TY - JOUR
T1 - Macrophage migration inhibitory factor
T2 - A novel inhibitor of apoptosis signal-regulating kinase 1-p38-xanthine oxidoreductase-dependent cigarette smoke-induced apoptosis
AU - Fallica, Jonathan
AU - Varela, Lidenys
AU - Johnston, Laura
AU - Kim, Bo
AU - Serebreni, Leonid
AU - Wang, Lan
AU - Damarla, Mahendra
AU - Kolb, Todd M.
AU - Hassoun, Paul M.
AU - Damico, Rachel
N1 - Funding Information:
This work was supported by Flight Attendants Medical Research Institute grants 072129 and 110627 (B.K. and R.D.) and National Institutes of Health grants K08HL088320 (R.D.) and R01HL049441 (P.M.H.).
Publisher Copyright:
Copyright © 2016 by the American Thoracic Society.
PY - 2016/4
Y1 - 2016/4
N2 - 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 EndoCsand amousemodel of CS-induced lung damage,weinvestigated 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. BothXORhyperactivation and apoptosis in the absence ofMIFoccurred 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 inthe lung, inpartbyantagonizing ASK1-p38-XOR-dependent apoptosis.
AB - 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 EndoCsand amousemodel of CS-induced lung damage,weinvestigated 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. BothXORhyperactivation and apoptosis in the absence ofMIFoccurred 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 inthe lung, inpartbyantagonizing ASK1-p38-XOR-dependent apoptosis.
KW - Apoptosis
KW - Apoptosis signal-regulating kinase 1
KW - Cigarette
KW - Migration inhibitory factor
KW - Xanthine oxidase
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U2 - 10.1165/rcmb.2014-0403OC
DO - 10.1165/rcmb.2014-0403OC
M3 - Article
C2 - 26390063
AN - SCOPUS:84963734048
VL - 54
SP - 504
EP - 514
JO - American Journal of Respiratory Cell and Molecular Biology
JF - American Journal of Respiratory Cell and Molecular Biology
SN - 1044-1549
IS - 4
ER -