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

Department of Biomedicine, Division for Physiology, University of Bergen, N-5009 Bergen, Norway

Submitted 4 December 2003 ; accepted in final form 17 March 2004

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 ₁-integrin-mediated interactions between connective tissue cells and extracellular matrix (ECM) fibers. 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 ¹²⁵I-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.

capillary permeability; inflammation; connective tissue; microtubuli

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