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,
* Department of Pediatrics,
Department of Internal Medicine, and
Department of Pathology, Yale University School of Medicine, New Haven, CT 06520;
Conway Institute of Biomolecular and Biomedical Research, University College, Dublin, Ireland; and
¶ Department of Pediatrics, Cooper University Hospital, Robert Wood Johnson Medical School, Camden, NJ 08103
Using a mouse model of neonatal respiratory distress syndrome (RDS), we demonstrate a central role for macrophage migration inhibitory factor (MIF) in lung maturation at the developmental stage when human neonates are most susceptible to RDS. We prematurely delivered mouse pups at embryonic day 18, during the early saccular stage of pulmonary development. Only 8% of the prematurely delivered pups genetically deficient in MIF survived 8 h vs 75% of wild-type controls (p < 0.001). This phenotype was corrected when pups of all genotypes were bred from dams heterozygote for MIF deficiency. Local production of MIF in the lung increased at embryonic day 18, continued until full-term at embryonic day 19.5, and decreased in adulthood, thus coinciding with this developmental window. The lungs of pups genetically deficient in MIF were less mature upon histological evaluation, and demonstrated lower levels of vascular endothelial growth factor and corticosterone – two factors that promote fetal lung maturation. In vitro studies support a role for MIF in surfactant production by pulmonary epithelial cells. In a cohort of human neonates with RDS, higher intrapulmonary MIF levels were associated with a lower likelihood of developing bronchopulmonary dysplasia, a sequelae of RDS (p < 0.03). This study demonstrates for the first time a role for MIF in lung maturation, and supports a protective role for MIF in newborn lung disease.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by National Institutes of Health Grants 1R01-AI042310 (to L.L. and R.J.B.), 1R01-AR050498 (to R.J.B.), K08 HL074195 (to V.B.), HLO7778 (to K.A.K.), and HL5041 (to A.B.-A.); and the Science Foundation (to S.C.D.).
2 Address correspondence and reprint requests to Dr. Richard Bucala, Department of Medicine, and Pathology, Yale University School of Medicine, Anlyan Center, S525, 300 Cedar Street, New Haven, CT 06520. E-mail address: Richard.Bucala{at}Yale.edu
3 Abbreviations used in this paper: RDS, respiratory distress syndrome; BPD, bronchopulmonary dysplasia; MIF, macrophage migration inhibitory factor; VEGF, vascular endothelial growth factor; MIF-KO, mif gene knockout; WT, wild type; SP, surfactant protein; SQ, starting quantity; siRNA, short interfering RNA.
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  J. V. Peter, P. John, P. L Graham, J. L Moran, I. A. George, and A. Bersten Corticosteroids in the prevention and treatment of acute respiratory distress syndrome (ARDS) in adults: meta-analysis BMJ, May 3, 2008; 336(7651): 1006 - 1009. [Abstract] [Full Text] [PDF]
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