Marek A. Stawiski

Increased cyclic GMP and decreased cyclic AMP levels in the hyperplastic, abnormally differentiated epidermis of psoriasis

Summary The genetic skin disease psoriasis has been examined as a model system that may provide an understanding of the control of normal epidermal specialization (differentiation) and the perturbed regulatory processes in proliferatioe diseases . The excessive glycogen accwnulation, increased proliferation and decreased tissue specialization characteristic of psoriasis involve cellular pro- cesses that have been shown to be regulated by cyclic AMP in other cells and tissues . It has also been suggested that cyclic GMP is a cellular ef- fector that may be involved in promoting cell pro- liferation and other events that oppose those be- lieved to be mediated by cyclic AMP . It was postulated, therefore, that the epidermis of the psoriasis lesion might exhibit an imbalance in the cellular concentrations of these two cyclic nucleo- tides . In this study the levels of cyclic AMP were measured in the involved epidermis (IE) and unin- volved epidermis (UE) from 25 psoriasis patients . The concentrations of cyclic AMP were found as reported previously using a different analytical procedure, to be significantly lower in IE based on protein and DNA . A comparison of the levels of cyclic .GMP in IE versus UE of 12 other psoriasis patients showed the levels of this cyclic nucleo- tide to be significantly increased in IE based on protein, DNA and wet weight . We suggest that this imbalance in the ratio of these two cyclic nucleo- tides may have pathophysiological relevance to the initiation and/or the maintenance of the psoriasis lesion .

Cyclic AMP and Cyclic GMP in Epidermal Physiology and Pathophysiology

The second messengers cyclic AMP and cyclic GMP in several organs appear to coordinate those molecular events which are responsible for specialized organ function. As a result of balanced cell proliferation and specialization, epidermis functions by terminal specialization which provides a barrier between man and environment. Since the epidermal component of psoriasis is a classic example of deranged epidermal homeostasis, which has a low level of cyclic AMP and a high level of cyclic GMP, it seems reasonable that rebalancing these cyclic nucleotides might ultimately be a safe and effective therapy for psoriasis and other proliferative skin diseases.

Molecular and clinical pharmacology of psoriasis

Psoriasis appears in most cases to be a genetic disease8 in which stratified squamous epithelium (epidermis) of skin in involved versus normal‐appearing uninvolved areas has the following prototypic features: (1) excessive cell proliferation and an accelerated cell cycle of the proliferating cells21; (2) incomplete epidermal specialization (keratinization) for tissue function; and (3) marked increase in glycogen content.7 It has been widely held that the relative lack of epidermal specialization is due to the rapid transit of cells through the epidermis (i.e., the cells are shed from the patient without sufficient time for normal keratinization to occur). However, an alternate explanation is that the excessive cell proliferation is the result of an inability of differentiated basal cells to make the commitment of specialization. For this reason we have listed incomplete specialization as one of the three characteristic findings in psoriasis lesions.