Citations (references)

Concussion and Neural Injury

Ahmad AS, Zhuang H, Dore S. Heme oxygenase-1 protects brain from acute excitotoxicity. Neuroscience 2006;141:1703-8.

Almeida, et al.  Carbon Monoxide Modulates Apoptosis by Reinforcing Oxidative Metabolism in Astrocytes.  The Journal of Biological Chemistry Vol. 287, No. 14, pp. 10761–10770, March 30, 2012.

Bani-Hani.  Modulation of Thrombin-Induced Neuroinflammation in BV-2 Microglia by Carbon Monoxide-Releasing Molecule 3.  The Journal of Pharmacology and Experimental Therapeutics. Vol. 318, No. 3.  2006.

Chao XD, Ma YH, Luo P, et al. Up-regulation of heme oxygenase-1 attenuates brain damage after cerebral ischemia via simultaneous inhibition of superoxide production and preservation of NO bioavailability. Experimental neurology 2013;239:163-9.

Choi YK, Maki T, Mandeville ET, Koh SH, Hayakawa K, Arai K, Kim YM, Whalen MJ, Xing C, Wang X, Kim KW, Lo EH.  Dual effects of carbon monoxide on pericytes and neurogenesis in traumatic brain injury. Nat Med. 2016 Sep 26. doi: 10.1038/nm.4188.

Chora AA, Fontoura P, Cunha A, Pais TF, Cardoso S, Ho PP, Lee LY, Sobel RA, Steinman L, Soares MP.  Heme oxygenase-1 and carbon monoxide suppress autoimmune neuroinflammation.  J Clin Invest. 2007 Feb;117(2):438-47.

Fagone P, Mangano K, Coco M, et al. Therapeutic potential of carbon monoxide in multiple sclerosis. Clinical and experimental immunology 2012;167:179-87.

Fagone P, Mangano K, Quattrocchi C, et al. Prevention of clinical and histological signs of proteolipid protein (PLP)-induced experimental allergic encephalomyelitis (EAE) in mice by the water-soluble carbon monoxide-releasing molecule (CORM)-A1. Clinical and experimental immunology 2011;163:368-74.

Klaus JA, Kibler KK, Abuchowski A, Koehler RC. Early treatment of transient focal cerebral ischemia with bovine PEGylated carboxy hemoglobin transfusion. Artificial cells, blood substitutes, and immobilization biotechnology 2010;38:223-9.

Liu Y, Zhu B, Luo L, Li P, Paty DW, Cynader MS. Heme oxygenase-1 plays an important protective role in experimental autoimmune encephalomyelitis. Neuroreport 2001;12:1841-5.

Mahan, VL.  Neuroprotective, neurotherapeutic, and neurometabolic effects of carbon monoxide.  Medical Gas Research 2012, 2:32.

Mahan VL, Zurakowski D, Otterbein LE, Pigula FA.  Inhaled Carbon Monoxide Provides Cerebral Cytoprotection in Pigs. PLoS ONE (2012) 7(8): e41982.

Nikolic I, Vujicic M, Stojanovic I, Stosic-Grujicic S, Saksida T. Carbon monoxide-releasing molecule-A1 inhibits Th1/Th17 and stimulates Th2 differentiation in vitro. Scandinavian journal of immunology 2014;80:95-100.

Pae HO, Oh GS, Choi BM, et al. Carbon monoxide produced by heme oxygenase-1 suppresses T cell proliferation via inhibition of IL-2 production. Journal of immunology 2004;172:4744-51.

Panahian N, Yoshiura M, Maines MD. Overexpression of heme oxygenase-1 is neuroprotective in a model of permanent middle cerebral artery occlusion in transgenic mice. Journal of neurochemistry 1999;72:1187-203.

Queiroga, C. S., Almeida, A. S., Martel, C., Brenner, C., Alves, P. M., and Vieira, H. L. (2010) Glutathionylation of adenine nucleotide translocase induced by carbon monoxide prevents mitochondrial membrane permeabilization and apoptosis. J. Biol. Chem. 285, 17077–17088.

