Modulation of urokinase-type and tissue-type plasminogen activator occurs at an early stage of progessing stages of chronic venous insufficiency

Chronic venous insufficiency (CVI) progresses through a series of clinical stages, from healthy skin to poorly healing leg ulcers, The aim of this stu dy was to analyse the distribution pattern and activity level of urokinase- type (UPA) and tissue-type plasminogen activators (tPA) in normal skin and in tissue biopsies of progressing stages of CVI, prior to and including ven ous ulceration. Biopsies 6 mm thick were taken from 14 healthy volunteers a nd 37 patients with 5 different stages of CVI: telangiectases; stasis derma titis; hyperpigmentation; lipodermatosclerosis; and leg ulcer. Changes in t he enzymatic activity and spatial localization of uPA and tPA during the pr ogression of CVI were examined using in situ histological zymography. Norma l skin and skin with telangiectases showed a punctate PA activity, consisti ng of both uPA and tPA activity. As CVI progressed, an increase in the dist ribution of UPA and a decrease in tPA activity was observed. The spatial lo calization of uPA was widespread within the dermis of biopsies from stasis dermatitis and lipodermatosclerosis and was associated in particular with t he dermoepidermal junction. Hyperpigmented skin revealed a pattern of PA ex pression similar to that of healthy skin. However, leg ulcer specimens exhi bited peak le, els of UPA with little tPA, Furthermore, a plasminogen-indep endent protease activity that was not present in any of the earlier stages of CVI appeared, Our results indicate that there are profound changes in PA activity during the progression of CVI and that these changes begin early in CVI, for example, in stasis dermatitis. We hypothesize that the balance or imbalance of the PA activity in the later stages of CVI is an important pathogenic factor for the development of venous leg ulcer.