Macrophage migration inhibitory factor is a novel determinant of cigarette smoke-induced lung damage

Jonathan Fallica, Laurent Boyer, Bo Soo Kim, Leonid Serebreni, Lidenys Varela, Omar Hamdan, Lan Wang, Tiffany Simms, Mahendra Damarla, Todd Matthew Kolb, Richard Bucala, Wayne A Mitzner, Paul M Hassoun, Rachel L Damico

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)94-103
Number of pages10
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume51
Issue number1
DOIs
StatePublished - 2014

Fingerprint

Macrophage Migration-Inhibitory Factors
Smoke
Tobacco Products
Lung
Endothelial cells
Apoptosis
Pulmonary diseases
Endothelial Cells
Emphysema
Tissue
Chronic Obstructive Pulmonary Disease
DNA Damage
Toxicity
Alveolar Epithelial Cells
Oxidative stress
DNA
Serum
Extracellular Matrix
Animals
Oxidative Stress

Keywords

  • Apoptosis
  • Cigarette
  • Emphysema
  • Endothelial
  • Macrophage migration inhibitory factor

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Macrophage migration inhibitory factor is a novel determinant of cigarette smoke-induced lung damage. / Fallica, Jonathan; Boyer, Laurent; Kim, Bo Soo; Serebreni, Leonid; Varela, Lidenys; Hamdan, Omar; Wang, Lan; Simms, Tiffany; Damarla, Mahendra; Kolb, Todd Matthew; Bucala, Richard; Mitzner, Wayne A; Hassoun, Paul M; Damico, Rachel L.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 51, No. 1, 2014, p. 94-103.

Research output: Contribution to journalArticle

Fallica, Jonathan ; Boyer, Laurent ; Kim, Bo Soo ; Serebreni, Leonid ; Varela, Lidenys ; Hamdan, Omar ; Wang, Lan ; Simms, Tiffany ; Damarla, Mahendra ; Kolb, Todd Matthew ; Bucala, Richard ; Mitzner, Wayne A ; Hassoun, Paul M ; Damico, Rachel L. / Macrophage migration inhibitory factor is a novel determinant of cigarette smoke-induced lung damage. In: American Journal of Respiratory Cell and Molecular Biology. 2014 ; Vol. 51, No. 1. pp. 94-103.
@article{49881a06d9eb4bc3a471412011b348a2,
title = "Macrophage migration inhibitory factor is a novel determinant of cigarette smoke-induced lung damage",
abstract = "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.",
keywords = "Apoptosis, Cigarette, Emphysema, Endothelial, Macrophage migration inhibitory factor",
author = "Jonathan Fallica and Laurent Boyer and Kim, {Bo Soo} and Leonid Serebreni and Lidenys Varela and Omar Hamdan and Lan Wang and Tiffany Simms and Mahendra Damarla and Kolb, {Todd Matthew} and Richard Bucala and Mitzner, {Wayne A} and Hassoun, {Paul M} and Damico, {Rachel L}",
year = "2014",
doi = "10.1165/rcmb.2013-0371OC",
language = "English (US)",
volume = "51",
pages = "94--103",
journal = "American Journal of Respiratory Cell and Molecular Biology",
issn = "1044-1549",
publisher = "American Thoracic Society",
number = "1",

}

TY - JOUR

T1 - Macrophage migration inhibitory factor is a novel determinant of cigarette smoke-induced lung damage

AU - Fallica, Jonathan

AU - Boyer, Laurent

AU - Kim, Bo Soo

AU - Serebreni, Leonid

AU - Varela, Lidenys

AU - Hamdan, Omar

AU - Wang, Lan

AU - Simms, Tiffany

AU - Damarla, Mahendra

AU - Kolb, Todd Matthew

AU - Bucala, Richard

AU - Mitzner, Wayne A

AU - Hassoun, Paul M

AU - Damico, Rachel L

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - Apoptosis

KW - Cigarette

KW - Emphysema

KW - Endothelial

KW - Macrophage migration inhibitory factor

UR - http://www.scopus.com/inward/record.url?scp=84903697989&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84903697989&partnerID=8YFLogxK

U2 - 10.1165/rcmb.2013-0371OC

DO - 10.1165/rcmb.2013-0371OC

M3 - Article

VL - 51

SP - 94

EP - 103

JO - American Journal of Respiratory Cell and Molecular Biology

JF - American Journal of Respiratory Cell and Molecular Biology

SN - 1044-1549

IS - 1

ER -