Steinman L. No Quiet Surrender: Molecular Guardians In Multiple Sclerosis Brain. Journal of Clinical Investigation In Press.

Tardif V, Riquelme SA, Remy S, et al. Carbon monoxide decreases endosome-lysosome fusion and inhibits soluble antigen presentation by dendritic cells to T cells. European journal of immunology 2013;43:2832-44.

Vieira HL, Queiroga CA, Alves PM (2008) Pre-conditioning induced by carbon monoxide provides neuronal protection against apoptosis. J Neurochem 107(2): 375–384.

Wang B, Cao W, Biswal S, Dore S. Carbon monoxide-activated Nrf2 pathway leads to protection against permanent focal cerebral ischemia. Stroke; a journal of cerebral circulation 2011;42:2605-10.

Wang XM, Kim HP, Nakahira K, Ryter SW, Choi AM. The heme oxygenase-1/carbon monoxide pathway suppresses TLR4 signaling by regulating the interaction of TLR4 with caveolin-1. Journal of immunology 2009;182:3809-18.

Zeynalov E, Dore S. Low doses of carbon monoxide protect against experimental focal brain ischemia. Neurotoxicity research 2009;15:133-7.

Zhang J, Cao S, Kwansa H, Crafa D, Kibler KK, Koehler RC. Transfusion of hemoglobin-based oxygen carriers in the carboxy state is beneficial during transient focal cerebral ischemia. Journal of applied physiology 2012;113:1709-17.

Zimmerman.  Cerebroprotective effects of the CO-releasing molecule CORM-A1 against seizure-induced neonatal vascular injury.  Am J Physiol Heart Circ Physiol 293: H2501–H2507, 2007.

Sickle Cell Disease

Aroutiounian S.Kh., Louderback J.G., Ballas S.K., Kim-Shapiro D.B. Evidence for carbon monoxide binding to sickle cell polymers during melting. Biophysical Chemistry 91 2001; 167-181.

Beckman J, Belcher, JD, Vineyard JV, Chen C, Nguyen J, Nwaneri MD, O’Sullivan MG, Gulbahee E, Hebbel RP, Vercellotti GM. Inhaled carbon monoxide reduces leukocytosis in a murine model of sickle cell disease. Am J Physiol Heart Circ Physiol 2009; 297: H1243–H1253.

Belcher JD, Mahaseth H, Welch TE, Otterbein LE, Hebbel RP, Vercellotti GM J. Heme oxygenase-1 is a modulator of inflammation and vaso-occlusion in transgenic sickle mice. Clin Invest 2006; 116: 808-816.

Belcher JD, Vineyard JV, Bruzzone CM, et al. Heme oxygenase-1 gene delivery by Sleeping Beauty inhibits vascular stasis in a murine model of sickle cell disease. J Mol Med (Berl). 2010;88(7):665-675

Belcher JD, Young M, Chen C, Nguyen J, Burhop K, Tran P, Vercellotti GM. MP4CO, a pegylated hemoglobin saturated with carbon monoxide, is a modulator of HO-1, inflammation and vaso-occlusion in transgenic sickle cell mice. Blood, 2013; 122 : 2757-2764.

Beutler E. The effect of carbon monoxide on red cell life span in sickle cell disease. Blood 1975; 46: 253–259.

Ferreira A, Margut I, Bechman I, Jeney V, Chora A, Palha NR, Rebelo S, Henri A, Beuzard Y, Soares MP. Sickle Hemoglobin confers tolerance to Plasmodium infection. Cell 2011; 145: 398-409.

Gomperts E, Belcher JD, Otterbein LE, Coates TD, Wood J, Skolnick BE, Levy H, Vercellotti GM.  The role of carbon monoxide and heme oxygenase in the prevention of sickle cell disease vaso-occlusive crises.  Am J Hematol. 2017 Jun;92(6):569-582.

Hebbel RP, Vercellotti GM, Nath KA. A systems biology consideration of the vasculopathy of Sickle Cell Anemia: The need for multi-modality chemo-prophylaxis. Cardiovasc Hematol Disord Drug Targets, 2009; 9 : 271-292.

