title: Endothelial CD74 mediates macrophage migration inhibitory factor protection in hyperoxic lung injury.
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.
authors.affiliation: Sections of *Pulmonary, Critical Care & Sleep Medicine and Rheumatology, Yale School of Medicine, and Department of Chemistry, Yale University, New Haven, Connecticut, USA.
authors.forename: Maor
authors.initials: M
authors.lastname: Sauler
authors.affiliation: Sections of *Pulmonary, Critical Care & Sleep Medicine and Rheumatology, Yale School of Medicine, and Department of Chemistry, Yale University, New Haven, Connecticut, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Sections of *Pulmonary, Critical Care & Sleep Medicine and Rheumatology, Yale School of Medicine, and Department of Chemistry, Yale University, New Haven, Connecticut, USA.
authors.forename: Jin-Na
authors.initials: JN
authors.lastname: Min
authors.affiliation: Sections of *Pulmonary, Critical Care & Sleep Medicine and Rheumatology, Yale School of Medicine, and Department of Chemistry, Yale University, New Haven, Connecticut, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.affiliation: Sections of *Pulmonary, Critical Care & Sleep Medicine and Rheumatology, Yale School of Medicine, and Department of Chemistry, Yale University, New Haven, Connecticut, USA.
authors.forename: Peiying
authors.initials: P
authors.lastname: Shan
authors.affiliation: Sections of *Pulmonary, Critical Care & Sleep Medicine and Rheumatology, Yale School of Medicine, and Department of Chemistry, Yale University, New Haven, Connecticut, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Roberts
authors.affiliation: Sections of *Pulmonary, Critical Care & Sleep Medicine and Rheumatology, Yale School of Medicine, and Department of Chemistry, Yale University, New Haven, Connecticut, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Jorgensen
authors.affiliation: Sections of *Pulmonary, Critical Care & Sleep Medicine and Rheumatology, Yale School of Medicine, and Department of Chemistry, Yale University, New Haven, Connecticut, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.affiliation: 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.
authors.forename: Patty J
authors.initials: PJ
authors.lastname: Lee
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D018496:Hyperoxia / Q000150:complications* / Q000503:physiopathology; D019746:Intramolecular Oxidoreductases / Q000502:physiology*; D008263:Macrophage Migration-Inhibitory Factors / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011971:Receptors, Immunologic / Q000502:physiology*
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D011971:Receptors, Immunologic; C033184:macrophage migration inhibitory factor receptor; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse
keywords: H2AX; MIF; apoptosis; endothelium