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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

Characterisation of TGFβ1 transgenic mice. A. Expression of the transgene in wild type and both line 18 and line 25 transgenic mice was assessed by PCR using TGFβ1 sequence specific primers. This figure is a representative agarose gel post amplification indicating expression of the TGFβ1 transgene in both line 18 and line 25 Tr+ transgenic mice (Lanes 1 and 2). Lanes 3 and 4 show absence of transgene in wild type mice. Figure B and C show PAIL lumineriferase assay results. To determine the effect of the transgene on circulating TGFβ1, both total (B) and active (C) TGFβ1 concentrations in sera was determined.
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Figure 1: Characterisation of TGFβ1 transgenic mice. A. Expression of the transgene in wild type and both line 18 and line 25 transgenic mice was assessed by PCR using TGFβ1 sequence specific primers. This figure is a representative agarose gel post amplification indicating expression of the TGFβ1 transgene in both line 18 and line 25 Tr+ transgenic mice (Lanes 1 and 2). Lanes 3 and 4 show absence of transgene in wild type mice. Figure B and C show PAIL lumineriferase assay results. To determine the effect of the transgene on circulating TGFβ1, both total (B) and active (C) TGFβ1 concentrations in sera was determined.

Mentions: Following breeding, TGFβ1 expression was confirmed by PCR amplification in Tr+ TGFβ1 transgenic mice (Figure 1a). To determine the effect of the TGFβ1 transgene in these mice, serum levels of both total and active TGFβ1 were determined. The Tr+ transgenic mice had higher levels of total TGFβ1 (2.2 ng/ml, SEM 0.23) compared to Tr- wild types (1.58 ng/ml, SEM 0.39), though this comparison did not reach statistical significance (p = 0.16) (Figure 1b); while, Tr+ transgenic mice had higher plasma levels of active TGFβ1 (mean 98.1 pg/ml, SEM 16.1) compared to Tr- wild types (mean 9.37, SEM 6.6) (p < 0.01). Individually, the line 18 mice had a similar level of active TGFβ1 (mean 87 pg/ml, SEM 19.2) to the line 25 mice (105.5 pg/ml, SEM 24.5) (Figure 1c).


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)

Characterisation of TGFβ1 transgenic mice. A. Expression of the transgene in wild type and both line 18 and line 25 transgenic mice was assessed by PCR using TGFβ1 sequence specific primers. This figure is a representative agarose gel post amplification indicating expression of the TGFβ1 transgene in both line 18 and line 25 Tr+ transgenic mice (Lanes 1 and 2). Lanes 3 and 4 show absence of transgene in wild type mice. Figure B and C show PAIL lumineriferase assay results. To determine the effect of the transgene on circulating TGFβ1, both total (B) and active (C) TGFβ1 concentrations in sera was determined.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Characterisation of TGFβ1 transgenic mice. A. Expression of the transgene in wild type and both line 18 and line 25 transgenic mice was assessed by PCR using TGFβ1 sequence specific primers. This figure is a representative agarose gel post amplification indicating expression of the TGFβ1 transgene in both line 18 and line 25 Tr+ transgenic mice (Lanes 1 and 2). Lanes 3 and 4 show absence of transgene in wild type mice. Figure B and C show PAIL lumineriferase assay results. To determine the effect of the transgene on circulating TGFβ1, both total (B) and active (C) TGFβ1 concentrations in sera was determined.
Mentions: Following breeding, TGFβ1 expression was confirmed by PCR amplification in Tr+ TGFβ1 transgenic mice (Figure 1a). To determine the effect of the TGFβ1 transgene in these mice, serum levels of both total and active TGFβ1 were determined. The Tr+ transgenic mice had higher levels of total TGFβ1 (2.2 ng/ml, SEM 0.23) compared to Tr- wild types (1.58 ng/ml, SEM 0.39), though this comparison did not reach statistical significance (p = 0.16) (Figure 1b); while, Tr+ transgenic mice had higher plasma levels of active TGFβ1 (mean 98.1 pg/ml, SEM 16.1) compared to Tr- wild types (mean 9.37, SEM 6.6) (p < 0.01). Individually, the line 18 mice had a similar level of active TGFβ1 (mean 87 pg/ml, SEM 19.2) to the line 25 mice (105.5 pg/ml, SEM 24.5) (Figure 1c).

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