Cell-free and alkylated hemoproteins improve survival in mouse models of carbon monoxide poisoning

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Abstract

I.v. administration of a high-affinity carbon monoxide–binding (CO-binding) molecule, recombinant neuroglobin, can improve survival in CO poisoning mouse models. The current study aims to discover how biochemical variables of the scavenger determine the CO removal from the RBCs by evaluating 3 readily available hemoproteins, 2,3-diphosphoglycerate stripped human hemoglobin (StHb); N-ethylmaleimide modified hemoglobin (NEMHb); and equine myoglobin (Mb). These molecules efficiently sequester CO from hemoglobin in erythrocytes in vitro. A kinetic model was developed to predict the CO binding efficacy for hemoproteins, based on their measured in vitro oxygen and CO binding affinities, suggesting that the therapeutic efficacy of hemoproteins for CO poisoning relates to a high M value, which is the binding affinity for CO relative to oxygen (KA,CO/KA,O2). In a lethal CO poisoning mouse model, StHb, NEMHb, and Mb improved survival by 100%, 100%, and 60%, respectively, compared with saline controls and were well tolerated in 48-hour toxicology assessments. In conclusion, both StHb and NEMHb have high CO binding affinities and M values, and they scavenge CO efficiently in vitro and in vivo, highlighting their therapeutic potential for point-of-care antidotal therapy of CO poisoning.

Authors

Qinzi Xu, Jason J. Rose, Xiukai Chen, Ling Wang, Anthony W. DeMartino, Matthew R. Dent, Sagarika Tiwari, Kaitlin Bocian, Xueyin N. Huang, Qin Tong, Charles F. McTiernan, Lanping Guo, Elmira Alipour, Trevor C. Jones, K. Burak Ucer, Daniel B. Kim-Shapiro, Jesús Tejero, Mark T. Gladwin