five day treatment period to a mean concentration of 7.35 mg/dl. There was no correlation between the serum haptoglobin concentrations and the rectal temperatures of the cows during the five days.
Subject(s)
Cattle Diseases/physiopathology , Haptoglobins/analysis , Puerperal Infection/veterinary , Animals , Anti-Bacterial Agents/administration & dosage , Biomarkers , Cattle , Female , Haptoglobins/pharmacokinetics , Puerperal Infection/physiopathologyABSTRACT
The rate of elimination from rat circulation of bovine or rat haptoglobin, of their complexes with homologous haemoglobin, and of preparations deprived of the terminal sialic acid (asialo-haptoglobin), was studied. The rate of elimination was identical for bovine haptoglobin and its complexes with bovine or rat haemoglobin (the half-life time, t1/2, was 10 h). The half-life time of complexes of rat haptoglobin with bovine or rat haemoglobin was about 2 h, and it was much shorter than t1/2 for rat haptoglobin (13 h). The shortest half-life time was observed for bovine and rat asialo-haptoglobin, 35 and 15 min, respectively. The elimination curves showed a biphasic or triphasic character, depending on the rate of elimination.