Hemopexin Metabolism in Sickle-Cell Disease, Porphyrias and Control Subjects — Effects of Heme Injection

Wochner, R. Dean; Spilberg, Isaias; A, Iio; Liem, H. H.; Müller‐Eberhard, Ursula

doi:10.1056/nejm197404112901503

Cited by 43 publications

(24 citation statements)

References 24 publications

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“…Albumin and other plasma proteins ultimately transfer hemin to Hx for delivery to the liver, the hemin/Hx complex is internalized, and hemin is degraded by HO-1. This catabolism occurs at an extremely rapid rate in SCD patients (40). Consequently, the Hx concentration in human SCD plasma is very low (39,40), which we have previously confirmed (0.24 ± 0.02 mg/ml, or 4.0 ± 0.33 μM; n = 81; ref.…”

Section: Discussionsupporting

confidence: 71%

“…This catabolism occurs at an extremely rapid rate in SCD patients (40). Consequently, the Hx concentration in human SCD plasma is very low (39,40), which we have previously confirmed (0.24 ± 0.02 mg/ml, or 4.0 ± 0.33 μM; n = 81; ref. 41).…”

Section: Discussionsupporting

confidence: 71%

“…SCD patients have raised plasma hemin concomitant with low Hx level (39,40); however, the clinical significance of this interrelated anomaly had not previously been defined. Indirect evidence from clinical studies suggests that alterations in hemin catabolism contribute to the development of ACS.…”

Section: Discussionmentioning

confidence: 99%

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Extracellular hemin crisis triggers acute chest syndrome in sickle mice

Ghosh¹,

Adisa²,

Chappa³

et al. 2013

J. Clin. Invest.

237

260

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The prevention and treatment of acute chest syndrome (ACS) is a major clinical concern in sickle cell disease (SCD). However, the mechanism underlying the pathogenesis of ACS remains elusive. We tested the hypothesis that the hemolysis byproduct hemin elicits events that induce ACS. Infusion of a low dose of hemin caused acute intravascular hemolysis and autoamplification of extracellular hemin in transgenic sickle mice, but not in sickle-trait littermates. The sickle mice developed multiple symptoms typical of ACS and succumbed rapidly. Pharmacologic inhibition of TLR4 and hemopexin replacement therapy prior to hemin infusion protected sickle mice from developing ACS. Replication of the ACS-like phenotype in nonsickle mice revealed that the mechanism of lung injury due to extracellular hemin is independent of SCD. Using genetic and bone marrow chimeric tools, we confirmed that TLR4 expressed in nonhematopoietic vascular tissues mediated this lethal type of acute lung injury. Respiratory failure was averted after the onset of ACS-like symptoms in sickle mice by treating them with recombinant hemopexin. Our results reveal a mechanism that helps to explain the pathogenesis of ACS, and we provide proof of principle for therapeutic strategies to prevent and treat this condition in mice.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionsupporting

confidence: 71%

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Extracellular hemin crisis triggers acute chest syndrome in sickle mice

Ghosh¹,

Adisa²,

Chappa³

et al. 2013

J. Clin. Invest.

237

260

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show abstract

“…However, these defenses are likely overwhelmed in SCD, as evidenced by the low haptoglobin concentrations seen in our sickle mice and low plasma hemopexin levels in SCD patients (74)(75)(76)(77). Moreover, the heme content and the overexpression of HO-1 in organs of sickle mice suggest that this is indeed the case.…”

Section: Figurementioning

confidence: 97%

Heme oxygenase-1 is a modulator of inflammation and vaso-occlusion in transgenic sickle mice

Belcher¹

2006

Journal of Clinical Investigation

236

225

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Transgenic sickle mice expressing β S hemoglobin have activated vascular endothelium that exhibits enhanced expression of NF-κB and adhesion molecules that promote vascular stasis in sickle, but not in normal, mice in response to hypoxia/reoxygenation. Sickle mice hemolyze rbcs in vivo as demonstrated by increased reticulocyte counts, plasma hemoglobin and bilirubin, and reduced plasma haptoglobin. The heme content is elevated in sickle organs, which promotes vascular inflammation and heme oxygenase-1 expression. Treatment of sickle mice with hemin further increases heme oxygenase-1 expression and inhibits hypoxia/reoxygenation-induced stasis, leukocyte-endothelium interactions, and NF-κB, VCAM-1, and ICAM-1 expression. Heme oxygenase inhibition by tin protoporphyrin exacerbates stasis in sickle mice. Furthermore, treatment of sickle mice with the heme oxygenase enzymatic product carbon monoxide or biliverdin inhibits stasis and NF-κB, VCAM-1, and ICAM-1 expression. Local administration of heme oxygenase-1 adenovirus to subcutaneous skin increases heme oxygenase-1 and inhibits hypoxia/reoxygenation-induced stasis in the skin of sickle mice. Heme oxygenase-1 plays a vital role in the inhibition of vaso-occlusion in transgenic sickle mice.

