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Host predisposition by endogenous Transforming Growth Factor-beta1 overexpression promotes pulmonary fibrosis following bleomycin injury.

Haider Y, Malizia AP, Keating DT, Birch M, Tomlinson A, Martin G, Ferguson MW, Doran PP, Egan JJ - J Inflamm (Lond) (2007)

Bottom Line: Idiopathic Pulmonary Fibrosis (IPF) is a progressive diffuse disease involving the lung parenchyma.Despite recent advances, the molecular mechanisms of the initiation and progression of this disease remain elusive.Previous studies have demonstrated TGFbeta1 as a key effector cytokine in the development of lung fibrosis.

View Article: PubMed Central - HTML - PubMed

Affiliation: National Heart and Lung Transplant Program, Mater Misericordiae University Hospital, University College Dublin, Dublin. jegan@mater.ie.

ABSTRACT

Background: Idiopathic Pulmonary Fibrosis (IPF) is a progressive diffuse disease involving the lung parenchyma. Despite recent advances, the molecular mechanisms of the initiation and progression of this disease remain elusive. Previous studies have demonstrated TGFbeta1 as a key effector cytokine in the development of lung fibrosis.

Methods: In this study we have used a transgenic mouse based strategy to identify the effect of overexpression of this key effector mediator on the development of pulmonary fibrosis in response to exogenous injury. We bred two lines (line 25 and 18) of transgenic mice (Tr+) that overexpressed active TGFbeta1. Three-month old transgenic and wild type mice were subsequently wounded with intraperitoneal bleomycin. Mice were sacrificed at 6 weeks post-bleomycin and their lungs analysed histologically and biochemically.

Results: The severity of lung fibrosis was significantly greater in the Tr+ mice compared to the wild type mice. Using an oligonucleotide microarray based strategy we identified discrete patterns of gene expression contributing to TGFbeta1 associated pulmonary fibrosis.

Conclusion: This data emphasises the importance of a host predisposition in the form of endogenous TGFbeta1, in the development of pulmonary fibrosis in response to an exogenous injury.

No MeSH data available.


Related in: MedlinePlus

TGFβ1 overexpression induces pronounced fibrotic response following bleomycin exposure. Tissue fibrosis was assessed in both Tr- wild type (A) and Tr+ transgenic (B) mice lung following exposure to 4500 IU bleomycin, as previously described. Shown are representative micrographs following haematoxylin/eosin staining of lung tissue, demonstrating fibrotic response in bleomycin treated wild type mouse lung that is significantly more severe in tissue from Tr+ TGFβ1 transgenic mice, suggesting that overexpression of the TGFβ1 transgene exacerbates subsequent lung injury. C. To quantify this fibrotic effect, fibrosis scores were determined as described. The graph shows enhanced fibrosis scores in Tr+ TGFβ1 transgenic mice versus their Tr- wild type counterparts in response to bleomycin exposure.
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Figure 5: TGFβ1 overexpression induces pronounced fibrotic response following bleomycin exposure. Tissue fibrosis was assessed in both Tr- wild type (A) and Tr+ transgenic (B) mice lung following exposure to 4500 IU bleomycin, as previously described. Shown are representative micrographs following haematoxylin/eosin staining of lung tissue, demonstrating fibrotic response in bleomycin treated wild type mouse lung that is significantly more severe in tissue from Tr+ TGFβ1 transgenic mice, suggesting that overexpression of the TGFβ1 transgene exacerbates subsequent lung injury. C. To quantify this fibrotic effect, fibrosis scores were determined as described. The graph shows enhanced fibrosis scores in Tr+ TGFβ1 transgenic mice versus their Tr- wild type counterparts in response to bleomycin exposure.

Mentions: Lung fibrosis induced by 4500 IU bleomycin in the Tr- wild type group was a mild patchy lung injury (Figure 5a). Tr+ transgenic mice, following exposure to comparable and smaller doses of bleomycin demonstrated marked lung injury hallmarked by grossly thickened alveolar walls, inflammation, fibroblast proliferation and collagen deposition in a peribronchial, interstitial and sub pleural distribution (Figure 5b).


