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(American Journal of Pathology. 2003;163:2555-2563.)
© 2003 American Society for Investigative Pathology

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

Leo E. Otterbein^*, Sherrie L. Otterbein^*, Emeka Ifedigbo, Fang Liu, Danielle E. Morse^*, Colleen Fearns, Richard J. Ulevitch, Roy Knickelbein^¶, Richard A. Flavell^|| and Augustine M. Choi

From the Section of Pulmonary and Critical Care Medicine,^* Yale University School of Medicine, New Haven, Connecticut; Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut; Howard Hughes Medical Institute and Section of Immunobiology|| and the Department of Pediatrics, ^¶ Yale University School of Medicine, New Haven, Connecticut; the Department of Immunology, The Scripps Research Institute, La Jolla, California; and Pulmonary and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

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/p38ß 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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