The differentiating and proliferative effects of transforming growth factor beta (TGFB) and epidermal growth factor (EGF) on asthmatic fibroblasts
The differentiating and proliferative effects of transforming growth factor beta (TGFB) and epidermal growth factor (EGF) on asthmatic fibroblasts
TGFβ2 caused growth arrest in fibroblasts and initiated their transformation into myofibroblasts, as shown by induction of αSMA. EGF induced fibroblasts to proliferate but did not induce their differentiation. In combination, EGF and TGFβ promoted fibroblasts proliferation. Initially αSMA expression was suppressed, suggesting a dominant EGF effect. Upon prolonged culture, TGFβ2 and EGF promoted fibroblast transformation into myofibroblasts indicating a shift towards TGFβ dominance. Changes in TFGβ receptor and ligand expression did not appear to be disease dependent. There was a trend for down regulation of the TGFβ signalling pathway (TGFβ RI, CTGF, αSMA) in quiescent asthmatic fibroblasts, although no difference was seen after TGFβ2 treatment.
EGF induced mRNA expression of AR and HB-EGF in normal and asthmatic fibroblasts. The increase in AR in response to EGF was higher in the asthmatic fibroblasts (p=0.019) compared to the normals. TGFβ had no effect on AR expression but caused a marked dose-dependent induction of HB-EGF expression which was significantly higher in the normal compared with asthmatic cultures (p=0.024). AR was detected in conditioned media and its release was promoted by cellular activation with phorbol ester. HB-EGF was detected in conditioned medium after stimulation with phorbol ester, TGFβ2 and hexadimethrine. There was a trend for lower HB-EGF release from asthmatic fibroblasts.
My study has revealed novel observations surrounding the complex control of TGFβ and EGF signalling in bronchial fibroblasts. In a TGFβ and EGF rich environment, akin to conditions in inflamed asthmatic airways, fibroblasts can undergo both proliferation and differentiation, potentially contributing to the fibrosis associated with airway remodelling. The suppressed release of AR and HB-EGF, growth factors with potent paracrine activity, lead to a proposal that there is a decline in signalling between the epithelium and asthmatic fibroblasts which may lead to an imbalance in bidirectional communication within the EMTU, leading to decreased epithelial proliferation and an increase in mesenchymal proliferation and differentiation.
University of Southampton
Boxall, Christine Barbara
8a86b0f4-154b-4e99-97cf-347ea45b4c3b
2004
Boxall, Christine Barbara
8a86b0f4-154b-4e99-97cf-347ea45b4c3b
Boxall, Christine Barbara
(2004)
The differentiating and proliferative effects of transforming growth factor beta (TGFB) and epidermal growth factor (EGF) on asthmatic fibroblasts.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
TGFβ2 caused growth arrest in fibroblasts and initiated their transformation into myofibroblasts, as shown by induction of αSMA. EGF induced fibroblasts to proliferate but did not induce their differentiation. In combination, EGF and TGFβ promoted fibroblasts proliferation. Initially αSMA expression was suppressed, suggesting a dominant EGF effect. Upon prolonged culture, TGFβ2 and EGF promoted fibroblast transformation into myofibroblasts indicating a shift towards TGFβ dominance. Changes in TFGβ receptor and ligand expression did not appear to be disease dependent. There was a trend for down regulation of the TGFβ signalling pathway (TGFβ RI, CTGF, αSMA) in quiescent asthmatic fibroblasts, although no difference was seen after TGFβ2 treatment.
EGF induced mRNA expression of AR and HB-EGF in normal and asthmatic fibroblasts. The increase in AR in response to EGF was higher in the asthmatic fibroblasts (p=0.019) compared to the normals. TGFβ had no effect on AR expression but caused a marked dose-dependent induction of HB-EGF expression which was significantly higher in the normal compared with asthmatic cultures (p=0.024). AR was detected in conditioned media and its release was promoted by cellular activation with phorbol ester. HB-EGF was detected in conditioned medium after stimulation with phorbol ester, TGFβ2 and hexadimethrine. There was a trend for lower HB-EGF release from asthmatic fibroblasts.
My study has revealed novel observations surrounding the complex control of TGFβ and EGF signalling in bronchial fibroblasts. In a TGFβ and EGF rich environment, akin to conditions in inflamed asthmatic airways, fibroblasts can undergo both proliferation and differentiation, potentially contributing to the fibrosis associated with airway remodelling. The suppressed release of AR and HB-EGF, growth factors with potent paracrine activity, lead to a proposal that there is a decline in signalling between the epithelium and asthmatic fibroblasts which may lead to an imbalance in bidirectional communication within the EMTU, leading to decreased epithelial proliferation and an increase in mesenchymal proliferation and differentiation.
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Published date: 2004
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Local EPrints ID: 465591
URI: http://eprints.soton.ac.uk/id/eprint/465591
PURE UUID: 82e14af9-b6c3-4bec-ae11-82b5dc9a6911
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Date deposited: 05 Jul 2022 01:56
Last modified: 16 Mar 2024 20:16
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Author:
Christine Barbara Boxall
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