SHH signalling in acute pulmonary cell injury and chronic fibrosis

• Main Author: Fitch, Paul Michael
• Published: University of Edinburgh 2005
• Subjects: 616.2
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.650937

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. <i>In vitro </i>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 <i>in vivo </i>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.