title: Conditional overexpression of TGFβ1 promotes pulmonary inflammation, apoptosis and mortality via TGFβR2 in the developing mouse lung.
abstract: BACKGROUND
  Earlier studies have reported that transforming growth factor beta 1(TGFβ1) is a critical mediator of hyperoxia-induced acute lung injury (HALI) in developing lungs, leading to impaired alveolarization and a pulmonary phenotype of bronchopulmonary dysplasia (BPD). However, the mechanisms responsible for the TGFβ1-induced inflammatory signals that lead to cell death and abnormal alveolarization are poorly understood. We hypothesized that TGFβ1 signaling via TGFβR2 is necessary for the pathogenesis of the BPD pulmonary phenotype resulting from HALI.
  
  
  METHODS
  We utilized lung epithelial cell-specific TGFβ1 overexpressing transgenic and TGFβR2 null mutant mice to evaluate the effects on neonatal mortality as well as pulmonary inflammation and apoptosis in developing lungs. Lung morphometry was performed to determine the impaired alveolarization and multicolor flow cytometry studies were performed to detect inflammatory macrophages and monocytes in lungs. Apoptotic cell death was measured with TUNEL assay, immunohistochemistry and western blotting and protein expression of angiogenic mediators were also analyzed.
  
  
  RESULTS
  Our data reveals that increased TGFβ1 expression in newborn mice lungs leads to increased mortality, macrophage and immature monocyte infiltration, apoptotic cell death specifically in Type II alveolar epithelial cells (AECs), impaired alveolarization, and dysregulated angiogenic molecular markers.
  
  
  CONCLUSIONS
  Our study has demonstrated the potential role of inhibition of TGFβ1 signaling via TGFβR2 for improved survival, reduced inflammation and apoptosis that may provide insights for the development of potential therapeutic strategies targeted against HALI and BPD.
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA. sua2011@med.cornell.edu.
authors.forename: Angara
authors.initials: A
authors.lastname: Sureshbabu
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA. Mansoor.syed@yale.edu.
authors.forename: Mansoor A
authors.initials: MA
authors.lastname: Syed
authors.affiliation: Department of Medicine and Yale Cancer Center, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA. sekhar.boddupalli@yale.edu.
authors.forename: Chandra Sekhar
authors.initials: CS
authors.lastname: Boddupalli
authors.affiliation: Department of Medicine and Yale Cancer Center, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA. madhav.dhodapkar@yale.edu.
authors.forename: Madhav V
authors.initials: MV
authors.lastname: Dhodapkar
authors.affiliation: Department of Pathology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA. Robert.homer@yale.edu.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Homer
authors.affiliation: Department of Pediatrics, University of Southern California, 1200 North State Street, Los Angeles, CA, 90033, USA. minoo@usc.edu.
authors.forename: Parviz
authors.initials: P
authors.lastname: Minoo
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA. vineet.bhandari@yale.edu.
authors.forename: Vineet
authors.initials: V
authors.lastname: Bhandari
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D056809:Alveolar Epithelial Cells / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D004195:Disease Models, Animal; D005838:Genotype; D006801:Humans; D018496:Hyperoxia / Q000150:complications; D008168:Lung / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype; D011014:Pneumonia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation
chemical_list: D018125:Receptors, Transforming Growth Factor beta; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II