seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide and Dermatitis--Atopic

To investigate the mechanisms underlying itching in atopic dermatitis, we examined whether thromboxane (TX) A2, an arachidonic acid metabolite, is involved in spontaneous scratching, an itch-related response, in NC mice with atopic dermatitis-like skin lesions. The TXA2 receptor (TP) antagonist ONO-3708 inhibited the spontaneous scratching. The mRNA expression of TX synthase (TXSyn) distributed mainly in epidermis and the concentration of TXB2, a metabolite of TXA2, were increased in lesional skin. Scratching caused by the PAR2 agonist SLIGRL-NH2 was suppressed by ONO-3708. SLIGRL-NH2-induced scratching decreased approximately 75% in TP-deficient mice, compared to wild-type mice. In primary cultures of mouse keratinocytes, SLIGRL-NH2 induced the production of TXA2, as evidenced by the increased TXB2, which was inhibited by the TXSyn inhibitor sodium ozagrel and a PAR2-neutralizing antibody. Taken together, these results suggest that epidermal TXA2, which may be produced via PAR2 activation, is involved in itching in atopic dermatitis.

Topics: Animals; Dermatitis, Atopic; Keratinocytes; Male; Methacrylates; Mice; Oligopeptides; Pruritus; Receptor, PAR-2; RNA, Messenger; Thromboxane A2

This study investigated the involvement of tryptase and proteinase-activated receptor (PAR) subtypes in spontaneous scratching, an itch-associated behavior, in NC mice. This strain of mice showed chronic atopy-like dermatitis and severe spontaneous scratching, when kept a long time in a conventional environment. The trypsin-like serine proteinase inhibitor nafamostat mesilate (1 - 10 mg/kg) dose-dependently inhibited spontaneous scratching in mice with dermatitis. The activity of tryptase was increased in the lesional skin, which was inhibited by nafamostat at a dose inhibiting spontaneous scratching. Enzyme histochemistry revealed the marked increase of toluidine blue-stained cells, probably mast cells, with tryptase activity in the dermis of the lesional skin. Intravenous injection of anti-PAR(2) antibody suppressed spontaneous scratching of mice with dermatitis. Intradermal injection of the PAR(2)-activating peptide SLIGRL-NH(2), but not PAR(1), (3), (4)-activating peptides, elicited scratching at doses of 10 - 100 nmol/site in healthy mice. PAR(2)-immunoreactivity was observed in the epidermal keratinocytes in healthy and dermatitis mice. These results suggest that PAR(2) and serine proteinase(s), mainly tryptase, are involved in the itch of chronic dermatitis.

Topics: Animals; Benzamidines; Chronic Disease; Dermatitis, Atopic; Disease Models, Animal; Dose-Response Relationship, Drug; Epidermal Cells; Epidermis; Guanidines; Keratinocytes; Male; Mast Cells; Mice; Oligopeptides; Protease Inhibitors; Receptor, PAR-2; Tryptases