Oral carbon monoxide therapy in murine sickle cell disease: Beneficial effects on vasoocclusion, inflammation and anemia

John D. Belcher, Edward Gomperts, Julia Nguyen, Chunsheng Chen, Fuad Abdulla, Zachary M. Kiser, David Gallo, Howard Levy, Leo E. Otterbein, Gregory M. Vercellotti

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Abstract

Carbon monoxide (CO) at low, non-toxic concentrations has been previously demonstrated to exert anti-inflammatory protection in murine models of sickle cell disease (SCD). However CO delivery by inhalation, CO-hemoglobin infusion or CO-releasing molecules presents problems for daily CO administration. Oral administration of a CO-saturated liquid avoids many of these issues and potentially provides a platform for self-administration to SCD patients. To test if orally-delivered CO could modulate SCD vaso-occlusion and inflammation, a liquid CO formulation (HBI-002) was administered by gavage (10 ml/kg) once-daily to NY1DD and Townes-SS transgenic mouse models of SCD. Baseline CO-hemoglobin (CO-Hb) levels were 1.6% and 1.8% in NY1DD and Townes-SS sickle mice and 0.6% in Townes-AS control mice. CO-Hb levels reached 5.4%, 4.7% and 3.0% within 5 minutes in NY1DD, SS and AS mice respectively after gavage with HBI-002. After ten treatments, each once-daily, hemoglobin levels rose from 5.3g/dL in vehicle-treated Townes-SS mice to 6.3g/ dL in HBI-002-treated. Similarly, red blood cell (RBC) counts rose from 2.36 × 106/μL in vehicle- treated SS mice to 2.89 × 106/μL in HBI-002-treated mice. In concordance with these findings, hematocrits rose from 26.3% in vehicle-treated mice to 30.0% in HBI-002-treated mice. Reticulocyte counts were not significantly different between vehicle and HBI-002- treated SS mice implying less hemolysis and not an increase in RBC production. White blood cell counts decreased from 29.1 × 103/μL in vehicle-treated versus 20.3 × 103/μL in HBI-002-treated SS mice. Townes-SS mice treated with HBI-002 had markedly increased Nrf2 and HO-1 e×pression and decreased NF-κB activation compared to vehicle-treated mice. These anti-inflammatory effects were examined for the ability of HBI-002 (administered orally once-daily for up to 5 days) to inhibit vaso-occlusion induced by hypoxia-reoxygenation. In NY1DD and Townes-SS sickle mice, HBI-002 decreased microvascular stasis in a duration-dependent manner. Collectively, these findings support HBI-002 as a useful anti-inflammatory agent to treat SCD and warrants further development as a therapeutic.

Original languageEnglish (US)
Article numbere0205194
JournalPloS one
Volume13
Issue number10
DOIs
StatePublished - Oct 2018

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