Leukotriene-Mediated Alteration of Endothelial Barrier Function

Abstract

In the host defense reaction to infection or tissue trauma inflammatory mediators act directly or indirectly on the endothelial cells (EC) to provoke increased permeability for macromolecules and extravasation of polymorphonuclear leukocytes (PMN). It is well established that enhanced macromolecular permeability in vivo in response to cysteinyl-leukotrienes (LTC₄-LTE₄), acting directly on the endothelium, is attributable to cell contraction and formation of interendothelial gaps [1]. To a limited extent, similar structural changes in EC shape may accompany PMN adhesion and migration across the endothelium in tissues stimulated with the chemotactic LTB₄ [2]. In this report, the kinetics of LT-induced changes in endothelial barrier function have been characterized, using confluent monolayers of bovine aorta and human umbilical EC, cultured on permeable membranes and mounted in a two-compartment diffusion chamber. This model permits continuous measurement of the electrical resistance across the monolayer (TEER) and analysis of transendothelial macromolecular efflux and PMN migration [3]. Our results indicate that LTC₄ acts directly on the EC, and LTB₄ via PMN activation and leukocytic CD18 adhesion-dependent mechanisms, to induce rapid rises in EC cytosolic [Ca²⁺] and rearrangement of actin filaments that permit extravasation of macromolecules. Furthermore, LTC₄ and histamine in threshold concentrations act in concert to markedly enhance the structural changes in EC.