MKK3 mitogen-activated protein kinase pathway mediates carbon monoxide-induced protection against oxidant-induced lung injury.
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/p38 beta 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.
Otterbein
Leo E
LE
Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
Otterbein
Sherrie L
SL
Ifedigbo
Emeka
E
Liu
Fang
F
Morse
Danielle E
DE
Fearns
Colleen
C
Ulevitch
Richard J
RJ
Knickelbein
Roy
R
Flavell
Richard A
RA
Choi
Augustine M
AM
D000818:Animals; D002248:Carbon Monoxide / Q000494:pharmacology*; D002263:Carboxyhemoglobin / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors; D019610:Cytoprotection; D004789:Enzyme Activation; D018496:Hyperoxia / Q000401:mortality / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors; D008168:Lung / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D048371:MAP Kinase Kinase 3; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects; D016877:Oxidants; D011014:Pneumonia / Q000517:prevention & control; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D016019:Survival Analysis; D048051:p38 Mitogen-Activated Protein Kinases
D016207:Cytokines; D018836:Inflammation Mediators; D016877:Oxidants; D002248:Carbon Monoxide; D002263:Carboxyhemoglobin; D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; C482531:Map2k3 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases