title: Inhaled carbon monoxide reduces leukocytosis in a murine model of sickle cell disease.
abstract: Carbon monoxide (CO) has anti-inflammatory properties. We previously reported that acute treatments with inhaled CO inhibit vascular inflammation and hypoxia-induced vasoocclusion in sickle cell disease mouse models. Therefore, we hypothesized that chronic CO inhalation would decrease vascular inflammation and organ pathology in a sickle cell disease mouse model. The treatment of sickle cell disease mice with 25 or 250 parts/million inhaled CO for 1 h/day, 3 days/wk for 8-10 wk significantly decreased the total mean white blood cell, neutrophil, and lymphocyte counts in peripheral blood. Eight weeks of 250 parts/million CO treatments reduced staining for myeloid and lymphoid markers in the bone marrow of sickle mice. Bone marrow from treated sickle mice exhibited a significant decrease in colony-forming unit granulocyte-macrophage during colony-forming cell assays. Anti-inflammatory signaling pathways phospho-Akt and phospho-p38 MAPK were markedly increased in CO-treated sickle livers. Importantly, CO-treated sickle mice had a significant reduction in liver parenchymal necrosis, reflecting the anti-inflammatory benefits of CO. We conclude that inhaled CO may be a beneficial anti-inflammatory therapy for sickle cell disease.
authors.affiliation: Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota MedicalSchool, Minneapolis, USA.
authors.forename: Joan D
authors.initials: JD
authors.lastname: Beckman
authors.forename: John D
authors.initials: JD
authors.lastname: Belcher
authors.forename: Julie V
authors.initials: JV
authors.lastname: Vineyard
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Chen
authors.forename: Julia
authors.initials: J
authors.lastname: Nguyen
authors.forename: M Osita
authors.initials: MO
authors.lastname: Nwaneri
authors.forename: M Gerard
authors.initials: MG
authors.lastname: O'Sullivan
authors.forename: Evin
authors.initials: E
authors.lastname: Gulbahce
authors.forename: Robert P
authors.initials: RP
authors.lastname: Hebbel
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Vercellotti
mesh_terms: D000280:Administration, Inhalation; D000755:Anemia, Sickle Cell / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D001052:Apoferritins / Q000378:metabolism; D002248:Carbon Monoxide / Q000008:administration & dosage*; D002263:Carboxyhemoglobin / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D015672:Erythroid Precursor Cells / Q000187:drug effects; D005260:Female; D055014:Granulocyte-Macrophage Progenitor Cells / Q000187:drug effects; D006410:Hematopoiesis / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006451:Hemoglobin, Sickle / Q000235:genetics / Q000378:metabolism; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D007958:Leukocyte Count; D007964:Leukocytosis / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009336:Necrosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D006451:Hemoglobin, Sickle; D008565:Membrane Proteins; C055657:hemoglobin S-Antilles; D002248:Carbon Monoxide; D001052:Apoferritins; D002263:Carboxyhemoglobin; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases