Novel Dermatological Treatment

About

The important role of hyaluronic acid (HA) in physiology is well known. However, evidence is now evolving on the importance of metabolism of HA in pathophysiology of many diseases including dermatological diseases. This is not surprising as, although HA is detected in all tissues, the bulk is found deposited in the skin representing almost 50% of the total body HA. These new public data are derived from examination of the presence and effects of degraded forms of HA (low molecular weight (LMW) HA) in various diseases as well as research on new HA-binding proteins, such as layilin, and new metabolizing proteins such as CEMIP (aka HYBID or KIAA1199). For example, the decrease in HMW HA in photoaged skin due to increased expression of CEMIP. It is known that LMW HA, produced during degradation/metabolism of HMW HA by enzymes and oxidative stress, can bind and activate toll-like receptor-4 (TLR4). TLR4 expression is shifted to the upper layers in diseased skin in patients with psoriasis or atopic dermatitis compared to control skin. Furthermore, the expression of hyaluronic acid synthase 3, which produces LMW HA as small as 100 kDa, is significantly overexpressed in the epidermis of atopic dermatitis patients. Esser et al. showed that contact sensitizers induce degradation of HA in the epidermis of mice induced innate inflammation mediated by TLR4. IL-18 has been implicated in various inflammatory skin diseases, including psoriasis, atopic dermatitis. To that end, LMW HA has also been shown to stimulate production of IL-18 in keratinocytes. Intriguingly, T-regulatory cells (Tregs) also play a key role in psoriatic inflammation and it has been recently reported that the LMW-HA binding protein, layilin, is found to be preferentially and highly expressed on Tregs in skin. Thus it is likely that LMW HA is produced in skin of psoriasis and atopic dermatitis and induces innate inflammation via TLR4 and novel HA-binding protein layilin, likely through the inflammasome pathway. The solution: Novel _N_-acyl analogs of hyaluronic acid, in particular N-butyl HA, prevent binding and activation of TLR4 by LMW HA and other TLR4 agonists. Queen’s researchers have now identified analogs of HA which lack this property and prevent native LMW HA from activating TLR4. Thus, N-acylating HA, in particular N-butylation of HA (BHA), removes this proinflammatory property while retaining positive effects of HA. In vitro studies on the macrophage cell line THP1 demonstrated the pro-inflammatory activity of LMW HA through TLR4 activation by stimulating cytokine release. BHA prevented cytokine stimulation by LMW HA as well as gold standard TLR4 agonist LPS-EC. In contrast the TLR2 agonist, PG-PS, produced much smaller cytokine release and this activation was not prevented by BHA, demonstrating that LMW HA and BHA have their effects mediated via TLR4. As a proof of concept in treating skin diseases the researchers have tested a novel topical BHA formulation in a rat full-thickness excisional wound model and compared it to a hydroxymethyl chitosan (HMC) formulation. The new formulation initiated wound healing at a significantly faster rate than CMC. The BHA formulation also showed less epidermal hyperplasia, less inflammatory cell infiltration, and better overall healing compared to HMC treatment, treatment with formulation minus BHA and no treatment controls. With the BHA formulation new hair follicles can be visualized by day 10. Mechanistically BHA treatment rapidly increased positive wound mediators TGFβ, SMADs 2,3 and 7, as well as collagens I and III that coincided with a more rapid healing process. Furthermore, BHA treatment significantly reduced negative inflammatory markers TNFα, p65 and p38 compared to HMC and controls. BHA treatment also significantly increased hydroxyproline that corresponded to increased collagen production.