Intravascular Neutrophil Activation Due to Carbon Monoxide Poisoning

Abstract

Rationale:We hypothesized that platelet-neutrophil interactions occur as a result of acute carbon monoxide (CO) poisoning, and subsequent neutrophil activation triggers events that cause neurologic sequelae. Objectives: To identify platelet-neutrophil interactions and neutrophil activation in patients and in animal models, and to establish the association between these intravascular events and changes linked to CO-mediated neurologic sequelae in an animal model. Measurements and Main Results: Blood was obtained from 50 consecutive patients. Abnormalities were variable depending on the carboxyhemoglobin level at study admission and duration of CO exposure. Platelet-neutrophil aggregates were detected and plasma myeloperoxidase (MPO) concentration was significantly elevated in those with confirmed CO poisoning. Among patients exposed to CO for over 3 h, flow cytometry scans of neutrophils revealed increased surface expression of CD18 and, in some groups, MPO on the cell surface. Animal models revealed consistent evidence of platelet-neutrophil aggregates, neutrophil activation and surface MPO, and plasma MPO elevation. MPO was deposited along the brain vascular lining and colocalized with nitrotyrosine. CO poisoning caused abnormalities in the charge pattern of myelin basic protein (MBP), changes linked to adaptive immunologic responses responsible for neurologic sequelae in this model. Changes did not occur in thrombocytopenic rats, those receiving tirofiban to inhibit platelet-neutrophil interactions, or those receiving L-nitroarginine methyl ester to inhibit nitric oxide synthesis. Alterations in MBP did not occur in CO-poisoned knockout mice lacking MPO. Conclusions: Acute CO poisoning causes intravascular neutrophil activation due to interactions with platelets. MPO liberated by neutrophils mediates perivascular oxidative stress, which is linked to immune-mediated neurologic sequelae.Keywords: myelin basic protein; myeloperoxidase; neuropathology Carbon monoxide (CO) is the leading agent of injury and death by poisoning worldwide (1). An elevated carboxyhemoglobin (COHb) level can precipitate tissue hypoxia due to direct effects of CO on hemoglobin and because of impaired perfusion from cardiac dysfunction. High COHb levels impair mitochondrial electron transport because CO binds to cytochrome c oxidase. In brain, this has been shown to impair ATP synthesis and increase mitochondrial production of reactive oxygen species (2, 3). Energy production and mitochondrial function are restored after COHb levels decrease, but the transient changes can cause Pathophysiologic mechanisms for CO-mediated brain injury are known to extend beyond hypoxic stress due to carboxyhemoglobin, but they are poorly understood. What This Study Adds to the FieldPlatelet-neutrophil activation due to CO poisoning was shown to occur in patients and animal models and plateletneutrophil aggregation with intravascular neutrophil degranulation was required for one form of CO-mediated brain injury in an animal model. neuronal necrotic or apopt...

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