Host predisposition by endogenous Transforming Growth Factor-beta1 overexpression promotes pulmonary fibrosis following bleomycin injury.

Haider Y, Malizia AP, Keating DT, Birch M, Tomlinson A, Martin G, Ferguson MW, Doran PP, Egan JJ - J Inflamm (Lond) (2007)

TGFβ1 overexpression induces pronounced fibrotic response following bleomycin exposure. Tissue fibrosis was assessed in both Tr- wild type (A) and Tr+ transgenic (B) mice lung following exposure to 4500 IU bleomycin, as previously described. Shown are representative micrographs following haematoxylin/eosin staining of lung tissue, demonstrating fibrotic response in bleomycin treated wild type mouse lung that is significantly more severe in tissue from Tr+ TGFβ1 transgenic mice, suggesting that overexpression of the TGFβ1 transgene exacerbates subsequent lung injury. C. To quantify this fibrotic effect, fibrosis scores were determined as described. The graph shows enhanced fibrosis scores in Tr+ TGFβ1 transgenic mice versus their Tr- wild type counterparts in response to bleomycin exposure.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2169220&req=5

Figure 5: TGFβ1 overexpression induces pronounced fibrotic response following bleomycin exposure. Tissue fibrosis was assessed in both Tr- wild type (A) and Tr+ transgenic (B) mice lung following exposure to 4500 IU bleomycin, as previously described. Shown are representative micrographs following haematoxylin/eosin staining of lung tissue, demonstrating fibrotic response in bleomycin treated wild type mouse lung that is significantly more severe in tissue from Tr+ TGFβ1 transgenic mice, suggesting that overexpression of the TGFβ1 transgene exacerbates subsequent lung injury. C. To quantify this fibrotic effect, fibrosis scores were determined as described. The graph shows enhanced fibrosis scores in Tr+ TGFβ1 transgenic mice versus their Tr- wild type counterparts in response to bleomycin exposure.
Mentions: Lung fibrosis induced by 4500 IU bleomycin in the Tr- wild type group was a mild patchy lung injury (Figure 5a). Tr+ transgenic mice, following exposure to comparable and smaller doses of bleomycin demonstrated marked lung injury hallmarked by grossly thickened alveolar walls, inflammation, fibroblast proliferation and collagen deposition in a peribronchial, interstitial and sub pleural distribution (Figure 5b).

Bottom Line: Idiopathic Pulmonary Fibrosis (IPF) is a progressive diffuse disease involving the lung parenchyma.Despite recent advances, the molecular mechanisms of the initiation and progression of this disease remain elusive.Previous studies have demonstrated TGFbeta1 as a key effector cytokine in the development of lung fibrosis.

View Article: PubMed Central - HTML - PubMed

Affiliation: National Heart and Lung Transplant Program, Mater Misericordiae University Hospital, University College Dublin, Dublin. jegan@mater.ie.

ABSTRACT

Background: Idiopathic Pulmonary Fibrosis (IPF) is a progressive diffuse disease involving the lung parenchyma. Despite recent advances, the molecular mechanisms of the initiation and progression of this disease remain elusive. Previous studies have demonstrated TGFbeta1 as a key effector cytokine in the development of lung fibrosis.

Methods: In this study we have used a transgenic mouse based strategy to identify the effect of overexpression of this key effector mediator on the development of pulmonary fibrosis in response to exogenous injury. We bred two lines (line 25 and 18) of transgenic mice (Tr+) that overexpressed active TGFbeta1. Three-month old transgenic and wild type mice were subsequently wounded with intraperitoneal bleomycin. Mice were sacrificed at 6 weeks post-bleomycin and their lungs analysed histologically and biochemically.

Results: The severity of lung fibrosis was significantly greater in the Tr+ mice compared to the wild type mice. Using an oligonucleotide microarray based strategy we identified discrete patterns of gene expression contributing to TGFbeta1 associated pulmonary fibrosis.

Conclusion: This data emphasises the importance of a host predisposition in the form of endogenous TGFbeta1, in the development of pulmonary fibrosis in response to an exogenous injury.

No MeSH data available.


Related in: MedlinePlus