Limits...
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

Oligonucleotide microarray analysis reveals coordinate patterns of gene expression in response to bleomycin lung injury. A. Gene expression in Bleomycin treated Tr- Wild Type (WT BL, WTB1, WTB2) and Tr+ TGFβ1 trasgenic mice (TGF BL, TGFBL1, TGFBL2), and untreated Tr+ TGFβ1 trasgenic mice (TGF, TGF1, TGF2) was assessed using Affymetrix Mouse Genome 430_2 oligonucleotide microarrays in duplicate (data are reported in the cluster dendogram as single analysis and average: cel1, cel2 and average, respectively). Average and actual expression values for all significantly dysregulated genes were used as input in unsupervised hierarchical cluster visualization. Shown is a representative cluster dendrograms indicating separation of the conditions based on gene expression profiles, highlighting an high homology (based on the t-score) of both bleomycin treated group, respect to untreated Tr+ transgenic mice group. Figure B summarises the total number of genes found to be significantly altered in each comparison (Tr+ and bleomycin vs Tr- WT and bleomycin; Tr+ and bleomycin vs Tr+; Tr+ vs Tr- WT and bleomycin). A high number of altered genes were found to be upregulated and dowwnregulated in bleomycin treated Tr+ vs Tr+ group. C. To further annotate the pulmonary fibrosis associated transcriptome, significantly perturbed genes from bleomycin treated Tr+ vs Tr+ group were used as input in searches of the Gene Ontology database to identify the biological function of the altered genes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2169220&req=5

Figure 4: Oligonucleotide microarray analysis reveals coordinate patterns of gene expression in response to bleomycin lung injury. A. Gene expression in Bleomycin treated Tr- Wild Type (WT BL, WTB1, WTB2) and Tr+ TGFβ1 trasgenic mice (TGF BL, TGFBL1, TGFBL2), and untreated Tr+ TGFβ1 trasgenic mice (TGF, TGF1, TGF2) was assessed using Affymetrix Mouse Genome 430_2 oligonucleotide microarrays in duplicate (data are reported in the cluster dendogram as single analysis and average: cel1, cel2 and average, respectively). Average and actual expression values for all significantly dysregulated genes were used as input in unsupervised hierarchical cluster visualization. Shown is a representative cluster dendrograms indicating separation of the conditions based on gene expression profiles, highlighting an high homology (based on the t-score) of both bleomycin treated group, respect to untreated Tr+ transgenic mice group. Figure B summarises the total number of genes found to be significantly altered in each comparison (Tr+ and bleomycin vs Tr- WT and bleomycin; Tr+ and bleomycin vs Tr+; Tr+ vs Tr- WT and bleomycin). A high number of altered genes were found to be upregulated and dowwnregulated in bleomycin treated Tr+ vs Tr+ group. C. To further annotate the pulmonary fibrosis associated transcriptome, significantly perturbed genes from bleomycin treated Tr+ vs Tr+ group were used as input in searches of the Gene Ontology database to identify the biological function of the altered genes.

Mentions: To determine the molecular events subserving the TGFβ1 mediated exacerbation of lung fibrosis we utilised an oligonucleotide microarray based strategy to identify altered key transcripts. Specifically, we probed the molecular contribution to the repetitive injury, namely the expression changes induced by TGFβ1 overexpression and the expression changes that result from bleomycin exposure in these Tr+ transgenic mice. Affymetrix Mouse Genome 430_2 microarrays were used to determine gene expression levels in lung tissue from a) untreated Tr+ TGFβ1 transgenic mice b) Tr- wild type mice treated with bleomycin and c) bleomycin treated Tr+ TGFβ1 transgenic mice, to identify the overall pattern of gene expression in this experiment. Significant changes in gene expression were associated with these tissue cohorts (-0.6 < SLR > 0.6, and p < 0.05) (Figure 4a). Distinct patterns of coordinate gene expression were observed throughout the exposures, with substantial transcriptomic effects in terms of both up and downregulation of gene expression separating the sample groups.


