Macrophage Migration Inhibitory Factor: A Novel Inhibitor of Apoptosis Signal-Regulating Kinase 1–p38–Xanthine Oxidoreductase–Dependent Cigarette Smoke–Induced Apoptosis

Cigarette smoke (CS) exposure is the leading cause of emphysema. CS mediates pathologic emphysematous remodeling of the lung via apoptosis of lung parenchymal cells resulting in enlargement of the airspaces, loss of the capillary bed, and diminished surface area for gas exchange. Macrophage migratio...

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Vydáno v:	American journal of respiratory cell and molecular biology Ročník 54; číslo 4; s. 504 - 514
Hlavní autoři:	Fallica, Jonathan, Varela, Lidenys, Johnston, Laura, Kim, Bo, Serebreni, Leonid, Wang, Lan, Damarla, Mahendra, Kolb, Todd M., Hassoun, Paul M., Damico, Rachel
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States American Thoracic Society 01.04.2016
Témata:	Animals Apoptosis Cells, Cultured Chronic obstructive pulmonary disease Cytotoxicity Deoxyribonucleic acid DNA Emphysema Enzyme Activation Enzymes Human subjects Humans Kinases Lungs Macrophage Migration-Inhibitory Factors - genetics Macrophage Migration-Inhibitory Factors - physiology MAP Kinase Kinase Kinase 5 - metabolism Mice Mice, Inbred C57BL Nicotiana Original Research Oxidative stress p38 Mitogen-Activated Protein Kinases - metabolism Phosphorylation Proteins Rats Reactive Oxygen Species - metabolism Rodents Smoke Xanthine Dehydrogenase - metabolism apoptosis cigarette migration inhibitory factor apoptosis signal–regulating kinase 1 xanthine oxidase
ISSN:	1044-1549, 1535-4989, 1535-4989
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Shrnutí:	Cigarette smoke (CS) exposure is the leading cause of emphysema. CS mediates pathologic emphysematous remodeling of the lung via apoptosis of lung parenchymal cells resulting in enlargement of the airspaces, loss of the capillary bed, and diminished surface area for gas exchange. Macrophage migration inhibitory factor (MIF), a pleiotropic cytokine, is reduced both in a preclinical model of CS-induced emphysema and in patients with chronic obstructive pulmonary disease, particularly those with the most severe disease and emphysematous phenotype. MIF functions to antagonize CS-induced DNA damage, p53-dependent apoptosis of pulmonary endothelial cells (EndoCs) and resultant emphysematous tissue remodeling. Using primary alveolar EndoCs and a mouse model of CS-induced lung damage, we investigated the capacity and molecular mechanism(s) by which MIF modifies oxidant injury. Here, we demonstrate that both the activity of xanthine oxidoreductase (XOR), a superoxide-generating enzyme obligatory for CS-induced DNA damage and EndoC apoptosis, and superoxide concentrations are increased after CS exposure in the absence of MIF. Both XOR hyperactivation and apoptosis in the absence of MIF occurred via a p38 mitogen-activated protein kinase-dependent mechanism. Furthermore, a mitogen-activated protein kinase kinase kinase family member, apoptosis signal-regulating kinase 1 (ASK1), was necessary for CS-induced p38 activation and EndoC apoptosis. MIF was sufficient to directly suppress ASK1 enzymatic activity. Taken together, MIF suppresses CS-mediated cytotoxicity in the lung, in part by antagonizing ASK1-p38-XOR-dependent apoptosis.
Bibliografie:	SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23
ISSN:	1044-1549 1535-4989 1535-4989
DOI:	10.1165/rcmb.2014-0403OC