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, Augustine M. Choi

Research output: Contribution to journalArticlepeer-review

171 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2555-2563
Number of pages9
JournalAmerican Journal of Pathology
Volume163
Issue number6
DOIs
StatePublished - Dec 2003

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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