EXPRESSION OF ELASTASE AND FIBRIN IN VENOUS LEG ULCER BIOPSIES - A PILOT-STUDY OF PENTOXIFYLLINE VERSUS PLACEBO

The pathogenesis of venous leg ulcers is based on the leakage of fibri nogen leading to a pericapillary fibrin cuff and plugging of capillari es by white blood cells. On the basis of a previous work, we had assum ed that the key event in the pathogenesis of venous leg ulcers is rela ted to inflammation generated by activated white blood cells that accu mulate under unrelieved blood pressure, because in ulcer biopsies we h ad detected the presence of tumor necrosis factor-alpha (TNF-alpha) in intracapillary monocytes, elastase in the polymorphonuclear leukocyte s near the vessels, and a pericapillary undegraded fibrin cuff causing a diffusion barrier to oxygen. This concept was developed because TNF -alpha synthesized by activated monocytes is responsible for many dele terious effects. It has a potent mitogenic effect on fibroblasts, lead ing to new collagen deposition and angiogenesis, it induces an increas e in collagenase production, it acts through upregulation of an intrac ellular adhesion molecule (ICAM-1), leading to leukocyte sequestration and consequently a release of toxic metabolites by the polymorphonucl ear cells, an early step in chronic inflammation, it activates the coa gulation pathway via a marked increase in monocyte-associated tissue f actor (TF) procoagulant activity, and it inhibits fibrinolysis by prom oting the release of PAI-1, contributing to undegraded fibrin depositi on. Therefore, we were interested in evaluating, in patients with veno us leg ulcers, the effect of pentoxifylline administered at 1,200 mg d aily (versus placebo) for 2-months, as this drug induces a decrease in TNF-alpha synthesis and also blocks its activity. This pilot assay wa s performed in blind, Evolution of several parameters in ulcer biopsie s are analyzed: TNF-alpha, intact fibrin, fibrin degradation products, ICAM-1, TF, and elastase. Pentoxifylline administration induced a dec rease of local elastase and of fibrin deposit. These results support t he hypothesis that accumulation of activated leukocytes is the key eve nt in venous leg ulcers.