The role of nitric oxide in psoriasis
I investigated the effect of inhibiting NO production in the psoriatic plaque. A 70% inhibition of NO was attained but overall there was no clinical benefit in 17 patients whereas with topical steroids benefit was very apparent with only 12 subjects. Immunocytochemical examination of these patients revealed a 50% reduction in endothelial cells, following L-NMMA treatment, supporting an important effect of NO in angiogenesis. ICAM-1 was also suppressed and there was an increase in CD8 positive cells and Langerhans' cells following L-NMMA. Surprisingly there was no inhibition of keratinocyte proliferation with L-NMMA. It is possible that some of the immunosuppressive effects of NO were inhibited, thus promoting some aspects of psoriasis at the same time as inhibiting others. Finally the direct effects of NO on normal skin were examined using acidified nitrite as a topically applied NO donor. In keeping with the observations in psoriasis there was a reduction in Langerhans' cells which lost dendricity and migrated from the epidermis. This suggests that NO may have some role in activating Langerhans's cells and thereby in antigen presentation. NO increased the adhesion molecules ICAM-1 and VCAM-1, attracting increased numbers of macrophages, T cells and neutrophils but had no effect on mast cell numbers. There was a tendency for higher doses of NO to produce lower levels of cellular infiltration, suggesting an immunosuppressive effect of higher doses. Nitrosotyrosine staining was not marked, suggesting only minor formation of peroxynitrite and this led to recoverable cytotoxicity manifesting as cloudy swelling of keratinocytes. There was some increase in wild type p53 in basal keratinocytes. Associated with this was an increase in apoptosis which was modest but manifested in the epidermis and dermis and was greater with the duration of exposure to NO. There was a high background level of cell proliferation and these cells were no more numerous in the NO treated skin than in the normal skin. However, there were significantly more proliferating cells in skin exposed to the higher dose of NO than those exposed to low dose suggesting that NO may promote keratinocyte proliferation at certain concentrations.