Cell-free and alkylated hemoproteins improve survival in mouse models of carbon monoxide poisoning
Qinzi Xu, … , Jesús Tejero, Mark T. Gladwin
Qinzi Xu, … , Jesús Tejero, Mark T. Gladwin
Published September 29, 2022
Citation Information: JCI Insight. 2022;7(21):e153296. https://doi.org/10.1172/jci.insight.153296.
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Research Article Pulmonology Therapeutics

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

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

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Figure 8

Computationally simulated in vivo scavenging kinetics in lethal–CO-poisoning model.

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Computationally simulated in vivo scavenging kinetics in lethal–CO-poiso...
See Supplemental Table 3 for specific parameters used in these models. (A) Comparison of initial (2–3 minutes) scavenging kinetics by oxyStHb (solid blue line), oxyMb (solid orange line), and Ngb-H64Q-CCC (solid purple line) in the lethal model, which starts at 95% for COHbRBC%. Altering only the koff of oxygen to adjust the M value (equation), StHb was changed to the M value of Mb (242 → 16, blue hashed lines) and Mb to the M value of StHb (16 → 242, orange hashed lines), resulting in scavenging kinetics approximating one another; however, the kinetic profiles are different, largely due to differences in the other individual rate constants between each protein. B–E depict scavenging by StHb from CO loaded RBCs (black line, native rate constant values) while increasing (blue lines) or decreasing (orange lines) the individual rate constants of the StHb scavenger in ways to maintain a constant M value at 242. (B) Increasing koff values concomitantly for CO and oxygen does not change scavenging kinetics much; however, decreasing koff values slows the scavenging rate. (C) If instead, the kon values are both increased or decreased simultaneously, no change is observed as the limitations stem from release of CO from the RBC and competition for oxygen and CO binding to the scavenger changes analogously. (D) Altering the kon and koff of CO in a manner where they generate the same affinity (KA) results in scavenging kinetics similar to B. (E) Changes in the kon and koff of oxygen the same amount does not alter the predicted rate of scavenging.