Ventilation-induced increases in EGFR ligand mRNA are not altered by intra-amniotic LPS or ureaplasma in preterm lambs.
Chorioamnionitis and mechanical ventilation are associated with bronchopulmonary dysplasia (BPD) in preterm infants. Mechanical ventilation at birth activates both inflammatory and acute phase responses. These responses can be partially modulated by previous exposure to intra-amniotic (IA) LPS or Ureaplasma parvum (UP). Epidermal growth factor receptor (EGFR) ligands participate in lung development, and angiotensin converting enzyme (ACE) 1 and ACE2 contribute to lung inflammation. We asked whether brief mechanical ventilation at birth altered EGFR and ACE pathways and if antenatal exposure to IA LPS or UP could modulate these effects. Ewes were exposed to IA injections of UP, LPS or saline multiple days prior to preterm delivery at 85% gestation. Lambs were either immediately euthanized or mechanically ventilated for 2 to 3 hr. IA UP and LPS cause modest changes in the EGFR ligands amphiregulin (AREG), epiregulin (EREG), heparin binding epidermal growth factor (HB-EGF), and betacellulin (BTC) mRNA expression. Mechanical ventilation greatly increased mRNA expression of AREG, EREG, and HB-EGF, with no additional increases resulting from IA LPS or UP. With ventilation AREG and EREG mRNA localized to cells in terminal airspace. EGFR mRNA also increased with mechanical ventilation. IA UP and LPS decreased ACE1 mRNA and increased ACE2 mRNA, resulting in a 4 fold change in the ACE1/ACE2 ratio. Mechanical ventilation with large tidal volumes increased both ACE1 and ACE2 expression. The alterations seen in ACE with IA exposures and EGFR pathways with mechanical ventilation may contribute to the development of BPD in preterm infants.
Division of Neonatology, Saint Louis University, Saint Louis, Missouri, United States of America; Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, United States of America.
Noah H
NH
Hillman
Division of Neonatology, Saint Louis University, Saint Louis, Missouri, United States of America.
Tate
T
Gisslen
School of Women and Infants' Health, University of Western Australia Perth, WA, Australia; The Ritchie Centre, Monash Institute of Medical Research, Monash University, Melbourne, VIC, Australia.
Graeme R
GR
Polglase
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, United States of America; School of Women and Infants' Health, University of Western Australia Perth, WA, Australia.
Suhas G
SG
Kallapur
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, United States of America; School of Women and Infants' Health, University of Western Australia Perth, WA, Australia.
Alan H
AH
Jobe
D000650:Amnion / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D017403:In Situ Hybridization; D008024:Ligands; D008070:Lipopolysaccharides / Q000378:metabolism*; D007752:Obstetric Labor, Premature; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism*; D012121:Respiration, Artificial; D012756:Sheep; D014509:Ureaplasma / Q000302:isolation & purification*
D008024:Ligands; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D066246:ErbB Receptors; D007703:Peptidyl-Dipeptidase A