Higgins JM, Eddington DT, Bhatia SN, Mahadevan L. Sickle cell vasoocclusion and rescue in a microfluidic device. Proc Natl Acad Sci USA, 2007; 104: 20496-20500.

Howard JLT, S.; Galacteros, F.; Anati, A.; Reid, M.; Keipert, P.E.; Small, T.N.; Booth, F. . Safety and Tolerability Of MP4CO: A Dose Escalation Study In Stable Patients With Sickle Cell Disease.  55th ASH Annual Meeting; 2013; New Orleans, LA: American Society of Hematology.

Sirs, J.A.The use of carbon monoxide to prevent sickle-cell formation. Lancet 1;1963: 971-2.

Yallop D, Duncan ER, Norris E, Fuller GW, Thomas N, Walters J, Dick MC, Height SE,   Thein SL, Rees DC. The associations between air quality and the number of hospital admissions for acute pain and sickle-cell disease in an urban environment. Br J Haematol2007; 136(6): 844-8.

Delayed Graft Function in Kidney Transplant

Akamatsu Y, Haga M, Tyagi S, Yamashita K, Graça-Souza AV, Ollinger R, Czismadia E, May GA, Ifedigbo E, Otterbein LE, Bach FH, Soares MP. Heme oxygenase-1-derived carbon monoxide protects hearts from transplant associated ischemia reperfusion injury. FASEB J. 2004 Apr;18(6):771-2.

Amano MT, Camara NO. The immunomodulatory role of carbon monoxide during transplantation. Med Gas Res. 2013; 3:1.

Correa-Costa M, Amano MT, Câmara NO. Cytoprotection behind heme oxygenase-1 in renal diseases. World J Nephrol. 2012; 1:4-11.

Hanto DW, Maki T, Yoon MH, Csizmadia E, Chin BY, Gallo D, Konduru B, Kuramitsu K, Smith NR, Berssenbrugge A, Attanasio C, Thomas M, Wegiel B, Otterbein LE. Intraoperative administration of inhaled carbon monoxide reduces delayed graft function in kidney allografts in Swine. Am J Transplant. 2010; 10:2421-30.

Lee SS, Gao W, Mazzola S, Thomas MN, Csizmadia E, Otterbein LE, Bach FH, Wang H. Heme oxygenase-1, carbon monoxide, and bilirubin induce tolerance in recipients toward islet allografts by modulating T regulatory cells. FASEB J. 2007 21:3450-3457.

Nakao A, Choi AM, Murase N. Protective effect of carbon monoxide in transplantation. J Cell Mol Med. 2006 10: 650-71

Nakao A, Toyoda Y. Application of carbon monoxide for transplantation. Curr Pharm Biotechnol. 2012; 13:827-36.

Neto, J., Nakao, A. Toyokawa, Kaizu, T., Azhipa, O., Stolz, D.B., Choi, A.M., Murase, N.  Low-dose carbon monoxide prevents development of chronic allograft nephropathy.  Am J. Physiolo. Renal Physiol. 2006. 290: F324-34.

Ozaki KS, Kimura S, Murase N. Use of carbon monoxide in minimizing ischemia/reperfusion injury intransplantation. Transplant Rev (Orlando). 2012 Apr;26(2):125-39.

Ramlawi B, Scott JR, Feng J, Mieno S, Raman KG, Gallo D, Csizmadia E, Yoke Chin B, Bach FH, Otterbein LE, Sellke FW. Inhaled carbon monoxide prevents graft-induced intimal hyperplasia in swine.  J Surg Res. 2007 138:121-7.

Sato, K., Balla, J., Otterbein, L., Smith, R.N., Brouard, S., Lin, Y., Csizmadia, E., Sevigny, J., Robson, S.C., Vercellotti, G., Choi, A.M., Bach, F.H., Soares, M.P. 2001. Carbon monoxide generated by heme oxygenase-1 suppresses the rejection of mouse-to-rat cardiac transplants. J Immunol. 166: 4185-4194.

