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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Sauler, M; Zhang, Y; Min, J-N; Leng, L; Shan, P; Roberts, S; Jorgensen, WL; Bucala, R; Lee, PJ

Published Date

  • May 2015

Published In

Volume / Issue

  • 29 / 5

Start / End Page

  • 1940 - 1949

PubMed ID

  • 25609432

Pubmed Central ID

  • PMC4415022

Electronic International Standard Serial Number (EISSN)

  • 1530-6860

Digital Object Identifier (DOI)

  • 10.1096/fj.14-260299


  • eng

Conference Location

  • United States