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Title: SHH signalling in acute pulmonary cell injury and chronic fibrosis
Author: Fitch, Paul Michael
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2005
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This thesis addresses the hypothesis that the sonic hedgehog (shh) signalling pathway is up regulated in response to cellular injury and that this signal acts as a potential pro-fibrogenic signal in pulmonary inflammation. In vitro studies utilised human (A549) and mouse (CMT) type II like epithelial cell lines in an analysis of epithelial response to injury. An immediate up regulation and release of soluble shh in response to hydrogen peroxide exposure was identified in mouse epithelium, utilising both RT-PCR and a novel shh ELISA developed here. Subsequent up-regulation and release of GM-CSF was shown to be shh independent. Human epithelial cells demonstrated a similar release of shh, suggesting a common pathway in both species. In contrast GM-CSF was not up regulated in human cells, but IL-8 up regulation did occur. The relevance of these studies to in vivo signalling was ascertained through use of the FITC instillation mouse model of inflammatory fibrosis. Observations correlating levels of FITC specific IgG1 antibody and disease severity in FITC treated animals suggest an immuno-modulatory role for T lymphocyte dependant, Th2 type antibodies in disease progression. In support of this iBALT has also been identified in diseased lung and T-lymphocyte depletion results in disease amelioration. Taken together these findings suggest that shh is an indicator of acute cellular injury, but that the principle component of FITC induced fibrotic disease progression is immune mediated and that this does not depend on shh up regulation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available