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Title: The Sonic Hedgehog and Wnt signalling pathways in interstitial lung disease and CD4⁺T cell activation
Author: Stewart, Gareth Alexander
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2003
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The Sonic Hedgehog (Shh) signalling pathway plays an important role in lung development where it promotes branching morphogenesis through epithelialmesenchymal interactions. Increased Shh expression promotes epithelial and mesenchymal proliferation in vitro and in vivo. TGFp is also expressed in embryonic lung where it acts to inhibit branching morphogenesis. TGFP overexpression results in lung hypoplasia, a similar phenotype to that seen in Shh'A mutants; suggesting that Shh and TGFP have opposing roles. Evidence to date would suggest that although TGFP and Shh may not directly interact in lung development, they probably have common targets and may function in a shared regulatory circuit. Interstitial lung disease (ILD) is the end result of a multiplicity of pathological processes. It has been recently proposed that the commonest form, Idiopathic Pulmonary Fibrosis (IPF) or Usual Interstitial Pneumonia (UIP), is due to abnormal wound healing in the lung, characterized by epithelial-fibroblast interactions; a process similar to foetal lung branching and epithelialization. TGFP has been strongly linked with ELD in both animal models and human disease. Based on the link between TGFP and Shh in lung morphogenesis, the initial aim of this thesis was to determine whether or not Shh signalling was upregulated in ILD. The work presented confirms that Shh and TGFP expression are increased in the airway epithelium of fibrotic but not non-fibrotic lung both in the murine FITC model of ILD and in biopsy sections from patients with IPF. Expression of Patched (Ptc), the Shh receptor, is unchanged in epithelial cells. Notably, Ptc is present both in alveolar macrophages and lymphocytic infiltrates. However, there is no discernible difference in the fibrotic response in the lungs of mice containing heterozygous mutations of Gli2 and 3, used as models of dysregulated Shh signalling, nor in mice treated with intra-tracheal SPC-Shh cDNA. The Shh pathway has recently been shown to play a role in thymocyte development. The findings presented demonstrate that both Shh and Ptc are expressed in human T cells. In addition, upregulation of Shh signalling enhances and blocking of endogenous Shh inhibits T cell receptor mediated T cell activation, respectively, as determined by proliferation, cytokine production and CD25 and CD69 expression. Wnt signalling is also thought to play a role in lung branching morphogenesis. It is known to interact both with Shh signalling and TGFβ. However, using presently available antibodies, there is no evidence of upregulation of Wnt signalling in ILD. In an attempt to drive the Wnt Pathway, a replication-deficient adenovirus expressing Dvll (Ad5-MCMV-Dvll) was successfully rescued. Although the virus drives Dvll mRNA and protein expression in vitro and in vivo, it does not consistently mimic Wnt signalling, nor does it appear to affect Shh or TGFβ signalling. Furthermore such Dvll overexpression has little effect on cell proliferation either in vitro or in vivo, and does not cause lung fibrosis in mice. Thus Shh signalling appears to be upregulated in fibrotic lung in mice and humans. However the work presented does not define whether or not the pathway plays a specific role in the pathogenesis of ILD. There is also no evidence relating Wnt signalling or Dvll upregulation to ILD. Finally, Shh is shown to influence TCR mediated signalling and clonal expansion. It may be that damaged epithelial cells and the immune system communicate via this pathway.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available