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FASEB J. 2015 May;29(5):1940-9. doi: 10.1096/fj.14-260299. Epub 2015 Jan 21.

Endothelial CD74 mediates macrophage migration inhibitory factor protection in hyperoxic lung injury.

Author information

1
Sections of *Pulmonary, Critical Care & Sleep Medicine and Rheumatology, Yale School of Medicine, and Department of Chemistry, Yale University, New Haven, Connecticut, USA.
2
Sections of *Pulmonary, Critical Care & Sleep Medicine and Rheumatology, Yale School of Medicine, and Department of Chemistry, Yale University, New Haven, Connecticut, USA patty.lee@yale.edu.

Abstract

Exposure to hyperoxia results in acute lung injury. A pathogenic consequence of hyperoxia is endothelial injury. Macrophage migration inhibitory factor (MIF) has a cytoprotective effect on lung endothelial cells; however, the mechanism is uncertain. We postulate that the MIF receptor CD74 mediates this protective effect. Using adult wild-type (WT), MIF-deficient (Mif(-/-)), CD74-deficient (Cd74(-/-)) mice and MIF receptor inhibitor treated mice, we report that MIF deficiency or inhibition of MIF receptor binding results in increased sensitivity to hyperoxia. Mif(-/-) and Cd74(-/-) mice demonstrated decreased median survival following hyperoxia compared to WT mice. Mif(-/-) mice demonstrated an increase in bronchoalveolar protein (48%) and lactate dehydrogenase (LDH) (68%) following 72 hours of hyperoxia. Similarly, treatment with MIF receptor antagonist resulted in a 59% and 91% increase in bronchoalveolar lavage protein and LDH, respectively. Inhibition of CD74 in primary murine lung endothelial cells (MLECs) abrogated the protective effect of MIF, including decreased hyperoxia-mediated AKT phosphorylation and a 20% reduction in the antiapoptotic effect of exogenous MIF. Treatment with MIF decreased hyperoxia-mediated H2AX phosphorylation in a CD74-dependent manner. These data suggest that therapeutic manipulation of the MIF-CD74 axis in lung endothelial cells may be a novel approach to protect against acute oxidative stress.

KEYWORDS:

H2AX; MIF; apoptosis; endothelium

PMID:
25609432
PMCID:
PMC4415022
DOI:
10.1096/fj.14-260299
[Indexed for MEDLINE]
Free PMC Article

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