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“…Hemopexin has a higher binding affinity for metalloporphyrins than albumin (15) and is instrumental in the disposal of heme (5,8,9,14,19). The liver is the site of hemopexin synthesis in rhesus monkeys (17), rabbits (17), and rats (12).…”

mentioning

confidence: 99%

Hemopexin Synthesis in Vitro by Human Fetal Tissues

et al. 1975

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ExtractSerum concentrations of hemopexin, transferrin, and albumin were measured for 12 fetuses between 14 and 36 weeks of gestational age. Hemopexin levels ranged from 7 to 64 pg/ml, transferrin levels ranged from 280 to 928 pg/ml, and albumin levels ranged from 13 to 59 mg/ml. In general, the serum concentrations of these three proteins increased with advancing gestation.Placenta, thymus, and colon did not incorporate 14C-labeled amino acids into hemopexin, transferrin, or albumin. By contrast, radioimmune precipitates for five culture supernatants of liver indicated significant synthesis of albumin and hemopexin.[MC]Albumin accounted for 22-73% and [14C]hemopexin 1.1-4.2% of the total 14C-labeled proteins. In each instance, the ["Cltransferrin was below 1% of the total l 4 C-labeled proteins. SpeculationThese data show considerable synthesis of albumin and hemopexin, but not transferrin, by the liver during fetal life. That hemopexin levels are lower in fetal than adult sera may reflect an increased requirement for heme disposal. Possibly, the increased turnover of hemopexin is related to the shortened lifespan of fetal in comparison with adult erythrocytes.Mammalian serum contains two major porphyrin-binding proteins, hemopexin and albumin (1 I). Hemopexin has a higher binding affinity for metalloporphyrins than albumin (15) and is instrumental in the disposal of heme (5,8,9,14,19). The liver is the site of hemopexin synthesis in rhesus monkeys (17), rabbits (17), and rats (12). In the present study, human fetal tissues were cultured and examined for the relative amounts of hemopexin, albumin, and transferrin produced. MATERIALS A N D METHODS FETAL TISSUESSerum samples of fetuses were obtained by heart puncture.Tissuc culturcs of livcr, placenta, thymus, a n d colon of h u m a n fetuses, 12-25 weeks old, were developed by Dr. Peter F. Kohler (20), employing [14C]lysine and [14C]isoleucine (4). Culture supernatants were dialyzed against 0.015 M phosphate-buffered saline (PBS), pH 7.4, lyophilized, dissolved in distilled water (0.2-0.3 ml), shipped to La Jolla on Dry Ice, and stored at 7 0°.Tissues for absorption of antisera were obtained from fetuses within 5 hr of saline-induced abortion. Small pieces of liver, placenta, thymus, and colon were passed through a stainless steel mesh with the aid of screen rakes. Cells were washed three times with PBS and mixed with 3 volumes antiserum/l volume of cells. The mixtures were incubated at 37O for 30 min, at 4' for 48 hr, and then the cells were removed by centrifugation at 1,200 x g for 30 min. T o 5-50-pl aliquots of culture supernatant, 50 1 1 normal human serum as carrier protein were added and the nonspecific radioactivity was precipitated by addition of equivalent amounts of R G G and anti-BGG. T h e mixture was incubated 37' for 30 min, at 4' overnight, and centrifuged at 1,200 x g for 30 min at 4'. The supernatants were then used for precipitation with the monospecific antisera added to antibody excess. The reaction mixtures were incubated and centrifuged as...

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Hemopexin Metabolism in Sickle-Cell Disease, Porphyrias and Control Subjects — Effects of Heme Injection

Cited by 43 publications

References 24 publications

Extracellular hemin crisis triggers acute chest syndrome in sickle mice

Extracellular hemin crisis triggers acute chest syndrome in sickle mice

Heme oxygenase-1 is a modulator of inflammation and vaso-occlusion in transgenic sickle mice

Hemopexin Synthesis in Vitro by Human Fetal Tissues

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