133 Simulations of pH-effects on kallikrein activity predict compromised skin barrier and predisposition to irritations and dryness characteristic of atopic dermatitis

Abstract

Skin barrier function is a crucial element in the pathophysiology of atopic dermatitis (AD). Even non-lesional skin of AD patients is clinically characterized by a compromised barrier compared to healthy cohorts. This is often due to the increased kallikrein (KLK) activity also related to increased skin pH. The aim of our work is to develop a computational model of compromised skin barrier characteristic of non-lesional AD skin. A dynamic agent-based model of healthy adult epidermis is adapted to include a previously published mathematical model of KLK activity and its influence on desquamation. Parameter values are then modified to represent the increase in KLK activity, due to the increased skin pH, observed in AD skin. Simulations of the two models (healthy and compromised) are compared in terms of model emerging parameters like the thicknesses of the stratum corneum (SC) and the viable epidermis (VE), the total amount of a topically applied substance that permeates in the SC and the VE, the resistance to water transport in the SC and the transepidermal water loss (TEWL). Increased KLK activity results in weakening of the skin barrier function, in both directions: inside-out (water loss) and outside-in (external penetration). The SC of the compromised skin model is 15% thinner compared to the model of healthy epidermis. TEWL is increased by 9% and the amount of the externally applied substance that permeates in the VE by 18.5%. Resistance to water transport is decreased particularly in the lower part of the SC. These results are in agreement with published data comparing healthy and non-lesional AD skin. This study emphasizes the important role played by skin pH and KLK activity. It shows that an increase of KLK activity due to more alkali pH alone affects both the skin permeability to external irritants and its capacity to retain water. These effects can begin to explain the predisposition of such skins to irritation and skin dryness characteristic of AD.