Erythrocyte Clearance

Lutz, Hans

doi:10.1007/978-1-4757-9528-8_4

Cited by 41 publications

(34 citation statements)

References 178 publications

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“…4, lanes 4 and 6). The pattern of alterations observed was identical to the aggregation of band 3, deposition of autologous antibodies and complement 39 observed in a number of different conditions in vitro, such as diamide treatment, 43 treatment with nonoxidant band 3 clustering agents, 39,40 oxidant treatments, 40 and in vivo such as cell senescence, 32,40,41 sickle cell anemia, 42 and dyserythropoietic anemia type II. 43 These reports indicate that the predominant pathway leading to band 3 aggregation is primarily of oxidative nature, similar to what was observed in RBCs of RBV-treated patients.…”

Section: Discussionsupporting

confidence: 63%

Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: Role of membrane oxidative damage

et al. 2000

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The antiviral drug ribavirin (RBV) is widely used in combination with interferon (IFN) in the treatment of chronic hepatitis C virus (HCV) infection. A major side effect of RBV is a reversible hemolytic anemia. We have evaluated the in vitro effects of RBV on erythrocyte adenosine triphosphate (ATP) content and on hexosemonophosphate shunt (HMS). The ATP levels were significantly decreased in the presence of RBV and the HMS was increased, suggesting the presence of red cell susceptibility to oxidation. In vivo, we have studied the hematologic effects of treatment with RBV alone or in combination with IFN in 11 patients with chronic hepatitis C: 6 were treated with RBV (1,000-1,200 mg/d) and 5 were treated with a combination of RBV and IFN (5 million U thrice weekly). Patients were studied at semi-monthly intervals from 0 to day 60 of therapy. Both treatments were associated with a significant reduction in hemoglobin levels (steady state level at day 45) and a marked increase in absolute reticulocyte counts. Erythrocyte Na-K pump activity was significantly diminished, whereas K-Cl cotransport and its dithiotreitol-sensitive fraction, malondialdehyde and methemoglobin levels were significantly increased. RBV-treated patients showed an increase in aggregated band 3, which was associated with a significantly increased binding of autologous antibodies and complement C3 fragments indicating an erithrophagocytic removal by reticuloendothelial system. (HEPATOLOGY 2000;31:997-1004.)Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, leading to cirrhosis, end-stage liver disease, and hepatocellular carcinoma worldwide. 1,2 A major therapeutic goal in HCV-infected patients is to achieve early eradication of the virus, and to prevent severe long-term clinical complications. Interferon alfa (IFN-␣) is currently the only therapy that has been shown to have beneficial effects in chronic hepatitis type C. However, with a standard regimen of 3 million U administered 3 times per week for 6 to 12 months, only a small fraction of approximately 15% to 20% of the patients showed a sustained response with normalization of serum alanine transferase levels and serum HCV-RNA clearance. 3 Ribavirin (1-␤-D-ribofuranosyl-1H-1, 2,4-triazole-3-carboxamide) (RBV) is a water soluble synthetic guanosine analog that exerts antiviral activity against DNA and RNA viruses after intracellular phosphorylation. 4 Current studies indicate that combination therapy with RBV and IFN is associated with higher rates of sustained virological, biochemical, and histological response compared to IFN monotherapy. [5][6][7][8][9][10] The major side effect of RBV treatment is the occurrence of a reversible hemolytic anemia in a substantial proportion of treated patients. 11 The underlying mechanism is unknown. Studies on steady-state pharmacokinetics of RBV have shown that erythrocyte concentration of RBV greatly exceeds plasma concentrations 12 and that RBV is a transported permeant for the (es) nucleoside transporter in human erythrocytes...

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Section: Discussionsupporting

confidence: 63%

Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: Role of membrane oxidative damage

et al. 2000

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“…The membrane alterations and opsonization that occur in senescent, oxidatively damaged or ring stage parasitized RBC (19,26,29) were apparently not operating in EPI-treated rings. In contrast, lowmicromolar EPI induced externalization of PS in rings, but not in nonparasitized RBC.…”

Section: Discussionmentioning

confidence: 93%

16α-Bromoepiandrosterone, an Antimalarial Analogue of the Hormone Dehydroepiandrosterone, Enhances Phagocytosis of Ring Stage Parasitized Erythrocytes: a Novel Mechanism for Antimalarial Activity