Sener A, Tran KC, Deng JP, Garcia B, Lan Z, Liu W, Sun T, Arp J, Salna M, Acott P, Cepinskas G, Jevnikar AM, Luke PP. Carbon monoxide releasing molecules inhibit cell death resulting from renal transplantation related stress. J Urol. 2013; 190:772-8.

Siriussawakul A, Chen LI, Lang JD. Medical gases: a novel strategy for attenuating ischemia-reperfusion injury in organ transplantation? J Transplant. 2012;2012:819382.

Snijder PM, van den Berg E, Whiteman M, Bakker SJ, Leuvenink HG, van Goor H. Emerging role of gasotransmitters in renal transplantation. Am J Transplant. 2013;13:3067-75.

Takahashi T, Morita K, Akagi R, Sassa S. Protective role of heme oxygenase-1 in renal ischemia. Antioxid Redox Signal. 2004; 6:867-77.

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Bathoorn E, Slebos DJ, Postma DS, et al. Anti-inflammatory effects of inhaled carbon monoxide in patients with COPD: a pilot study. The European respiratory journal 2007;30:1131-7.

Howard JLT, S.; Galacteros, F.; Anati, A.; Reid, M.; Keipert, P.E.; Small, T.N.; Booth, F.. Safety and Tolerability Of MP4CO: A Dose Escalation Study In Stable Patients With Sickle Cell Disease.  55th ASH Annual Meeting; 2013; New Orleans, LA: American Society of Hematology.

Mahan VL. Neuroprotective, neurotherapeutic, and neurometabolic effects of carbon monoxide. Medical gas research 2012;2:32.

Misra H, Lickliter J, Kazo F, Abuchowski A. PEGylated carboxyhemoglobin bovine (SANGUINATE): results of a phase I clinical trial. Artif Organs. 2014 Aug;38(8):702-7. doi: 10.1111/aor.12341. Epub 2014 Aug 12.

Mayr FB1, Spiel A, Leitner J, Marsik C, Germann P, Ullrich R, Wagner O, Jilma B.  Effects of carbon monoxide inhalation during experimental endotoxemia in humans.  Am J Respir Crit Care Med. 2005 Feb 15;171(4):354-60. Epub 2004 Nov 19.

Rhodes MA, Carraway MS, Piantadosi CA, Reynolds CM, Cherry AD, Wester TE, Natoli MJ, Massey EW, Moon RE, Suliman HB.Am J Physiol Heart Circ Physiol. Carbon monoxide, skeletal muscle oxidative stress, and mitochondrial biogenesis in humans. 2009 Jul;297(1):H392-9. doi: 10.1152/ajpheart.00164.2009. Epub 2009 May 22.

HBI-002, Heme Oxygenase, and Carbon Monoxide

Abraham N, Kappas A.  Pharmacological and Clinical Aspects of Heme Oxygenase.  Pharmacological Reviews March 2008   vol. 60no. 179-127

Chung J , Shin DY, Zheng M, Joe Y, Pae HO, Ryter SW, Chung HT.  Carbon monoxide, a reaction product of heme oxygenase-1, suppresses the expression of C-reactive protein by endoplasmic reticulum stress through modulation of the unfolded protein response. Mol Immunol. 2011 Sep;48(15-16):1793-9.

Da-Yong Shin, Jihwa Chung, Yeonsoo Joe, Hyun-Ock Pae, Ki Churl Chang, Gyeong Jae Cho, Stefan Ryter, Hun-Taeg Chung. Pretreatment with CO-releasing molecules suppresses hepcidin expression during inflammation and endoplasmic reticulum stress through inhibition of the STAT 3 and CREBH pathways. Blood 2012: 119 ; 2523-2532.

Foresti R, Hammad J, Clark JE, Johnson TR, Mann BE, Friebe A, Green CJ, Motterlini R.  Vasoactive properties of CORM-3, a novel water-soluble carbon monoxide-releasing molecule.  Br J Pharmacol. 2004 Jun;142(3):453-60.

