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Title: Effects of irritants in the epidermis : the role of kallikrein 5 and 7 and protease activated receptor 2
Author: Underwood, Joanne
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2013
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Contact dermatitis affects 0.5-1.9 cases per 1,000 full-time workers annually, with 80% of cases accounted for by irritant contact dermatitis. The mechanisms underlying irritant contact dermatitis are incompletely understood and there is also a large need in industry for screening tools to identify the irritant potential of novel chemical compounds. The aim of this thesis was to investigate whether disruption of the stratum corneum barrier by irritants induces epidermal serine proteases such as KLKs which act through the PAR2 receptor to cause a pro-inflammatory response. Croton oil (3%) and SDS (5%) were applied to ex vivo human skin and expression of KLK5, KLK7 and PAR2 analysed. Both croton oil and SDS increased KLK5 (p=0.0001 and 0.0002 respectively), KLK7 (p=0.0027 and 0.0009 respectively), and PAR2 (p=0.0057 and p=0.0215 respectively). In addition, protease activity within the epidermis was concomitantly increased (p=0.0094 for croton oil and p=0.0185 for SDS). Although these findings help to provide mechanistic insight, and could have some use as a screening tool, the availability of human skin is a limiting factor in an industrial setting. Using Rho kinase-inhibition to increase the proliferative capacity of adult human keratinocytes to generate 3D epidermal equivalents, it was noted that the resulting stratum corneum was insufficiently resilient to withstand application of SDS, even at reduced concentrations. However, in monolayer cultures it was noted that, following initial screening using qPCR arrays, croton oil and dithranol caused upregulation of IL6, IL36A, CCL5 and CSF2 in Rho kinase-inhibited keratinocytes, and that CCL5 and CSF2 were similarly upregulated in normal human keratinocytes exposed to these compounds. Thus, in Rho kinase-inhibited keratinocytes, CCL5 and CSF2 (and possibly IL6 and IL36A) may form a useful screening tool for potential irritants generated in industry, although further work will be required to test sensitivity and specificity of this approach.
Supervisor: Healy, Eugene ; Friedmann, Peter Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available