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

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 × 10 6 /μL in vehicle- treated SS mice to 2.89 × 10 6 /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 × 10 3 /μL in vehicle-treated versus 20.3 × 10 3 /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 1 2018

Fingerprint

sickle cell anemia
carbon monoxide
Sickle Cell Anemia
Carbon Monoxide
anemia
Anemia
mouth
inflammation
Inflammation
therapeutics
mice
Therapeutics
Hemoglobins
Blood
Anti-Inflammatory Agents
hemoglobin
Rosa
Cells
animal models
Liquids

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

Cite this

Oral carbon monoxide therapy in murine sickle cell disease : Beneficial effects on vasoocclusion, inflammation and anemia. / Belcher, John D; Gomperts, Edward; Nguyen, Julia; Chen, Chunsheng; Abdulla, Fuad; Kiser, Zachary M.; Gallo, David; Levy, Howard; Otterbein, Leo E.; Vercellotti, Gregory M.

In: PloS one, Vol. 13, No. 10, e0205194, 01.10.2018.

Research output: Contribution to journalArticle

Belcher, John D ; Gomperts, Edward ; Nguyen, Julia ; Chen, Chunsheng ; Abdulla, Fuad ; Kiser, Zachary M. ; Gallo, David ; Levy, Howard ; Otterbein, Leo E. ; Vercellotti, Gregory M. / Oral carbon monoxide therapy in murine sickle cell disease : Beneficial effects on vasoocclusion, inflammation and anemia. In: PloS one. 2018 ; Vol. 13, No. 10.
@article{3cf8e17bc3394974861df41586e595ab,
title = "Oral carbon monoxide therapy in murine sickle cell disease: Beneficial effects on vasoocclusion, inflammation and anemia",
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 × 10 6 /μL in vehicle- treated SS mice to 2.89 × 10 6 /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 × 10 3 /μL in vehicle-treated versus 20.3 × 10 3 /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.",
author = "Belcher, {John D} and Edward Gomperts and Julia Nguyen and Chunsheng Chen and Fuad Abdulla and Kiser, {Zachary M.} and David Gallo and Howard Levy and Otterbein, {Leo E.} and Vercellotti, {Gregory M}",
year = "2018",
month = "10",
day = "1",
doi = "10.1371/journal.pone.0205194",
language = "English (US)",
volume = "13",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "10",

}

TY - JOUR

T1 - Oral carbon monoxide therapy in murine sickle cell disease

T2 - Beneficial effects on vasoocclusion, inflammation and anemia

AU - Belcher, John D

AU - Gomperts, Edward

AU - Nguyen, Julia

AU - Chen, Chunsheng

AU - Abdulla, Fuad

AU - Kiser, Zachary M.

AU - Gallo, David

AU - Levy, Howard

AU - Otterbein, Leo E.

AU - Vercellotti, Gregory M

PY - 2018/10/1

Y1 - 2018/10/1

N2 - 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 × 10 6 /μL in vehicle- treated SS mice to 2.89 × 10 6 /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 × 10 3 /μL in vehicle-treated versus 20.3 × 10 3 /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.

AB - 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 × 10 6 /μL in vehicle- treated SS mice to 2.89 × 10 6 /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 × 10 3 /μL in vehicle-treated versus 20.3 × 10 3 /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.

UR - http://www.scopus.com/inward/record.url?scp=85054768819&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85054768819&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0205194

DO - 10.1371/journal.pone.0205194

M3 - Article

VL - 13

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 10

M1 - e0205194

ER -