Mathematical Modelling of Nitric Oxide Regulation of Rete Peg Formation in Psoriasis

Abstract

Recent experiments have shown that in patients with psoriasis, highly elevated levels of nitric oxide (NO) are released at the surface of psoriatic plaques. Nitric oxide is a central biological regulator of many aspects of physiology, and it is a natural possibility that the high nitric oxide levels in psoriasis play a causal role in the onset of the disease. Here, we use mathematical modelling to investigate this possibility. We begin by discussing a simple model consisting of a single equation for nitric oxide concentration, which enables nitric oxide secretion rates in the basal epidermis to be calculated from the observed NO release rates at the skin surface. Using this key parameter value, we then develop an extended model that tests the hypothesis that nitric oxide regulates the formation of the extended rete pegs seen in psoriatic plaques. This occurs via the peroxynitrite-dependent activation of the collagenase MMP}8, which is produced by neutrophils present at high levels in psoriatic plaques. The plausibility of the hypothesis is demonstrated and speci"c testable quantitative predictions about the roles of the various cell types and signalling molecules are made. Academic Press

Kinetic Modeling of Nitric-Oxide-Associated Reaction Network

“…Using mathematical modeling, Vaughn et al (15) predicted the rate of NO production by vascular endothelium of õ10 j5 M/s. In addition, the NO production rate by basal epidermal cell was estimated to be 1.7 Â 10 j7 M/s (24). Cultured keratinocyte cells (25) and fibroblasts (26) generated O À 2 at a rate of õ10 j6 M/s and õ10 j5 M/s, respectively.…”

Stem Cell Niche Structure as an Inherent Cause of Undulating Epithelial Morphologies

“…Another possible explanation for these morphologies is derived from hydrodynamic instability that arises from assuming that the epithelia serves as an incompressible fluid that neighbors a viscoelastic stroma (24), though it does not consider the stem cell niche as the source of tissue renewal. Other studies use models to examine how the size of rete pegs are regulated by nitric oxide (25) or may be controlled during psoriasis through radiative treatment (26), but neither explores the mechanisms that drive rete peg formation.…”

Modelling Blood Flow Regulation by Nitric Oxide in Psoriatic Plaques

“…The potential for NO having a causal effect in plaque formation arises from the many aspects of skin biology that are regulated by NO, including epidermal cell division and differentiation (Krischel et al, 1998), endothelial cell growth and migration (Ziche et al, 1994), and extracellular matrix turnover (Okamoto et al, 1997;Maeda et al, 1998). In a separate study (Savill et al, 2002), we have used mathematical modelling to investigate this last effect, suggesting that the NO-dependence of matrix degradation may help to explain the elongated rete pegs observed in psoriatic plaques.…”