title: Role of the urokinase plasminogen activator system in responses to acute gastric mucosal injury and in Helicobacter infection
Creators: name: Lyons, Suzanne
Publisher: name: University of Liverpool Repository
Year: 2014

description: In common with other hollow organs, the gastric mucosa consists of exocrine and endocrine epithelial cells and sub-epithelial stromal cells, all of which secrete mediators into the tissue microenvironment that define mucosal architecture and maintain organ function. Gastric myofibroblasts are an important stromal cell population involved in maintaining mucosal integrity, and are implicated in pathophysiological processes including chronic inflammation, fibrosis and cancer. Urokinase plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor (PAI)-1 are secreted by gastric epithelial and stromal cells and, together with the uPA receptor (uPAR), are believed to be involved in epithelial-mesenchymal signalling. However, the role of the uPA system in regulating gastric mucosal morphological homeostasis and responses to acute and chronic challenges is not yet fully understood. In this thesis, it was shown that transgenic PAI-1-H/Kβ mice, which have increased expression of PAI-1 in gastric parietal cells, have elevated concentrations of circulating PAI-1 and develop age-dependent increases in corpus mucosal thickness, independent of changes in parietal cell and myofibroblast abundance. PAI-1 did not have a direct trophic effect on gastric epithelial cells, indicating that PAI-1 might act via an indirect mechanism to modulate gastric epithelial cell turnover. In order to determine whether PAI-1 influences the gastric tissue microenvironment via myofibroblast gene expression, global transcript expression profiles of gastric myofibroblasts from wild-type and PAI-1 null (PAI-1-/-) mice were compared. Whole genome microarrays and subsequent validation by immunofluorescence indicated that mouse antral myofibroblasts are highly heterogeneous, including both desmin positive and desmin negative cells with distinct global transcript expression profiles. Furthermore, there was evidence that antral myofibroblasts displayed phenotypic plasticity in vitro, developing a neuroendocrine-like phenotype marked by expression of secretogranin-2. Plasticity may be functionally significant in vivo, supporting the role of myofibroblasts in wound healing. The role of PAI-1 in gastric mucosal responses to chronic Helicobacter infection was investigated using the H. felis model in wild-type, PAI-1-/- and PAI-1-H/Kβ mice. Both absence of PAI-1 and increased expression of gastric PAI-1 were protective against Helicobacter-induced preneoplastic gastric histopathology. Responses to acute gastric mucosal injury were investigated using intragastric indomethacin administration. Gastric PAI-1 protected against the development of lesions, whilst exogenous PAI-1 exacerbated the development of indomethacin induced gastric mucosal injury. Gastric uPA expression did not effect the development of lesions, whilst absence of uPAR tended to exacerbate lesion development. Taken together, the data presented in this thesis suggest a broadly protective role of PAI-1 in the gastric mucosa. A common therapeutic strategy for the prevention of NSAID-induced gastric injury, ulcer complications and progression of Helicobacter-induced gastric preneoplasia might be emerging, aimed at specifically increasing PAI-1 bioavailability in the gastric mucosa.