Journal
RESPIRATORY RESEARCH
Volume 16, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s12931-015-0202-x
Keywords
Transforming growth factor beta; Bone morphogenetic proteins; Bleomycin; Pulmonary fibrosis
Categories
Funding
- Flanders Research Foundation (FWO Vlaanderen) [G.0592.09]
- FWO Vlaanderen
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Background: Effective treatments for fibrotic diseases such as idiopathic pulmonary fibrosis are largely lacking. Transforming growth factor beta (TGF beta) plays a central role in the pathophysiology of fibrosis. We hypothesized that bone morphogenetic proteins (BMP), another family within the TGF beta superfamily of growth factors, modulate fibrogenesis driven by TGF beta. 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 (R) 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, TGF beta and BMP signaling followed an inverse course, with dynamic activation of TGF beta 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 TGF beta, in particular increasing endogenous BMP signals, may therefore be a therapeutic target in fibrotic lung disease.
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