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The effects of transforming growth factor beta on asthmatic and non-asthmatic fibroblasts : their role in the epithelial-mesenchymal trophic unit

The effects of transforming growth factor beta on asthmatic and non-asthmatic fibroblasts : their role in the epithelial-mesenchymal trophic unit
The effects of transforming growth factor beta on asthmatic and non-asthmatic fibroblasts : their role in the epithelial-mesenchymal trophic unit

The aim of this study was to investigate the hypothesis that asthmatic fibroblasts exhibit hyperproliferation due to the production of autocrine growth factors.  Although the cytoskeletal and cytocontractile immunoreactivity observed in non-asthmatic and asthmatic fibroblasts is identical, asthmatic fibroblasts exhibit an ability to proliferate in serum free medium, whereas non-asthmatic fibroblasts remain quiescent.  Endothelin (ET)-1, connective tissue growth factor (CTGF) and transforming growth factor (TGF)β1, were investigated as candidate autocrine growth factors.  ET-1 and CTGF expression was significantly higher in asthmatic fibroblasts, but were observed to have little or no role in proliferation but roles in differentiation to myofibroblasts.  TGFβ1 gene expression was equal in non-asthmatic and asthmatic fibroblasts however, protein levels in conditioned medium of asthmatic fibroblasts was significantly lower suggesting autocrine use.  Specific neutralisation of TGFβ1 resulted in an inhibition of the hyperproliferation.  Cultured medium from asthmatic fibroblasts resulted in increased mitogenesis of NR6/HER fibroblasts, which was significantly blocked with AG1478 and anti-EGFR antibodies, suggesting EGFR ligands may also contribute to the hyperproliferation.  Addition of AG1478 and anti-EGFR antibodies also inhibited hyperproliferation of asthmatic fibroblasts.  HB-EGF gene expression was seen to be higher in asthmatic fibroblasts, which was significantly reduced by specific neutralisation of autocrine TGFβ1.  These observations suggested that autocrine TGFβ1 could result in activation of EGFR through expression of HB-EGF, which may be responsible for driving the hyperproliferation.  These observations may lead to novel therapeutic targets, which may dampen down the remodelling response in asthma.

University of Southampton
Chaudhary, Nveed
Chaudhary, Nveed

Chaudhary, Nveed (2003) The effects of transforming growth factor beta on asthmatic and non-asthmatic fibroblasts : their role in the epithelial-mesenchymal trophic unit. University of Southampton, Doctoral Thesis.

Record type: Thesis (Doctoral)

Abstract

The aim of this study was to investigate the hypothesis that asthmatic fibroblasts exhibit hyperproliferation due to the production of autocrine growth factors.  Although the cytoskeletal and cytocontractile immunoreactivity observed in non-asthmatic and asthmatic fibroblasts is identical, asthmatic fibroblasts exhibit an ability to proliferate in serum free medium, whereas non-asthmatic fibroblasts remain quiescent.  Endothelin (ET)-1, connective tissue growth factor (CTGF) and transforming growth factor (TGF)β1, were investigated as candidate autocrine growth factors.  ET-1 and CTGF expression was significantly higher in asthmatic fibroblasts, but were observed to have little or no role in proliferation but roles in differentiation to myofibroblasts.  TGFβ1 gene expression was equal in non-asthmatic and asthmatic fibroblasts however, protein levels in conditioned medium of asthmatic fibroblasts was significantly lower suggesting autocrine use.  Specific neutralisation of TGFβ1 resulted in an inhibition of the hyperproliferation.  Cultured medium from asthmatic fibroblasts resulted in increased mitogenesis of NR6/HER fibroblasts, which was significantly blocked with AG1478 and anti-EGFR antibodies, suggesting EGFR ligands may also contribute to the hyperproliferation.  Addition of AG1478 and anti-EGFR antibodies also inhibited hyperproliferation of asthmatic fibroblasts.  HB-EGF gene expression was seen to be higher in asthmatic fibroblasts, which was significantly reduced by specific neutralisation of autocrine TGFβ1.  These observations suggested that autocrine TGFβ1 could result in activation of EGFR through expression of HB-EGF, which may be responsible for driving the hyperproliferation.  These observations may lead to novel therapeutic targets, which may dampen down the remodelling response in asthma.

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Published date: 2003

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Local EPrints ID: 465137
URI: http://eprints.soton.ac.uk/id/eprint/465137
PURE UUID: ab8e64e9-e8be-4b57-be31-d142448d66da

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Date deposited: 05 Jul 2022 00:25
Last modified: 05 Jul 2022 04:20

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Author: Nveed Chaudhary

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