title: Abnormal Sonic hedgehog signaling in the lung of rats with esophageal atresia induced by adriamycin.
abstract: BACKGROUND
  Abnormal lung development was recently described in the rat model of esophageal atresia and tracheoesophageal fistula (EA-TEF). Since in this condition the ventral-to-dorsal switch of Shh expression in the foregut is disturbed, the present study tested the hypothesis that this abnormal expression at the emergence of the tracheobronchial bud might be translated into the developing lung.
  
  
  METHODS
  Pregnant rats received either 1.75 mg/kg i.p. adriamycin or vehicle from E7 to E9. Three groups were studied: control and adriamycin-exposed with and without EA-TEF. Embryos were recovered and the lungs were harvested and processed for reverse transcription polymerase chain reaction and immunofluorescence analysis of the Shh signaling cascade.
  
  
  RESULTS
  Shh signaling was downregulated at the late embryonic stage of lung development (E13) in embryos with EA-TEF. Throughout the subsequent stages of development, the expression of both Shh and its downstream components increased significantly and remained upregulated throughout gestation. Immunofluorescent localization was consistent with these findings.
  
  
  CONCLUSIONS
  Defective Shh signaling environment in the foregut is present beyond the emergence of lung buds and probably impairs lung development. Later in gestation, lungs exhibited a remarkable ability to upregulate the Shh cascade, suggesting a compensatory response. These findings may be relevant to understand pulmonary disease suffered by children with EA-TEF.
authors.affiliation: 1] Department of Pediatric Surgery, Hospital Universitario La Paz, Madrid, Spain [2] Laboratory of Congenital Malformations, INGEMM and IdiPaz Research Laboratory, Madrid, Spain [3] Faculty of Medicine, University of Porto, Porto, Portugal.
authors.forename: Ana Catarina
authors.initials: AC
authors.lastname: Fragoso
authors.affiliation: 1] Department of Pediatric Surgery, Hospital Universitario La Paz, Madrid, Spain [2] Laboratory of Congenital Malformations, INGEMM and IdiPaz Research Laboratory, Madrid, Spain.
authors.forename: Leopoldo
authors.initials: L
authors.lastname: Martinez
authors.affiliation: Faculty of Medicine, University of Porto, Porto, Portugal.
authors.forename: José
authors.initials: J
authors.lastname: Estevão-Costa
authors.affiliation: 1] Department of Pediatric Surgery, Hospital Universitario La Paz, Madrid, Spain [2] Laboratory of Congenital Malformations, INGEMM and IdiPaz Research Laboratory, Madrid, Spain.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Tovar
mesh_terms: D000818:Animals; D004317:Doxorubicin / Q000009:adverse effects*; D004933:Esophageal Atresia / Q000139:chemically induced* / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000196:embryology* / Q000378:metabolism; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D015398:Signal Transduction
chemical_list: D053823:Hedgehog Proteins; D012333:RNA, Messenger; C546888:Shh protein, rat; D004317:Doxorubicin