Extracellular hemin crisis triggers acute chest syndrome in sickle mice
Samit Ghosh, … , David Robert Archer, Solomon Fiifi Ofori-Acquah
Samit Ghosh, … , David Robert Archer, Solomon Fiifi Ofori-Acquah
Published October 1, 2013
Citation Information: J Clin Invest. 2013;123(11):4809-4820. https://doi.org/10.1172/JCI64578.
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Research Article Hematology

Extracellular hemin crisis triggers acute chest syndrome in sickle mice

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.

Authors

Samit Ghosh, Olufolake Adetoro Adisa, Prasanthi Chappa, Fang Tan, Kesmic Ann Jackson, David Robert Archer, Solomon Fiifi Ofori-Acquah

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Figure 1

Sudden death associated with EHC.

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Sudden death associated with EHC. (A) Relatively low dose of hemin (35 μ...
(A) Relatively low dose of hemin (35 μmol/kg) caused sudden death in SS mice, but not in control AS and AA mice (n = 9). (B) Lethality associated with hemin in Townes sickle mice was dose dependent (n = 6). 100% lethality of sickle mice challenged with 70 μmol/kg hemin was confirmed using the Berkeley sickle mouse model (n = 6). (C–F) Characterization of EHC associated with sudden death in SS mice. n = 9 (SS); 6 (AA and AS). (C) Plasma Hx was significantly lower in SS mice at baseline (t = 0) and declined sharply in all 3 groups after hemin challenge. (D) SS mice had markedly higher TPH than AS and AA mice at baseline. TPH initially increased to the same level in all 3 groups. Hemin clearance by AA and AS mice and amplification by SS mice explains the significantly different values at 30 minutes. (E) metHb and (F) PFH in SS and control mice at baseline and 5 and 30 minutes after hemin challenge. *P < 0.05, ***P < 0.001.