Extracellular hemin crisis triggers acute chest syndrome in sickle mice
Samit Ghosh, Olufolake Adetoro Adisa, Prasanthi Chappa, Fang Tan, Kesmic Ann Jackson, David Robert Archer, Solomon Fiifi Ofori-Acquah
Samit Ghosh, Olufolake Adetoro Adisa, Prasanthi Chappa, Fang Tan, Kesmic Ann Jackson, David Robert Archer, Solomon Fiifi Ofori-Acquah
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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 5

Extracellular and intracellular hemin species cause unique organ toxicities.

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Extracellular and intracellular hemin species cause unique organ toxicit...
(A–D) SS mice were given 70 and 25 μmol/kg hemin to induce EHC and NCEH, respectively (n = 6–11). (A) SpO2 measured 20 minutes after induction. (B) Prognosis of SS mice. Death occurred within 2 hours in 100% of EHC mice and 12–72 hours later in 45% of NCEH mice. (C and D) Plasma concentration of (C) ALT and (D) AST, determined at baseline and either 20 minutes (EHC) or 24 hours (NCEH) after hemin challenge. (E) Representative H&E-stained sections of postmortem lung and liver in SS mice with EHC and NCEH and Perl’s Prussian blue (PPB) staining of the liver sections. Note the region of tissue damage (TD) likely caused by apoptosis and necrosis in the NCEH liver. Distribution of iron in Kupffer cells (arrow) and hepatocytes (arrowhead) was unique, with diffuse cytoplasmic staining in the hepatocytes. Original magnification, ×100 (H&E); ×200 (Perls); ×400 (insets). **P < 0.01, ***P < 0.001.