Enhanced endogenous bone morphogenetic protein signaling protects against bleomycin induced pulmonary fibrosis

Abstract

BackgroundEffective 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.MethodsLung 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.ResultsNog+/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.ConclusionsUpon 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.

Methylation-mediated BMPER expression in fibroblast activation in vitro and lung fibrosis in mice in vivo

“…And in bleomycin-induced lung fibrosis, TGF-β and BMP signaling followed an inverse course, with dynamic activation of TGF-β signaling and repression of BMP signaling activity. Modulating the balance between BMP and TGF-β may be a therapeutic target in fibrotic lung disease 41 .…”

“…In short, upon 200× magnification, each successive field was given a score ranging from 0 (normal) to 8 (total fibrous obliteration of the field). All scores from 5 sections were averaged 41 .…”

Unanswered Questions Regarding Sex and BMP/TGF-β Signaling

“…oppose fibrosis in multiple organs [44][45][46][47][48][49][50][51][52][53][54]. Different ligands often promote alternative lineage choices.…”

Comparison of Hibiscus sabdariffa L. Extract and Enalapril with Regard to Their Effect on Lung Fibrosis in a Bleomycin-induced Rat Model of Lung Fibrosis

“…Fibrosis is defined as the accumulation of components of the extracellular matrix, such as fibronectins, collagen proteins, and hyaluronic acid, at the site of the injured tissue; fibrosis results in decreased function and failure of the organ and finally death (2). Tissue or organ fibrosis is generally considered as an uncontrolled wound healing process (3). Acute distress syndrome caused by acute lung injures and traumas results in chronic interstitial pulmonary fibrosis, which is characterized by progression of fibrosis and collagen deposition (4).…”

“…flammatory cytokines and chemokines play a major role in amplifying, mediating, and perpetuating the lung injury and fibrotic process (5). Among them, transforming growth factor beta (TGF-β) is considered as the major profibrotic cytokine, which promotes proliferation, the conversion of fibroblasts to myofibroblasts, and finally, the deposition of extracellular matrix proteins, orchestrating fibroblast function as a chemotactic factor (3). A large body of studies has documented the modulating role of angiotensin-converting enzyme (ACE) and its related peptide, angiotensin II (ANG II), in the pathogenesis of lung fibrosis (6).…”