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The molecular mechanisms involved in rhinovirus-induced asthma exacerbation and its potential therapy

The molecular mechanisms involved in rhinovirus-induced asthma exacerbation and its potential therapy
The molecular mechanisms involved in rhinovirus-induced asthma exacerbation and its potential therapy
Rhinovirus (RV) infection is a major cause of asthma exacerbation in children and adults. Previous studies have shown that primary bronchial epithelial cells (PBECs) obtained from asthmatic subjects have a deficient interferon (IFN) response against RV infection, the molecular mechanism of which is unknown (Wark et al 2005; Contoli et al 2006).

Initially it was hypothesised that this deficiency is inherent to other cell types in the airway, such as bronchial fibroblasts. In a rhinovirus infection model, it was shown that fibroblasts respond with a vigorous pro-inflammatory response. However this response was accompanied by no significant IFN response. Fibroblasts produced IFN when we treated with a synthetic double-stranded RNA. However, no differences were observed between normal and asthmatic cells, indicating that the deficient innate immune response in asthmatic epithelium is not inherent to other cell types. We suggest that in vivo, bronchial fibroblasts may contribute to the inflammatory state in asthma when infected with RV. This might occur when an epithelial cell barrier with disrupted tight junctions might allow penetration and infection of the underlying mesenchymal cell layer.

To investigate the innate immune response of asthmatic PBECs we hypothesised that the anti-inflammatory cytokine transforming growth factor beta (TGF-β) dampened the innate immune response against rhinovirus infection. It has been shown previously that TGF-β is elevated in asthmatics. It was found that PBEC cultures from asthmatic subjects produce significantly more endogenous TGF-β2 compared to healthy controls. When PBECs from healthy donors were treated with exogenous TGF-β2 it promoted RV replication, which was coupled with a decreased IFN response. Conversely, treatment of PBECs from asthmatic subjects with a neutralizing antibody against TGF-β decreased RV replication. These observations provide an interesting link between an anti-inflammatory environment in the asthmatic airways contributing to a defective innate immune response in asthma.

To understand the TGF-β-mediated effect on RV replication, the importance of src kinases as one of the upstream signaling molecules in TGF-β-dependent alterations of cellular physiology was investigated. We found that inhibitors of src, in particular the SU6656 compound, were very potent in inhibiting RV replication. Inhibition by SU6656 was coupled with a significant increase in IFN response. These findings may pave the way towards designing compounds of similar structure, which are able to augment the IFN response and therefore provide a new form of therapy against asthma exacerbation.
University of Southampton
Bedke, Nicole
981dbd61-1912-4231-b6d5-42520c38178d
Bedke, Nicole
981dbd61-1912-4231-b6d5-42520c38178d
Davies, D.
b08c4b54-6246-4c36-bcb7-a78313526985

Bedke, Nicole (2010) The molecular mechanisms involved in rhinovirus-induced asthma exacerbation and its potential therapy. University of Southampton, Doctoral Thesis, 202pp.

Record type: Thesis (Doctoral)

Abstract

Rhinovirus (RV) infection is a major cause of asthma exacerbation in children and adults. Previous studies have shown that primary bronchial epithelial cells (PBECs) obtained from asthmatic subjects have a deficient interferon (IFN) response against RV infection, the molecular mechanism of which is unknown (Wark et al 2005; Contoli et al 2006).

Initially it was hypothesised that this deficiency is inherent to other cell types in the airway, such as bronchial fibroblasts. In a rhinovirus infection model, it was shown that fibroblasts respond with a vigorous pro-inflammatory response. However this response was accompanied by no significant IFN response. Fibroblasts produced IFN when we treated with a synthetic double-stranded RNA. However, no differences were observed between normal and asthmatic cells, indicating that the deficient innate immune response in asthmatic epithelium is not inherent to other cell types. We suggest that in vivo, bronchial fibroblasts may contribute to the inflammatory state in asthma when infected with RV. This might occur when an epithelial cell barrier with disrupted tight junctions might allow penetration and infection of the underlying mesenchymal cell layer.

To investigate the innate immune response of asthmatic PBECs we hypothesised that the anti-inflammatory cytokine transforming growth factor beta (TGF-β) dampened the innate immune response against rhinovirus infection. It has been shown previously that TGF-β is elevated in asthmatics. It was found that PBEC cultures from asthmatic subjects produce significantly more endogenous TGF-β2 compared to healthy controls. When PBECs from healthy donors were treated with exogenous TGF-β2 it promoted RV replication, which was coupled with a decreased IFN response. Conversely, treatment of PBECs from asthmatic subjects with a neutralizing antibody against TGF-β decreased RV replication. These observations provide an interesting link between an anti-inflammatory environment in the asthmatic airways contributing to a defective innate immune response in asthma.

To understand the TGF-β-mediated effect on RV replication, the importance of src kinases as one of the upstream signaling molecules in TGF-β-dependent alterations of cellular physiology was investigated. We found that inhibitors of src, in particular the SU6656 compound, were very potent in inhibiting RV replication. Inhibition by SU6656 was coupled with a significant increase in IFN response. These findings may pave the way towards designing compounds of similar structure, which are able to augment the IFN response and therefore provide a new form of therapy against asthma exacerbation.

Text
Nicole Bedke Final Thesis with author's declaration - Version of Record
Available under License University of Southampton Thesis Licence.
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Published date: January 2010

Identifiers

Local EPrints ID: 415752
URI: https://eprints.soton.ac.uk/id/eprint/415752
PURE UUID: e9632a6d-68d2-4a69-bb96-e1ca70bef889

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Date deposited: 22 Nov 2017 17:30
Last modified: 13 Mar 2019 19:13

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