Abstract
The Fra-1/AP-1 transcription factor plays a key role in tumor epithelial cell progression; however, its role in pathogenic lung fibrosis remains unclear. In the present study, using a genetic approach (Fra-1 deficient mice), we have demonstrated a novel regulatory (protective) role for Fra-1 in lung fibrosis. We found greater levels of progressive interstitial fibrosis, characterized by increased levels of inflammation, collagen accumulation, and profibrotic and fibrotic gene expression in the lungs of Fra-1 Δ/Δ mice than in those of Fra-1+/+ mice following bleomycin treatment. Fra-1 knockdown in human lung epithelial cells caused the upregulation of mesenchymal marker N-cadherin, concomitant with a downregulation of the epithelial phenotype marker E-cadherin, under basal conditions and in response to bleomycin and TGF-β1. Furthermore, Fra-1 knockdown caused an enhanced expression of type 1 collagen and the downregulation of collagenase (MMP-1 and MMP-13) gene expression in human lung epithelial cells. Collectively, our findings demonstrate that Fra-1 mediates anti-fibrotic effects in the lung through the modulation of proinflammatory, profibrotic and fibrotic gene expression, and suggests that the Fra-1 transcription factor may be a potential target for pulmonary fibrosis, a progressive disorder with poor prognosis and treatment.
Highlights
Pulmonary fibrosis is a chronic, progressive disorder that leads to morbidity and mortality and is associated with poor prognosis and treatment
Our results demonstrate that Fra-1-deficient mice develop a severe and progressive lung fibrosis, suggesting that Fra-1 negatively regulates the development of fibrosis
The greater neutrophilic alveolitis seen in the lungs of Fra-1D/D mice at day 7 of the post-bleomycin challenge were associated with a transient up-regulation of cytokine and chemokine gene expression such as TNF-a, MIP-1a and MIP-2 (Fig. 1C)
Summary
Pulmonary fibrosis is a chronic, progressive disorder that leads to morbidity and mortality and is associated with poor prognosis and treatment This disease is characterized by fibroblast proliferation, extracellular matrix (ECM) accumulation, and alterations in parenchymal architecture leading to scar formation [1], but the exact mechanisms underlying this pathogenic fibrosis are not completely defined. The matrix metalloproteinase (MMP) family members regulate ECM turnover, whereas collagenases (members of MMP subfamily) cleave the interstitial collagens, types I, II and III under both physiologic and pathologic conditions. The activities of these enzymes are controlled at multiple levels, in particular through the interactions with their specific inhibitors, known as the tissue inhibitors of metalloproteinases (TIMPs). The loss of this coordinated regulation of MMP and TIMP expression has been shown to contributes to the development and progression of several diseases, including fibrosis [5,6,7]
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