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)

Oligonucleotide microarray analysis reveals coordinate patterns of gene expression in response to bleomycin lung injury. A. Gene expression in Bleomycin treated Tr- Wild Type (WT BL, WTB1, WTB2) and Tr+ TGFβ1 trasgenic mice (TGF BL, TGFBL1, TGFBL2), and untreated Tr+ TGFβ1 trasgenic mice (TGF, TGF1, TGF2) was assessed using Affymetrix Mouse Genome 430_2 oligonucleotide microarrays in duplicate (data are reported in the cluster dendogram as single analysis and average: cel1, cel2 and average, respectively). Average and actual expression values for all significantly dysregulated genes were used as input in unsupervised hierarchical cluster visualization. Shown is a representative cluster dendrograms indicating separation of the conditions based on gene expression profiles, highlighting an high homology (based on the t-score) of both bleomycin treated group, respect to untreated Tr+ transgenic mice group. Figure B summarises the total number of genes found to be significantly altered in each comparison (Tr+ and bleomycin vs Tr- WT and bleomycin; Tr+ and bleomycin vs Tr+; Tr+ vs Tr- WT and bleomycin). A high number of altered genes were found to be upregulated and dowwnregulated in bleomycin treated Tr+ vs Tr+ group. C. To further annotate the pulmonary fibrosis associated transcriptome, significantly perturbed genes from bleomycin treated Tr+ vs Tr+ group were used as input in searches of the Gene Ontology database to identify the biological function of the altered genes.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Oligonucleotide microarray analysis reveals coordinate patterns of gene expression in response to bleomycin lung injury. A. Gene expression in Bleomycin treated Tr- Wild Type (WT BL, WTB1, WTB2) and Tr+ TGFβ1 trasgenic mice (TGF BL, TGFBL1, TGFBL2), and untreated Tr+ TGFβ1 trasgenic mice (TGF, TGF1, TGF2) was assessed using Affymetrix Mouse Genome 430_2 oligonucleotide microarrays in duplicate (data are reported in the cluster dendogram as single analysis and average: cel1, cel2 and average, respectively). Average and actual expression values for all significantly dysregulated genes were used as input in unsupervised hierarchical cluster visualization. Shown is a representative cluster dendrograms indicating separation of the conditions based on gene expression profiles, highlighting an high homology (based on the t-score) of both bleomycin treated group, respect to untreated Tr+ transgenic mice group. Figure B summarises the total number of genes found to be significantly altered in each comparison (Tr+ and bleomycin vs Tr- WT and bleomycin; Tr+ and bleomycin vs Tr+; Tr+ vs Tr- WT and bleomycin). A high number of altered genes were found to be upregulated and dowwnregulated in bleomycin treated Tr+ vs Tr+ group. C. To further annotate the pulmonary fibrosis associated transcriptome, significantly perturbed genes from bleomycin treated Tr+ vs Tr+ group were used as input in searches of the Gene Ontology database to identify the biological function of the altered genes.
Mentions: To determine the molecular events subserving the TGFβ1 mediated exacerbation of lung fibrosis we utilised an oligonucleotide microarray based strategy to identify altered key transcripts. Specifically, we probed the molecular contribution to the repetitive injury, namely the expression changes induced by TGFβ1 overexpression and the expression changes that result from bleomycin exposure in these Tr+ transgenic mice. Affymetrix Mouse Genome 430_2 microarrays were used to determine gene expression levels in lung tissue from a) untreated Tr+ TGFβ1 transgenic mice b) Tr- wild type mice treated with bleomycin and c) bleomycin treated Tr+ TGFβ1 transgenic mice, to identify the overall pattern of gene expression in this experiment. Significant changes in gene expression were associated with these tissue cohorts (-0.6 < SLR > 0.6, and p < 0.05) (Figure 4a). Distinct patterns of coordinate gene expression were observed throughout the exposures, with substantial transcriptomic effects in terms of both up and downregulation of gene expression separating the sample groups.

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