Eclectic mechanisms of heme regulation of hematopoiesis

Abraham, Nader G.; Levere, Richard D.; Lutton, John D.

doi:10.1002/stem.5530090304

Cited by 21 publications

(24 citation statements)

References 94 publications

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“…Heme stimulates ALAS expression and this results in an increase in erythroid progenitors and pluripotent stem cells [31]. Stimulation of ALAS is ac companied by suppression of heme oxygenase (HO) in erythroid bone marrow cultures, however, it is not the case in nonerythroid cells such as the liver cells where heme suppresses ALAS and induces HO [31,32], HO is the rate-limiting enzyme in heme degradation. Hb and heme cause induction of HO in vitro and in vivo in many tissues and cell types.…”

Section: Discussionmentioning

confidence: 99%

“…Induction of HO may minimize the amount of Hb (heme) to which tissues are exposed and therefore may lessen toxicity and injury to the tissues and cells in question [28][29][30][31][32], The induction of HO causes an increase in free iron, bilirubin and biliverdin; all are important in modulating responses to injury and consid ered to be beneficial in the protection of cells from oxida tive injury due to Hb. Additionally, the release of iron may be a contributing factor in transcriptional or transla tional regulation of erythroid ALAS since excess iron plays an important role in the expression of ALAS [31,32], The activity of HO is induced by its substrate heme. A decrement in HO activity may be an important feature of the differentiation process of hematopoietic progenitor cells in bone marrow [30,32], Elevated levels of HO have been detected in a variety of hematopoietic disorders [17,[30][31][32][33] and a fall in HO activity appears to be a prerequi site event for bone marrow erythroid growth and differen tiation to take place [29,31].…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, the release of iron may be a contributing factor in transcriptional or transla tional regulation of erythroid ALAS since excess iron plays an important role in the expression of ALAS [31,32], The activity of HO is induced by its substrate heme. A decrement in HO activity may be an important feature of the differentiation process of hematopoietic progenitor cells in bone marrow [30,32], Elevated levels of HO have been detected in a variety of hematopoietic disorders [17,[30][31][32][33] and a fall in HO activity appears to be a prerequi site event for bone marrow erythroid growth and differen tiation to take place [29,31]. A concomitant increase of ALAS is also required for adequate erythropoiesis.…”

Section: Discussionmentioning

confidence: 99%

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Effect of Blood Substitute, Recombinant Hemoglobin, on in vivo Hematopoietic Recovery from AZT Toxicity

Moqattash

Lutton²,

Rosenthal³

et al. 1997

Acta Haematol

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We determined the in vivo ability of infused human recombinant hemoglobin 1.1 (hr-Hb) and erythropoietin to rescue the hematopoietic activity from the suppressive effects of AZT in normal and in a murine model of AIDS (MAIDS) mice. Mice were fed with AZT for 8 weeks with or without treatment in the last 4 weeks by administering various concentrations of hr-Hb and/or erythropoietin (Epo). Blood parameters, body weight (BW) and erythroid burst-forming units (BFU-E) for all mice were determined. AZT-treated normal and MAIDS mice showed a significant decrease in hematocrit (64 and 78.1%), hemoglobin (27.2 and 45.5%), BW (17.5 and 35.5%), number of white (66.9 and 42.1 %) and red blood cells (65.5 and 38%), and the number of BFU-E (73 and 59%), whereas the AZT-treated normal and MAIDS mice that received hr-Hb (5 mg/kg BW/day) and/or Epo (2 U/mouse/day) showed significant alleviation of AZT cytotoxicity. This was evident by the recovery in all blood indices examined, the number of BFU-E and the BW of mice treated. BFU-E recovery in MAIDS (97%) was greater than that in normal mice (63%) as compared to their controls. hr-Hb produced a similar response as the combination, however recovery was slightly better with the latter in some hematological parameters. Higher concentrations of hr-Hb (10-15 mg) did not result in a more significant increase in most blood indices. Our results indicate that infusion with hr-Hb can alleviate AZT toxicity in normal and in immunodeficient mice, and that hr-Hb may be clinically useful in preventing severe bone marrow depression brought about by various drugs or agents such as AZT.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Effect of Blood Substitute, Recombinant Hemoglobin, on in vivo Hematopoietic Recovery from AZT Toxicity

Moqattash

Lutton²,

Rosenthal³

et al. 1997

Acta Haematol

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“…Irrespective of the mechanisms involved in the accelerated hematopoietic regeneration induced by hemin in mice exposed to benzene, the use of hemin along or with a combination of growth factors may be of clinical importance (25). In fact, hemin has a beneficial effect on improvement of the anemia seen in patients with myelodysplasia (30).…”

