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MKK3 Mitogen-Activated Protein Kinase Pathway Mediates Carbon Monoxide-Induced Protection Against Oxidant-Induced Lung Injury

https://doi.org/10.1016/S0002-9440(10)63610-3Get rights and content

The stress-inducible gene heme oxygenase (HO-1) has previously been shown to provide cytoprotection against oxidative stress. The mechanism(s) by which HO-1 provides this cytoprotection is poorly understood. We demonstrate here that carbon monoxide (CO), a byproduct released during the degradation of heme by HO, plays a major role in mediating the cytoprotection against oxidant-induced lung injury. We show in vitro that CO protects cultured epithelial cells from hyperoxic damage. By using dominant negative mutants and mice deficient in the genes for the various MAP kinases, we demonstrate that the cytoprotective effects of CO are mediated by selective activation of the MKK3/p38β protein MAP kinase pathway. In vivo, our experiments demonstrate that CO at a low concentration protects the lungs, extends the survival of the animals, and exerts potent anti-inflammatory effects with reduced inflammatory cell influx into the lungs and marked attenuation in the expression of pro-inflammatory cytokines.

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Supported by grants from the American Heart Association (0160332U); by an Atorvastatin Research Award (from the AHA) sponsored by Pfizer (awarded to L.E.O.); and by National Institutes of Health grant HL60234 (to A.M.K.C.).

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