title: Prevention of early postnatal hyperalimentation protects against activation of transforming growth factor-β/bone morphogenetic protein and interleukin-6 signaling in rat lungs after intrauterine growth restriction.
abstract: BACKGROUND
  Intrauterine growth restriction (IUGR) is intimately linked with postnatal catch-up growth, leading to impaired lung structure and function. However, the impact of catch-up growth induced by early postnatal hyperalimentation (HA) on the lung has not been addressed to date.
  
  
  OBJECTIVE
  The aim of this study was to investigate whether prevention of HA subsequent to IUGR protects the lung from 1) deregulation of the transforming growth factor-β(TGF-β)/bone morphogenetic protein (BMP) pathway, 2) activation of interleukin (IL)-6 signaling, and 3) profibrotic processes.
  
  
  METHODS
  IUGR was induced in Wistar rats by isocaloric protein restriction during gestation by feeding a control (Co) or a low-protein diet with 17% or 8% casein, respectively. On postnatal day 1 (P1), litters from both groups were randomly reduced to 6 pups per dam to induce HA or adjusted to 10 pups and fed with standard diet: Co, Co with HA (Co-HA), IUGR, and IUGR with HA (IUGR-HA).
  
  
  RESULTS
  Birth weights in rats after IUGR were lower than in Co rats (P < 0.05). HA during lactation led to accelerated body weight gain from P1 to P23 (Co vs. Co-HA, IUGR vs. IUGR-HA; P < 0.05). At P70, prevention of HA after IUGR protected against the following: 1) activation of both TGF-β [phosphorylated SMAD (pSMAD) 2; plasminogen activator inhibitor 1 (Pai1)] and BMP signaling [pSMAD1; inhibitor of differentiation (Id1)] compared with Co (P < 0.05) and Co or IUGR (P < 0.05) rats, respectively; 2) greater mRNA expression of interleukin (Il) 6 and Il13 (P < 0.05) as well as activation of signal transducer and activator of transcription 3 (STAT3) signaling (P < 0.05) after IUGR-HA; and 3) greater gene expression of collagen Iα1 and osteopontin (P < 0.05) and increased deposition of bronchial subepithelial connective tissue in IUGR-HA compared with Co and IUGR rats. Moreover, HA had a significant additive effect (P < 0.05) on the increased enhanced pause (indicator of airway resistance) in the IUGR group (P < 0.05) at P70.
  
  
  CONCLUSIONS
  This study demonstrates a dual mechanism in IUGR-associated lung disease that is 1) IUGR-dependent and 2) HA-mediated and thereby offers new avenues to develop innovative preventive strategies for perinatal programming of adult lung diseases.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University of Cologne, Cologne, Germany; and miguel.alejandre-alcazar@uk-koeln.de.
authors.forename: Miguel Angel Alejandre
authors.initials: MA
authors.lastname: Alcázar
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University of Cologne, Cologne, Germany; and.
authors.forename: Katharina
authors.initials: K
authors.lastname: Dinger
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University of Cologne, Cologne, Germany; and.
authors.forename: Eva
authors.initials: E
authors.lastname: Rother
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University of Erlangen, Erlangen, Germany.
authors.forename: Iris
authors.initials: I
authors.lastname: Östreicher
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University of Cologne, Cologne, Germany; and.
authors.forename: Christina
authors.initials: C
authors.lastname: Vohlen
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University of Erlangen, Erlangen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Plank
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University of Cologne, Cologne, Germany; and.
authors.forename: Jörg
authors.initials: J
authors.lastname: Dötsch
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D018753:Diet, Protein-Restricted; D005260:Female; D005317:Fetal Growth Retardation / Q000628:therapy; D005786:Gene Expression Regulation; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D007774:Lactation; D008168:Lung / Q000254:growth & development* / Q000473:pathology; D008171:Lung Diseases / Q000517:prevention & control; D008297:Male; D044343:Overnutrition / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015430:Weight Gain / Q000187:drug effects
chemical_list: D019485:Bone Morphogenetic Proteins; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D016212:Transforming Growth Factor beta
keywords: IL-6/STAT3 signaling; TGF-β/BMP signaling; catch-up growth; early origins of lung disease; early postnatal hyperalimentation; intrauterine growth restriction