The role of venular endothelial cells in the regulation of macromolecular permeability.

It is well documented that inflammatory mediators produce increases in fluid filtration promoting massive edema formation in limb skin and skeletal muscle. The edema is attributable to an increase in the transmural hydrostatic pressure gradient subsequent to an increase in microvascular pressure (Pmv) and, more importantly, to a decrease in the transmural colloid osmotic pressure gradient subsequent to an increase in vascular permeability to macromolecules. The mediators produce increases in net fluid filtration, protein clearance, the L/P total protein ratio, and edema formation in the absence of increases in blood flow and Pmv demonstrating that increases in vascular permeability are not dependent on changes in blood flow, Pmv, or surface area per se. Since the inflammatory mediators produce increases in the L/P protein ratio and edema formation in vascular beds perfused with cell-free, artificial perfusates, the increase in permeability likely results from an interaction between the mediator and the vascular endothelium. The findings demonstrating that mediator-stimulated increases in net fluid filtration, protein clearance, the L/P ratio, and edema formation are subject to inhibition by selective mediator receptor antagonists suggests that the increase in vascular permeability is dependent on the activation of a receptor mediated physiological mechanism which regulates the porosity of the vascular endothelium to macromolecules. Findings from microscopic studies demonstrate that the inflammatory mediators trigger the extravasation of macromolecules exclusively from the postcapillary venules, and that increases in the flux of macromolecules between the vascular and interstitial fluid compartments is dependent on the formation of leakage sites in the postcapillary venules. Electron microscopic studies of the vascular leakage sites reveals the formation of large gaps between adjacent endothelial cells, and changes in cell shape including a wrinkling of the nucleus suggestive of endothelial cell contraction. Contractile proteins and receptors for many substances including inflammatory mediators are found in endothelial cells, and receptor modulated changes in endothelial cell shape associated with active changes in the contractile proteins have been demonstrated in endothelial cells in culture. The inflammatory mediators appear to trigger active endothelial cell contraction inducing the transient, reversible formation of large junctional gaps between adjacent cells in the postcapillary venules.(ABSTRACT TRUNCATED AT 400 WORDS)