Modulating Myeloperoxidase‐Induced Endothelial Permeability by a Carbon Monoxide‐Releasing Molecule, CORM‐3

Previous work has demonstrated that CORM‐derived carbon monoxide (CO) supresses inflammation. However, the mechanisms are not well understood. Neutrophil (PMN)‐derived myeloperoxidase (MPO) is known to play a significant role in the pathophysiology of numerous inflammatory disorders through: 1) direct peroxidation and 2) producing hypohalous acids, particularly hypochlorous acid. Thus, an overwhelming MPO‐dependent production of oxidants in the sub‐endothelial space after PMN degranulation, contributes to tissue damage and propagating inflammation. We hypothesized that CORM‐3‐derived CO interferes with MPO's catalytic activity, and thereby mitigates endothelial inflammatory damage. In vitro assays were used to study the inhibition of MPO's catalytic activity. Further, live cell in vitro assays were used to investigate endothelial damage through measuring reactive oxygen species (ROS) and cellular permeability. Our results indicate that CORM‐3 inhibits total MPO activity as well as MPO's peroxidation and halogenation cycles. Cellular assays determined that ROS production and cellular permeability are decreased when extracellular MPO is treated with CORM‐3. In all assays inactivated CORM‐3 (iCORM‐3) was significantly less effective than CORM‐3. We conclude that CO may mitigate inflammatory damage partly through inhibition of MPO activity. Support: HSFO‐393 and LHRI IRF‐025–09