Ayi

Giribaldi

Skorokhod

et al. 2002

Antimicrob Agents Chemother

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Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S), which are the most abundant hormones secreted by the adrenal cortex and are present in plasma at approximately 6 M, as well as their analogue, 16␣-bromoepiandrosterone (EPI), exerted antimalarial activities against two chloroquine-sensitive Plasmodium falciparum strains (Palo Alto, 50% inhibitory concentration [IC 50 ] of EPI, 4.8 ؎ 0.68 M; T996/86, IC 50 of EPI, 7.5 ؎ 0.91 M, and IC 50 of DHEA-S, 19 ؎ 2.6 M) and one mildly chloroquine-resistant strain (FCR-3, IC 50 of EPI, 6.5 ؎ 1.01 M). Both EPI and DHEA/DHEA-S are potent inhibitors of glucose-6-phosphate dehydrogenase (G6PD), and G6PD deficiency is known to exert antimalaria protection via enhanced opsonization and phagocytosis of rings, the early forms of the parasite. Plasma-compatible antimalarial EPI concentrations did not inhibit G6PD activity and did not induce ring opsonization by immunoglobulin G and complement fragments, as observed in G6PD deficiency, but nevertheless remarkably stimulated ring phagocytosis. Plasmacompatible, low-micromolar concentrations of EPI induced exposure on the ring surface of phosphatidylserine, a signal for phagocytic removal independent of opsonization. We propose that enhanced ring phagocytosis due to exposure of negatively charged membrane phospholipids may explain the antimalarial activity of EPI.Recently, it has been shown that 16␣-bromoepiandrosterone (EPI), an analogue of the human adrenal steroid hormones dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S), was endowed with antimalarial activity against several strains of Plasmodium falciparum in vitro and against Plasmodium berghei in a mouse model (7). Interestingly, another study (16) has indicated that age-related decreases in the frequency and density of P. falciparum parasitemia were greater during puberty and that the blood level of DHEA-S was a significant predictor of resistance. Both EPI and DHEA/DHEA-S inhibit glucose-6-phosphate dehydrogenase (G6PD) (10) and cell proliferation (13, 24). G6PD deficiency is known to afford antimalaria protection (12), possibly mediated by enhanced phagocytosis of rings, the early parasite stage within the erythrocytes (RBC) (3). Therefore, we explored whether the antimalarial activity of EPI could be related to inhibition of erythrocytic G6PD. The present results confirm the antimalarial activities of EPI and DHEA-S and indicate that sub-and low-micromolar EPI concentrations remarkably stimulated ring phagocytosis. EPI did not inhibit G6PD activity and did not enhance deposition of phagocytic opsonins, but enhanced exposure on the ring surface of phosphatidylserine (PS), a signal for phagocytic removal independent of opsonization (30). We propose that enhanced ring stage phagocytosis due to exposure of negatively charged membrane phospholipids may explain the antimalarial activity of EPI. MATERIALS AND METHODS Materials.Buffers, culture media, substrates, enzymes and coenzymes, adenine, heparin, gentamicin, mannitol, dehydroepiandrosterone sulfate (5-androsten-...

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“…Increased exposure of PE and PS has been reported in senescent or aged erythrocytes (60), erythrocytes from chronic myeloid leukemia patients (61 ), and malaria-infected erythrocytes (62). For some of these conditions, there is evidence for complement activation as well (63,64). Increased PS has been shown to enhance senescent erythrocyte adherence to phagocytes and endothelial cells (2,8,9).…”

Section: Discussionmentioning

confidence: 99%

Activation of the alternative complement pathway by exposure of phosphatidylethanolamine and phosphatidylserine on erythrocytes from sickle cell disease patients.

Wang¹,

Phillips²,

Medof³

et al. 1993

J. Clin. Invest.

118

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Deoxygenation of erythrocytes from sickle cell anemia (SCA) patients alters membrane phospholipid distribution with increased exposure of phosphatidylethanolamine (PE) and phosphatidylserine (PS) on the outer leaflet. This study investigated whether altered membrane phospholipid exposure on sickle erythrocytes results in complement activation. In vitro deoxygenation of sickle but not normal erythrocytes resulted in complement activation measured by C3 binding. Additional evidence indicated that this activation was the result of the alterations in membrane phospholipids. First, complement was activated by normal erythrocytes after incubation with sodium tetrathionate, which produces similar phospholipid changes. Second, antibody was not required for complement activation by sickle or tetrathionate-treated erythrocytes. Third, the membrane regulatory proteins, decay-accelerating factor (CD55) and the C3b/C4b receptor (CD35), were normal on sickle and tetrathionate-treated erythrocytes. Finally, insertion of PE or PS into normal erythrocytes induced alternative pathway activation. SCA patients in crisis exhibited increased plasma factor Bb levels compared with baseline, and erythrocytes isolated from hospitalized SCA patients had increased levels of bound C3, indicating that alternative pathway activation occurs in vivo. Activation of complement may be a contributing factor in sickle crisis episodes, shortening the life span of erythrocytes, and decreasing host defense against infections. (J. Clin. Invest. 1993. 92:1326-1335

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Erythrocyte Clearance

Cited by 41 publications

References 178 publications

Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: Role of membrane oxidative damage

Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: Role of membrane oxidative damage

16α-Bromoepiandrosterone, an Antimalarial Analogue of the Hormone Dehydroepiandrosterone, Enhances Phagocytosis of Ring Stage Parasitized Erythrocytes: a Novel Mechanism for Antimalarial Activity

Activation of the alternative complement pathway by exposure of phosphatidylethanolamine and phosphatidylserine on erythrocytes from sickle cell disease patients.

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