Section: Discussionmentioning

confidence: 99%

“…We have found that exogenous hemin can counteract some toxic effects brought about by inhibition of heme synthesis by heavy metals and drugs (21)(22)(23), and more recently we have studied the effect of hemin on hematopoiesis in longterm bone marrow culture (LTBMC) (24). Heme is an essential component of cytochrome P450 and the drug-metabolizing system and plays a central role in the regulatory network of hematopoiesis under conditions of stress (25).…”

Section: Introductionmentioning

confidence: 99%

Hematopoietic Effects of Benzene Inhalation Assessed by Long-Term Bone Marrow Culture

Abraham¹

1996

Environmental Health Perspectives

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The strong and long-lasting hematotoxic effect after benzene exposure in vivo (300 ppm, 6 hr/day, 5 days/week for 2 weeks) was assessed in mice with bone marrow cells grown in longterm bone marrow culture (LTBMC). Bone marrow cultures initiated 1 day after the last benzene exposure did not produce adequate numbers of hematopoietic cells over 3 weeks and, in most cases, no erythroid or myeloid clonogenic cells could be recovered. The adherent cell layer of these cultures had a lower capacity for supporting in vitro hematopoiesis after the second seeding with normal bone marrow cells compared with control cultures. Two weeks after the last benzene exposure, body weight, hematocrit, bone marrow cellularity, and committed hematopoietic progenitor content (BFU-E and CFU-GM) were regenerated to normal or subnormal values, whereas hematopoiesis in LTBMC was very poor. Over 8 weeks, little or no significant committed progenitor production was observed. Treatment of mice exposed to benzene with hemin (three doses of 3 pg/g bw iv over 2 weeks for a total dose of 9 pg/g) partially overcame the toxic effect of benzene on the hematopoietic system as measured by the LTBMC method. Cultures from mice treated with hemin had a modest recovery of BFU-E and CFU-GM clonogenic potential after 5 to 6 weeks in LTBMC. In contrast, little or no recovery was obtained for the adherent cell layer clonogenic capacity, even after hemin treatment. These results clearly indicate a strong, longlasting toxic effect on the bone marrow stroma and a limited recovery of hematopoietic potential by clonogenic cells of the nonadherent population after in vivo hemin treatment. Environ Health Perspect 104(Suppl 6): 1277-1282 (1996)

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Elevated levels of heme oxygenase‐1 activity and mRNA in peripheral blood adherent cells of acquired immunodeficiency syndrome patients

et al. 1993

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Patients with the acquired immunodeficiency syndrome (AIDS) commonly develop hematological abnormalities, including anemia, leukopenia, and thrombocytopenia. Heme synthesis and heme degradation are critical to the maintenance of cellular heme homeostasis and to hematopoietic differentiation. We examined heme oxygenase activity and expression of the heme oxygenase gene in adherent cells (monocytes-macrophages) obtained from the peripheral blood of AIDS patients and normal controls. Heme oxygenase activity in normal control cells was 43 +/- 16 pmol bilirubin formed/4 x 10(5) cells/hr as compared to 133 +/- 30 pmol bilirubin formed/4 x 10(5) cells/hr in the AIDS patients. Via blot hybridization analysis with human heme oxygenase cDNA, heme oxygenase mRNA levels in cells of the normal and the AIDS patients were compared. Total RNA from normal cells displayed only weak hybridization with the cDNA probe. In contrast, cells from peripheral blood of the AIDS patients displayed marked increases over normal levels in heme oxygenase mRNA. Heme oxygenase activity could be substantially suppressed by the competitive inhibitor of the enzyme, Sn-mesoporphyrin. Elevated heme oxygenase activity in cells of AIDS patients could produce a decrease in cellular heme needed for transductional signalling for the growth factor network, which regulates the hematopoietic microenvironment, and for other metabolic purposes. Suppression of heme catabolism by inhibitors of this enzyme may thus be useful in potentiating erythropoietic responses in this disorder.

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Eclectic mechanisms of heme regulation of hematopoiesis

Cited by 21 publications

References 94 publications

Effect of Blood Substitute, Recombinant Hemoglobin, on in vivo Hematopoietic Recovery from AZT Toxicity

Effect of Blood Substitute, Recombinant Hemoglobin, on in vivo Hematopoietic Recovery from AZT Toxicity

Hematopoietic Effects of Benzene Inhalation Assessed by Long-Term Bone Marrow Culture

Elevated levels of heme oxygenase‐1 activity and mRNA in peripheral blood adherent cells of acquired immunodeficiency syndrome patients

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