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Cited by 282Hemoglobinopathies and Related DisordersHemoglobin structure and functionBlood groups and transfusion

Extracellular hemin crisis triggers acute chest syndrome in sickle mice

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Ghosh, Samit, Adisa, Olufolake Adetoro, Chappa, Prasanthi, Tan, Fang, Jackson, Kesmic Ann, Archer, David Robert, Ofori-Acquah, Solomon Fiifi·2013·Journal of Clinical Investigation
DOI 10.1172/jci64578PMC PMC3809772
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Abstract

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. Results Extracellular hemin elevation causes a lethal hemolytic crisis in sickle mice.To mimic acute extracellular hemin release, transgenic Townes sickle mice (referred to herein as SS mice; see Methods) and control sickletrait (AS) and wild-type human Hb (AA) mice were infused with a relatively low dose of purified hemin (35 μmol/kg).No adverse effects were seen in the control mice, but a majority of SS mice developed labored breathing and died within 2 hours (Figure 1A).We confirmed these acute adverse effects in a second murine model of SCD (Berkeley sickle mice; see Methods) and showed that the lethality rate was dependent on the dose of hemin (Figure 1B).A previous study had shown that 40 μmol/kg hemin given i.p. did not cause any fatalities in the Berkeley sickle mouse (26).A higher dose (70 μmol/kg) given i.v. had no adverse effects in wild-type mice (17, 27); moreover, the SS mouse deaths occurred 24 hours before hepatic failure onset, due to hemin overload in septic mice (28).Thus, our results in the SS mice revealed an unusual effect of extracellular hemin that had not previously been described.Plasma hemopexin (Hx) levels decreased sharply in all animals, coincident with nearly 50% clearance of the hemin bolus within Conflict of interest: The authors have declared that no conflict of interest exists.

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  • Animal models show that heme is directly responsible for acute lung injury in sickle cell disease mouse models.

    “animal models showing that heme is directly responsible for acute lung injury in SCD mouse models (89).”

    From Pathophysiology of Sickle Cell Disease (2019) · cites this paper as [89]

  • High levels of hemopexin can rescue acute lung injury, while HO-1 deficiency potentiates it.

    “high levels of hemopexin, the enzyme that scavenges heme, can rescue acute lung injury (89), while HO-1 deficiency potentiates it (57).”

    From Pathophysiology of Sickle Cell Disease (2019) · cites this paper as [89]

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Authors
Ghosh, S., Adisa, O. A., Chappa, P., Tan, F., Jackson, K. A., Archer, D. R., & Ofori-Acquah, S. F.
Affiliations
Emory University (US)
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2013-10-01
Volume
123
Issue
11
Pages
4809-4820
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci64578
PMC
PMC3809772
OpenAlex
W2100360129
Cited by
282
References
72
Citations by year
2026: 18 · 2025: 14 · 2024: 14 · 2023: 23 · 2022: 17 · 2021: 29 · 2020: 24 · 2019: 19 · 2018: 25 · 2017: 19 · 2016: 37 · 2015: 23 · 2014: 18 · 2013: 2
FWCI
13.13
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Heart Association
  • Emory University
  • National Heart, Lung, and Blood Institute (R01HL106192, K02HL088026, U01HL117721)
Topics
  • Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
  • Health Sciences › Medicine › Hematology › Blood groups and transfusion
Keywords
acute chest syndrome, sickle cell disease, hemolysis, TLR4, hemopexin, acute lung injury, respiratory failure, TLR4 inhibition, lung injury pathogenesis, bone marrow chimeras
MeSH terms
Anemia, Sickle Cell, Animals, Disease Models, Animal, Extracellular Space, Hemin, Hemoglobin, Sickle, Hemolysis, Hemopexin, Humans, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Mutant Strains, Mice, Transgenic, Recombinant Proteins, Sickle Cell Trait, Sulfonamides, Mice, Knockout, Toll-Like Receptor 4, Mice, Acute Chest Syndrome

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