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Fra-1/AP-1 transcription factor negatively regulates pulmonary fibrosis in vivo.

Rajasekaran S, Vaz M, Reddy SP - PLoS ONE (2012)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois, United States of America.

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.

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Fra-1Δ/Δ mice develop exaggerated pulmonary fibrosis after injury. A:Representative results of Masson’s trichrome staining of the lung from the saline-treated mice (n = 3) or bleomycin treated mice for 14 (n = 3) and 31 (n = 4) days. B: Right lung was collected for biochemical analysis of bleomycin-induced pulmonary fibrosis as measured by hydroxyproline content at 31-day post-PBS and -bleomycin treatment (n = 5). ∗p<0.05, PBS vs bleomycin; †p<0,05, Fra-1Δ/Δ vs Fra-1+/+ mice. Images in a are shown at x4, whereas a1 represent boxed areas of a, shown at x20.
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pone-0041611-g004: Fra-1Δ/Δ mice develop exaggerated pulmonary fibrosis after injury. A:Representative results of Masson’s trichrome staining of the lung from the saline-treated mice (n = 3) or bleomycin treated mice for 14 (n = 3) and 31 (n = 4) days. B: Right lung was collected for biochemical analysis of bleomycin-induced pulmonary fibrosis as measured by hydroxyproline content at 31-day post-PBS and -bleomycin treatment (n = 5). ∗p<0.05, PBS vs bleomycin; †p<0,05, Fra-1Δ/Δ vs Fra-1+/+ mice. Images in a are shown at x4, whereas a1 represent boxed areas of a, shown at x20.

Mentions: The increased extracellular collagen accumulation is a key abnormal event in fibrosis. We therefore next analyzed the extent of collagen deposition in lung tissues of Fra-1Δ/Δ and Fra-1+/+ mice treated with vehicle or bleomycin. As shown by Masson’s trichrome staining (Fig. 4A), the lungs of mice examined 14 days after challenge typically demonstrated that Fra-1Δ/Δ mice had more peribronchiolar and parenchymal fibrosis than corresponding wild-type littermates. The extent of these changes at 14 days after bleomycin administration was substantially increased in Fra-1Δ/Δ mice at the end of 31 days. In contrast, the areas of collagen accumulation in the lungs of bleomycin-treated Fra-1+/+ mice were fewer in number and considerably less dense at the end of 31 days. The lungs of PBS-treated mice appeared normal, with no collagen accumulation adjacent to large vessels or airways. Furthermore, to quantitatively assess the difference in the extent of fibrosis, we measured hydroxyproline as a surrogate marker for collagen deposition. Hydroxyproline levels were significantly lower in the lungs of Fra-1+/+ mice than in Fra-1Δ/Δ mice treated with bleomycin for 31 days (Fig. 4B). Treatment of mice with PBS did not affect the lung hydroxyproline content, regardless of their genotype. Consistent with the morphological findings, these results indicate that the loss of Fra-1 results in increased levels of interstitial collagen deposition in response to bleomycin treatment.


Fra-1/AP-1 transcription factor negatively regulates pulmonary fibrosis in vivo.

Rajasekaran S, Vaz M, Reddy SP - PLoS ONE (2012)

Fra-1Δ/Δ mice develop exaggerated pulmonary fibrosis after injury. A:Representative results of Masson’s trichrome staining of the lung from the saline-treated mice (n = 3) or bleomycin treated mice for 14 (n = 3) and 31 (n = 4) days. B: Right lung was collected for biochemical analysis of bleomycin-induced pulmonary fibrosis as measured by hydroxyproline content at 31-day post-PBS and -bleomycin treatment (n = 5). ∗p<0.05, PBS vs bleomycin; †p<0,05, Fra-1Δ/Δ vs Fra-1+/+ mice. Images in a are shown at x4, whereas a1 represent boxed areas of a, shown at x20.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3404039&req=5

pone-0041611-g004: Fra-1Δ/Δ mice develop exaggerated pulmonary fibrosis after injury. A:Representative results of Masson’s trichrome staining of the lung from the saline-treated mice (n = 3) or bleomycin treated mice for 14 (n = 3) and 31 (n = 4) days. B: Right lung was collected for biochemical analysis of bleomycin-induced pulmonary fibrosis as measured by hydroxyproline content at 31-day post-PBS and -bleomycin treatment (n = 5). ∗p<0.05, PBS vs bleomycin; †p<0,05, Fra-1Δ/Δ vs Fra-1+/+ mice. Images in a are shown at x4, whereas a1 represent boxed areas of a, shown at x20.
Mentions: The increased extracellular collagen accumulation is a key abnormal event in fibrosis. We therefore next analyzed the extent of collagen deposition in lung tissues of Fra-1Δ/Δ and Fra-1+/+ mice treated with vehicle or bleomycin. As shown by Masson’s trichrome staining (Fig. 4A), the lungs of mice examined 14 days after challenge typically demonstrated that Fra-1Δ/Δ mice had more peribronchiolar and parenchymal fibrosis than corresponding wild-type littermates. The extent of these changes at 14 days after bleomycin administration was substantially increased in Fra-1Δ/Δ mice at the end of 31 days. In contrast, the areas of collagen accumulation in the lungs of bleomycin-treated Fra-1+/+ mice were fewer in number and considerably less dense at the end of 31 days. The lungs of PBS-treated mice appeared normal, with no collagen accumulation adjacent to large vessels or airways. Furthermore, to quantitatively assess the difference in the extent of fibrosis, we measured hydroxyproline as a surrogate marker for collagen deposition. Hydroxyproline levels were significantly lower in the lungs of Fra-1+/+ mice than in Fra-1Δ/Δ mice treated with bleomycin for 31 days (Fig. 4B). Treatment of mice with PBS did not affect the lung hydroxyproline content, regardless of their genotype. Consistent with the morphological findings, these results indicate that the loss of Fra-1 results in increased levels of interstitial collagen deposition in response to bleomycin treatment.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois, United States of America.

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.

Show MeSH
Related in: MedlinePlus