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