Gomperts E, Forman HJ, Liu Honglei, Lee Martin.  The pharmacokinetic evaluation of oral administered carbon monoxide instilled in a liquid formulation (CO-LF) to rats to determine carbon monoxide hemoglobin levels with potential efficacy in patients with Sickle Cell Disease (SCD).  American Society of Hematology 2013, Abstract 3431. 

Kim KM, Pae HO, Zheng M, Park R, Kim YM, Chung HT.  Carbon Monoxide Induces Heme Oxygenase-1 via Activation of Protein Kinase R-Like Endoplasmic Reticulum Kinase and Inhibits Endothelial Cell Apoptosis Triggered by Endoplasmic Reticulum Stress.  Circ Res. 2007;101:919-927.

Morse D, Lin L, Choi AM, Ryter SW. Heme oxygenase-1, a critical arbitrator of cell death pathways in lung injury and disease. Free radical biology & medicine 2009;47:1-12.

Motterlini R, Clark JE, Foresti R, Sarathchandra P, Mann BE, Green CJ.  Carbon monoxide-releasing molecules: characterization of biochemical and vascular activities.  Circ Res. 2002 Feb 8;90(2):E17-24.

Motterlini R, Haas B, Foresti R.  Emerging concepts on the anti-inflammatory actions of carbon monoxide-releasing molecules (CO-RMs).  Med Gas Res. 2012 Nov 21;2(1):28

Motterlini R, Otterbein LE.  The therapeutic potential of carbon monoxide.  Nat Rev Drug Discov. 2010 Sep;9(9):728-43.

Motterlini R, Sawle P, Bains S, Hammad J, Alberto R, Foresti R, Green CJ. CORM-A1: A new pharmacologically active carbon-monoxide-releasing molecule. FASEB; 2004; 10:1096: 1-24.

Otterbein LE , Bach FH, Alam J, Soares M, Tao Lu H, Wysk M, Davis RJ, Flavell RA, Choi AM.  Carbon monoxide has anti-inflammatory effects involving the mitogenactivated protein kinase pathway.  Nat Med. 2000 Apr;6(4):422-8.

Otterbein LE, Soares M, Yamashita K, Bach FH.  Heme oxygenase-1: unleashing the protective properties of heme.  TRENDS in Immunology Vol.24 No.8 August 2003.

Sawle P, Foresti R, Mann BE, Johnson TR, Green CJ, Motterlini R.  Carbon monoxide-releasing molecules (CO-RMs) attenuate the inflammatory response elicited by lipopolysaccharide in RAW264.7 murine macrophages.  Br J Pharmacol. 2005 Jul;145(6):800-10.

Shin DY, Chung J, Joe Y, Pae HO, Chang KC, Cho GJ, Ryter SW, Chung HT.  Pretreatment with CO-releasing molecules suppresses hepcidin expression during inflammation and endoplasmic reticulum stress through inhibition of the STAT3 and CREBH pathways.  Blood. 2012 Mar 15;119(11):2523-32.

Zhang X, Shan P, Alam J, Fu XY, Lee PJ.  Carbon monoxide differentially modulates STAT1 and STAT3 and inhibits apoptosis via a phosphatidylinositol 3-kinase/Akt and p38 kinase-dependent STAT3 pathway during anoxia-reoxygenation injury.  J Biol Chem. 2005 Mar 11;280(10):8714-21.



The United States Centers for Disease Control (CDC) at and

The National Institute of Neurological Disorders and Stroke at

The Brain Trauma Foundation at


Sickle Cell Disease

The United States Centers for Disease Control (CDC) at

The National Heart, Lung and Blood Institute (NIH/NHLBI) at

The Sickle Cell Disease Association of America at 

The Foundation for Sickle Cell Disease Research at

The Sickle Cell Society (UK) at


Kidney Transplant

The United States Centers for Disease Control (CDC) at

The National Kidney Foundation at

The National Institute of Diabetes and Digestive and Kidney Disease at