Pemphigus vulgaris (PV) is a blistering autoimmune disease
characterized by IgG autoantibodies against desmoglein 3. Nitric oxide synthases
(NOS) may contribute to the increase of inflammation in tissues by the generation
of nitrotyrosine residues (NTR). OBJECTIVES: To investigate whether the
production of NTR mediated by NOS may participate in the development of
inflammation and acantholysis in PV. METHODS: Mice were pretreated or not with
NOS, tyrosine-kinase (TK) or nuclear factor (NF)-kappaB inhibitors, and then
injected with PV-IgG. PV manifestations were examined in all mice. The expression
of NTR, constitutive NOS (cNOS) [endothelial NOS (eNOS) and neuronal NOS (nNOS)],
inducible NOS (iNOS) and NF-kappaB factor were studied in epidermis of mice using
immunohistochemical techniques. RESULTS: After PV-IgG injection, expressions of
NTR, iNOS, eNOS and nNOS increased in acantholytic cells, as did nuclear
translocation of NF-kappaB in the basal cells of the epidermis. Pretreatment of
mice with inhibitors of TK, nNOS and nonselective NOS, completely prevented NTR
expression and the clinical and histological findings of PV in mice. TK inhibitor
genistein inhibited both nNOS and iNOS expression on the membrane of basal
keratinocytes, and nuclear translocation of NF-kappaB. CONCLUSIONS: Upregulation
of cNOS and iNOS, NTR generation and nuclear translocation of NF-kappaB may
contribute to increased inflammation and tissue damage in PV lesions. The absence
of the clinical and histological findings of PV and NTR expression in mice
injected with PV-IgG, through pretreatment with TK and nNOS inhibitors, provides
compelling evidence that these signalling molecules should be considered as
potential therapeutic targets in PV
