Inflammatory mechanisms of carbon monoxide toxicity

CO activates platelets by displacing platelet nitric oxide (NO) from surface hemoproteins. NO reacts with oxygen free radicals (O₂–) to produce peroxynitrite (ONOO–), which inhibits mitochondrial function and activates platelets and neutrophils itself. Inhibited mitochondria leads to further production of reactive oxygen species (ROS) and causes release of free heme and ensuing increase of heme oxygenase 1 (HO-1), further causing oxidative stress. HO-1 metabolizes free heme to produce more endogenous CO, creating a positive feedback loop locally. Activated neutrophils will degranulate and release myeloperoxidase, causing more neutrophil activation as well as adhesion. Proteases released from neutrophils can oxidize endothelial cell xanthine dehydrogenase (XD) to xanthine oxidase (XO), generating reactive oxygen species causing cellular damage as well as lipid peroxidation, specifically on myelin basic protein (MBP). When peroxidated, MBP forms adducts that cause lymphocyte proliferation, microglia activation and ultimately, neurologic injury. The general effects of hypoxia and effect of CO toxicity directly on mitochondria cause glutamate release, which activates N-Methyl-D-aspartate (NDMA) receptors, further leading to neurologic injury.