Inhibition of Myeloperoxidase by a Carbon Monoxide‐Releasing Molecule, CORM‐3

Carbon monoxide (CO)‐releasing molecules (CORMs) have recently been shown to suppress inflammation by interfering with neutrophil function. However, the mechanisms are not completely understood. Neutrophilic myeloperoxidase (MPO) is known to induce tissue damage through: 1) the direct oxidation and/or 2) through the hypohalous acid‐dependent oxidation of targets. We hypothesized that CORM‐released CO inhibits MPO activity and thereby reduces neutrophil‐associated injury. In these studies, we used a water‐soluble, ruthenium‐based CORM (CORM‐3) that we synthesized and known to suppress inflammation. In vitro assays were used to study CO release under conditions relevant to inflammation. Further studies investigated CORM‐3's ability to inhibit total MPO activity as well as the activity of the peroxidation and halogenation components. Results indicate that CORM‐3‐released CO inhibited total MPO activity in a dose‐dependent manner. Furthermore, both the peroxidation and halogenation activities of MPO were inhibited by CORM‐3 in a dose‐dependent manner. On the contrary, control molecules; inactive CORM‐3 (a CORM lacking CO), or RuCl 3 were less effective. In summary, CORM‐3‐derived CO inhibits MPO activity and therefore may suppress neutrophil‐induced tissue damage. (HSFO NA6914 and LHRI IRF‐025‐09)