Nuttall, A.; (2010) The role of the epidermis in pathogenesis of systemic sclerosis. Doctoral thesis , UCL (University College London).

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Abstract

Studies into the pathogenesis of systemic sclerosis (SSc) skin fibrosis to date have concentrated on dermal changes in the disease. Little attention has been paid to the epidermis in SSc. Epithelial-fibroblast interactions are believed to regulate wound healing and contribute to a number of fibrotic diseases. Recent proteomic data from our laboratory reveals altered keratinocyte (KC) specific proteins in SSc skin consistent with a wound healing phenotype of the disease epidermis. I therefore studied SSc KCs focusing on differentiation and KC-fibroblast interaction. I found that KC maturation is altered in SSc with abnormal persistence of cytokeratins 1, 10 and 14 into suprabasal layers. Cytokeratins 6 and 16, induced in wound healing KCs, were shown to be expressed in SSc epidermis. In addition, IL-1, a pivotal cytokine involved in KC and fibroblast events post epidermal injury, and its downstream signalling phosphoproteins p38 and JNK were elevated in SSc epidermis. I went on to study the effect of SSc epidermis on normal human fibroblasts. I found that SSc epidermis promoted fibroblast activation in an ET-1, TGF-β, and IL-1 dependent fashion. I suggest a double paracrine loop initiated by KC-derived IL-1 as a mechanism for epidermal-dermal co-activation in the disease, similar to that previously demonstrated for wound healing. There is a need for developing antifibrotic agents targeting epithelium-derived factors and their signalling pathways. I went on to study normal epidermal wound healing. A paradox during epithelial repair is that KCs proliferate despite a TGF-β dominated environment, which is known to be anti-proliferative. Our laboratory previously showed that prostanoids antagonise TGF-β-dependent events in human cells. The induction of prostanoids following injury could transiently free KCs from the anti-proliferative effects of TGF-β. I test this hypothesis by confirming transient induction of epidermal COX II and PGE2 following injury. I also show that PGE2 antagonises the anti-proliferative and pro-migratory effects of TGF-β on KCs. My work supports a model where induction of epidermal wound edge COX II leads to antagonism of TGF-β and allows KCs to proliferate prior to migration over the wound.

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