Effects of the taxanes paclitaxel and docetaxel on edema formation and interstitial fluid pressure.

Abstract

Interstitial fluid pressure (P(if)) is important for maintaining constant interstitial fluid volume. In several acute inflammatory reactions, a dramatic lowering of P(if) has been observed, increasing transcapillary filtration pressure and favoring initial and rapid edema formation. This lowering of P(if) seems to involve dynamic beta(1)-integrin-mediated interactions between connective tissue cells and extracellular matrix (ECM) fibers. beta(1)-Integrins are adhesion receptors responsible for the attachment of connective tissue cells to the ECM providing a force-transmitting physical link between the ECM and cytoskeleton. Disruption of actin filaments leads to lowering of P(if) and edema formation, suggesting a role for actin filaments. The aim of this study was to further investigate the role of the cytoskeleton in the control of P(if) by studying the effect of microtubuli fixation using paclitaxel and docetaxel. P(if) was measured with the micropuncture technique. Albumin extravasation (E(alb)) was measured using (125)I-labeled albumin. Paclitaxel and docetaxel were tested locally on foot skin in female Wistar rats. Paclitaxel (6 mg/ml) reduced P(if) from -1.5 +/- 1.0 mmHg in controls to -4.9 +/- 2.6 mmHg after 30 min (P < 0.05) in a dose-dependent manner (P < 0.05). Docetaxel caused a similar lowering of P(if). Both paclitaxel and docetaxel increased E(alb) compared with Cremophor EL and saline control (P < 0.05). Pretreatment with phalloidin before paclitaxel, causing fixation of actin filaments, abolished the lowering of P(if) caused by paclitaxel. This study confirms several previous studies demonstrating that connective tissue cells influence P(if) and edema formation.