Macrophage migration inhibitory factor is a novel determinant of cigarette smoke-induced lung damage.
Cigarette smoke (CS) is the most common cause of chronic obstructive pulmonary diseases (COPD), including emphysema. CS exposure impacts all cell types within the airways and lung parenchyma, causing alveolar tissue destruction through four mechanisms: (1) oxidative stress; (2) inflammation; (3) protease-induced degradation of the extracellular matrix; and (4) enhanced alveolar epithelial and endothelial cell (EC) apoptosis. Studies in human pulmonary ECs demonstrate that macrophage migration inhibitory factor (MIF) antagonizes CS-induced apoptosis. Here, we used human microvascular ECs, an animal model of emphysema (mice challenged with chronic CS), and patient serum samples to address both the capacity of CS to alter MIF expression and the effects of MIF on disease severity. We demonstrate significantly reduced serum MIF levels in patients with COPD. In the murine model, chronic CS exposure resulted in decreased MIF mRNA and protein expression in the intact lung. MIF deficiency (Mif(-/-)) potentiated the toxicity of CS exposure in vivo via increased apoptosis of ECs, resulting in enhanced CS-induced tissue remodeling. This was linked to MIF's capacity to protect against double-stranded DNA damage and suppress p53 expression. Taken together, MIF appears to antagonize CS-induced toxicity in the lung and resultant emphysematous tissue remodeling by suppressing EC DNA damage and controlling p53-mediated apoptosis, highlighting a critical role of MIF in EC homeostasis within the lung.
1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, Baltimore, Maryland.
Jonathan
J
Fallica
Laurent
L
Boyer
Bo
B
Kim
Leonid
L
Serebreni
Lidenys
L
Varela
Omar
O
Hamdan
Lan
L
Wang
Tiffany
T
Simms
Mahendra
M
Damarla
Todd M
TM
Kolb
Richard
R
Bucala
Wayne
W
Mitzner
Paul M
PM
Hassoun
Rachel
R
Damico
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D004249:DNA Damage / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D019746:Intramolecular Oxidoreductases / Q000502:physiology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008263:Macrophage Migration-Inhibitory Factors / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D011656:Pulmonary Emphysema / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D012906:Smoke / Q000009:adverse effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D008263:Macrophage Migration-Inhibitory Factors; D012906:Smoke; D016159:Tumor Suppressor Protein p53; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse
apoptosis; cigarette; emphysema; endothelial; macrophage migration inhibitory factor