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Title: Investigation of the underlying mechanisms leading to the development of incontinence-associated dermatitis
Author: Koudounas, Sofoklis
ISNI:       0000 0004 7967 1498
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2019
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Incontinence-associated dermatitis (IAD) is an inflammatory response caused by the prolonged contact of the skin to urine and/or faeces. Although several theories exist to explain the pathophysiology of IAD, most are based on animal models, or derived from studies on the related condition of diaper dermatitis ('nappy rash') that occurs in babies. Thus, their relevance to IAD in adults is limited and the underlying mechanisms of IAD remain poorly understood. The motivation for this novel work was to develop and validate both in vivo and in vitro techniques to simulate IAD to provide empirical evidence on the biophysical and biochemical disruption of skin in IAD. The integrity of the skin was evaluated by measuring changes in skin blood flow, transepidermal water loss (TEWL), hydration of the stratum corneum (SC) and skin surface pH. Synthetic-urine (s-urine) and a proteolytic solution were used to simulate the effects of urinary- and faecal- incontinence, respectively. The release of inflammatory biomarkers was investigated in vivo by two distinct sampling techniques, namely microdialysis and Sebutape™. In vitro investigations were also conducted with human keratinocytes to support in vivo studies, with cell viability and the secretion of inflammatory cytokines serving as output measures. Results of the current study showed that while urine disrupts the integrity of intact skin, causing a significant increase in skin blood flow, TEWL, SC hydration and skin surface pH (p < 0.05), its effects are not pH dependent. In contrast, exposure of the skin to the proteolytic solution led to an enhanced increase in these biophysical parameters. This was also supported by in vitro keratinocyte experiments which indicated that the proteolytic solution is more deleterious than urine, as revealed by a decreased cell viability. Of particular importance is the finding that the permeability and susceptibility of the skin to urine depends on skin condition, with chemically-irritated skin, exacerbated by frequent cleansing activities, presenting an increased risk of IAD. Increased skin permeability was also associated with an elevated skin surface pH. In this respect, in vitro investigations highlighted that pH is an important regulator for the function of keratinocytes and consequently the maintenance of skin barrier function. Additionally, it was shown that the effects of urinary pH are time-dependent. Importantly, exposure of skin to urine and the proteolytic solution resulted in an increase in the release of pro-inflammatory biomarkers and indeed during exposure there was a time-dependent accumulation of biomarkers in the interstitium. In particular, a significant increase was estimated in the ratio of IL-1α/IL-1RA (p < 0.05) following exposure to s-urine. Additionally, results demonstrated that s-urine resulted in an increase in IL-1α, whereas the proteolytic solution caused a marked increase in TNF-α. The increase in pro-inflammatory cytokines following exposure to urine was further supported by the in vitro studies. In these studies, an increase in the pH upregulated the release of inflammatory biomarkers, more particularly IL-1α. These data propose that in future studies, IL-1α and TNF-α have the potential to serve as responsive markers of skin damage caused by incontinence. The findings presented in this thesis extend current knowledge on IAD, with noteworthy implications for the direction of future IAD research and the development of targeted clinical interventions. Additionally, the data add to the scientific body of evidence and propose that the damage caused by frequent cleansing activities and the release of inflammatory biomarkers are two mechanisms implicated in the pathophysiology of IAD. Additionally, an internal pH mechanism for keratinocytes function is also proposed, which needs to be further examined. Overall, this work establishes the methods to investigate IAD in an experimental setting, which can be translated to clinical studies.
Supervisor: Bader, Daniel Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available