title: Small molecular modulation of macrophage migration inhibitory factor in the hyperoxia-induced mouse model of bronchopulmonary dysplasia.
abstract: BACKGROUND
  The role and mechanism of action of MIF in bronchopulmonary dysplasia (BPD) are not known. We hypothesized that increased MIF signaling would ameliorate the pulmonary phenotype of BPD in the mouse lung.
  
  
  METHODS
  We studied newborn wild type (WT), MIF knockout (MIFKO), and lung MIF transgenic (MIFTG) mice in room air and a BPD model, and examined the effects of administering a small molecule MIF agonist and antagonist. Lung morphometry was performed and mRNA and protein expression of vascular mediators were analyzed.
  
  
  RESULTS
  The pulmonary phenotype of MIFKO and MIFTG mice lungs in room air (RA) and BPD model were comparable to the WT-BPD mice at postnatal (PN) day 14. Vascular endothelial growth factor (VEGF)-A, -R1 and Angiopoietin (Ang)1 mRNA were decreased, and Ang2 increased in the WT-BPD, MIFKO-RA, MIFKO-BPD, MIFTG-RA and MIFTG-BPD mice lungs, compared to appropriate controls. The protein expression of Ang1 in the MIFKO-RA was similar to WT-RA, but decreased in MIFTG-RA, and decreased in all the BPD groups. Ang2 was increased in MIFKO-RA, MIFTG-RA and in all 3 BPD groups. Tie2 was increased in WT-BPD compared to WT-RA, but decreased in MIFKO- and MIFTG- RA and BPD groups. VEGFR1 was uniformly decreased in MIFKO-RA, MIFTG-RA and in all 3 BPD groups. VEGF-A had a similar expression across all RA and BPD groups. There was partial recovery of the pulmonary phenotype in the WT-BPD model treated with the MIF agonist, and in the MIFTG mice treated with the MIF antagonist.
  
  
  CONCLUSIONS
  These data point to the careful regulatory balance exerted by MIF in the developing lung and response to hyperoxia and support the potential therapeutic value of small molecule MIF modulation in BPD.
authors: Department of Pediatrics, Yale University, New Haven, CT 06520, USA.
authors: Huanxing
authors: H
authors: Sun
authors: Rayman
authors: R
authors: Choo-Wing
authors: Juan
authors: J
authors: Fan
authors: Lin
authors: L
authors: Leng
authors: Mansoor A
authors: MA
authors: Syed
authors: Alissa A
authors: AA
authors: Hare
authors: William L
authors: WL
authors: Jorgensen
authors: Richard
authors: R
authors: Bucala
authors: Vineet
authors: V
authors: Bhandari
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001997:Bronchopulmonary Dysplasia / Q000209:etiology* / Q000378:metabolism*; D002630:Chemotactic Factors / Q000378:metabolism*; D006801:Humans; D018496:Hyperoxia / Q000150:complications* / Q000378:metabolism*; D007231:Infant, Newborn; D008168:Lung / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015854:Up-Regulation
chemical_list: D002630:Chemotactic Factors; C053609:macrophage migration enhancement factor