Development and Application of Chymase Inhibitors: Therapeutic Potential of a Specific Chymase Inhibitor in Atopic Dermatitis

Abstract

ABSTRACT-A novel therapeutic mechanism may be the key to improving the chief symptoms and signs of atopic dermatitis (AD), which are persistent pruritus and high serum IgE. We demonstrate here that mast cell chymase may be a possible initiating factor and that the orally active specific inhibitor Y-40613 may have a therapeutic potential in the treatment of AD. We found that Y-40613dose-dependently suppressed the scratching response in a mouse pruritus model, with inhibitory efficacy enhanced by combination with conventional drugs, suggesting that chymase contributes to the development of pruritus by a unique mechanism or mechanisms. In fact, chymase injected in the model induced the scratching response. In vitro IgE production from mouse B cells was increased by purified rat chymase and suppressed by Y-40613. Increased serum IgE observed in Brown Norway rats injected with mercury chloride was suppressed by Y-40613. Furthermore, Y-40613 lowered ear thickness as well as serum IgE level in a mouse contact dermatitis model. Taken together, these findings suggest that the specific chymase inhibitor Y-40613 may ameliorate symptoms of AD through the dual inhibition of the chymase-dependent IgE production pathway and itching sensation.

Alpha‐tryptase gene variation is associated with levels of circulating IgE and lung function in asthma

“…It is of interest also that a polymorphism in the promoter region of the gene for chymase, a protease costored with tryptase, has been found to be associated with serum total IgE levels in adult atopic dermatitis in the same large UK Caucasian family cohort 46 . Moreover, IgE levels in a mouse model of atopic dermatitis can be suppressed by administration of an inhibitor of chymase, and chymase itself has been reported to increase IgE production from cultured mouse B lymphocytes 47 .…”

Serine Proteinase Inhibitors in the Skin: Role in Homeostasis and Disease

“…Since increased IgE levels are typical for both Netherton syndrome and atopic dermatitis, a pathophysiological role of chymase in these disorders is obvious. Accordingly, specific synthetic chymase is able to abate the symptoms like scratching response or swelling, and decreases serum IgE levels in mouse models [146][147][148][149].…”

Association between SNP rs1800875, serum chymase and immunoglobulin E levels in patients with coronary heart disease

“…On the other hand, a previous study demonstrated that IgE synthesis could be promoted by the addition of a rat chymase to a culture of murine spleen cells motivated by IL-4 and lipopolysaccharide (Yoshikawa et al, 2001). As well, administration of a synthetic chymase inhibitor (Y-40613) suppressed total IgE levels in a rat model of atopic dermatitis (Imada et al, 2002). However, this may not explain the relationship between CMA1 genotypes and high serum IgE level if one only considers the actions of human chymase.…”