| dc.description.abstract | Skin disorders such as psoriasis and chronic wounds are characterised by chronic inflammation accompanied by hyper-proliferation. Inflammation and proliferation are also phases in normal cutaneous wound healing. Upon wounding, an inflammatory response leads to the activation of the regenerative capacities of cells in the vicinity of the wound site. Thus, psoriasis and chronic wounds may involve de-regulation of mechanisms involved in normal wound healing. The adverse effects of classical treatments against psoriasis are such that they are usually only of net benefit to the most seriously affected patients. Novel treatment strategies are thus clearly needed.
Platelet activating factor (PAF) is produced during the inflammatory phase of wound healing, and is present in excess in psoriatic skin. PAF may be produced as a result of the activity of phospholipase A2 (PLA2) isoenzymes, which release unsaturated fatty acids from cell membranes such as arachidonic acid (AA). AA is a precursor for a group of lipid hormones known as eicosanoids, many of which are pro-inflammatory. The role of PAF in skin is incompletely understood.
The main objective of this thesis is to characterise the role of PAF in inflammation and proliferation in mature HaCaT keratinocytes, in order to identify potential targets for therapeutic intervention in chronic inflammatory disorders. PAF has been found to activate cPLA2 GIVA, which selectively releases arachidonic acid, and iPLA2 GVIA, a less well understood non-arachidonyl-selective enzyme. Transcriptome profiling of genes responsive to PAF-induced AA-release revealed involvement in wound healinglinked processes such as proliferation, changes in cell morphology and motility, and differentiation. A notable lack of evidence of a pro-inflammatory effect was also found
at the level of gene expression. Wound scratch experiments supported that PAF triggers re-epithelialisation. Further studies of the proliferative effect of PAF suggest that PAF induces proliferation via heparin-bound epidermal growth factor (HB-EGF)-induced transactivation of the epidermal growth factor receptor (EGFR) in HaCaT, resulting in activation of ERK and p38. A potential for triggering proliferative signalling through the canonical Wnt pathway in response to PAF was also revealed. The role of Wnt signalling in normal mature interfollicular skin is very little studied. However, both psoriatic skin and chronic wounds exhibit abnormal Wnt signalling activity, and further study of connections between inflammation and Wnt signalling may therefore reveal novel mechanisms which link inflammation and hyperproliferation.
PAF has been shown to trigger multiple signalling pathways leading to a complex sequence of events. Computer modelling may facilitate studies of signal transduction dynamics, allowing the prediction of key regulatory steps for further experimental study. The use of simulations of signal transduction pathways may also forward an improved general understanding of their dynamic nature, which all experimental biologists may benefit from. This suggests that simulations may have a role in teaching. A survey of existing simulation tools indicates that improved use of visualisation and real-time interactivity may lower the threshold for adaptation of simulation tools in teaching of undergraduate biology students, and a design for an improved tool is proposed.
In summary, PAF may be involved in the transition from the inflammatory to the proliferative phase in wound healing. Targeting the PAF signalling pathway, including phospholipase A2 enzymes, may modulate hyperproliferative skin disorders such as psoriasis or chronic wounds. | nb_NO |
