Leukocyte activation study during occlusive arterial disease of the lower limb: effect of pentoxifylline infusion

Abstract

Granulocytes play a significant role in vascular diseases. The mechanisms of neutrophil-mediated vascular injury include their increased endothelial adhesion and activation with release of inflammatory mediators. Pentoxifylline (PTX) has a well-demonstrated ability to act on the activated neutrophils. It increases chemotaxis and decreases their adherence to endothelial cells, oxidative burst, and enzyme release. In this preliminary study, we investigated the effects of PTX on ischemia-induced changes in polymorphonuclear neutrophils (PMN) activation and cytokine release. A double-blind, randomized, placebo-controlled trial was carried out in 14 patients (age range 46-86 years) suffering from critical ischemia, as defined by the European Consensus Document, or subacute ischemia due to occlusive arterial disease of the lower limb. Femoral and antecubital venous blood samples on the side of the ischemic leg were obtained from patients immediately before (TO) and after infusion (T24) of PTX or placebo. PMN activation was evaluated by study of cell migration, beta 2 integrin expression (CD11b/ CD18), oxidative burst, and elastase release. Inflammation proteins were analyzed, such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), interleukin-6 (IL-6), C-reactive protein (CRP), and fibrinogen. Before treatment, our results demonstrate an important activation in both femoral and antecubital venous blood. PMN activation markers, cytokine release, and other inflammation proteins were significantly increased compared with normal subjects. In the experimental group there was no significant difference between femoral and antecubital venous blood. Six patients received PTX infusion and seven patients were in the placebo group. The effect of PTX was evaluated after 24 h of treatment (1,200 mg). In the PTX group the following variables were improved compared with the placebo group: CD11b expression on PMNs, elastase released from PMNs, fibrinogen, CRP, TNF-alpha, and IL6 in plasma. These preliminary results should be interpreted with caution because of the small sample size. Further trials may contribute to more complete understanding.