A role for macrophage migration inhibitory factor in the neonatal respiratory distress syndrome.
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.
Kevill
Katharine A
KA
Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520, USA.
Bhandari
Vineet
V
Kettunen
Mika
M
Leng
Lin
L
Fan
Juan
J
Mizue
Yuka
Y
Dzuira
James D
JD
Reyes-Mugica
Miguel
M
McDonald
Courtney L
CL
Baugh
John A
JA
O'Connor
Christine L
CL
Aghai
Zubair H
ZH
Donnelly
Seamas C
SC
Bazzy-Asaad
Alia
A
Bucala
Richard J
RJ
D000818:Animals; D001997:Bronchopulmonary Dysplasia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D003345:Corticosterone / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007231:Infant, Newborn; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000502:physiology*; D008168:Lung / Q000196:embryology / Q000276:immunology* / Q000473:pathology; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000235:genetics; D011014:Pneumonia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D037661:Pulmonary Surfactant-Associated Proteins / Q000378:metabolism; D012127:Respiratory Distress Syndrome, Newborn / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D008263:Macrophage Migration-Inhibitory Factors; D037661:Pulmonary Surfactant-Associated Proteins; D042461:Vascular Endothelial Growth Factor A; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse; D003345:Corticosterone