title: Enhanced endogenous bone morphogenetic protein signaling protects against bleomycin induced pulmonary fibrosis.
abstract: BACKGROUND
  Effective treatments for fibrotic diseases such as idiopathic pulmonary fibrosis are largely lacking. Transforming growth factor beta (TGFβ) plays a central role in the pathophysiology of fibrosis. We hypothesized that bone morphogenetic proteins (BMP), another family within the TGFβ superfamily of growth factors, modulate fibrogenesis driven by TGFβ. We therefore studied the role of endogenous BMP signaling in bleomycin induced lung fibrosis.
  
  
  METHODS
  Lung fibrosis was induced in wild-type or noggin haploinsufficient (Nog +/LacZ ) mice by intratracheal instillation of bleomycin, or phosphate buffered saline as a control. Invasive pulmonary function tests were performed using the flexiVent® SCIREQ system. The mice were sacrificed and lung tissue was collected for analysis using histopathology, collagen quantification, immunohistochemistry and gene expression analysis.
  
  
  RESULTS
  Nog +/LacZ mice are a known model of increased BMP signaling and were partially protected from bleomycin-induced lung fibrosis with reduced Ashcroft score, reduced collagen content and preservation of pulmonary compliance. In bleomycin-induced lung fibrosis, TGFβ and BMP signaling followed an inverse course, with dynamic activation of TGFβ signaling and repression of BMP signaling activity.
  
  
  CONCLUSIONS
  Upon bleomycin exposure, active BMP signaling is decreased. Derepression of BMP signaling in Nog +/LacZ mice protects against bleomycin-induced pulmonary fibrosis. Modulating the balance between BMP and TGFβ, in particular increasing endogenous BMP signals, may therefore be a therapeutic target in fibrotic lung disease.
authors: Ellen
authors: E
authors: De Langhe
authors: Frederic
authors: F
authors: Cailotto
authors: Vanessa
authors: V
authors: De Vooght
authors: Carolina
authors: C
authors: Aznar-Lopez
authors: Jeroen Alfons
authors: JA
authors: Vanoirbeek
authors: Frank Prosper
authors: FP
authors: Luyten
authors: Rik Jozef Urbain
authors: RJ
authors: Lories
mesh_terms: D000818:Animals; D017209:Apoptosis; D001761:Bleomycin; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D057895:Haploinsufficiency; D008168:Lung / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008170:Lung Compliance; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015398:Signal Transduction; D051896:Smad Proteins, Receptor-Regulated / Q000378:metabolism; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D000099176:Noggin Protein
chemical_list: D001761:Bleomycin; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D003094:Collagen; D051896:Smad Proteins, Receptor-Regulated; D053773:Transforming Growth Factor beta1; D000099176:Noggin Protein; C508961:Tgfb1 protein, mouse