Physiological and pharmacological evidence for the regulation of permeability.

Local intraarterial infusions of histamine-type mediators produce increases in microvascular pressure (Pmv), protein efflux, and net fluid filtration that promote edema formation. The rise in Pmv is not the primary determinant of edema formation inasmuch as mediator-stimulated edema formation develops without an increase in Pmv. The inflammatory mediators increase the hydraulic conductivity of the microvascular membrane as evidenced by a large increase in the capillary filtration coefficient (CFC) subsequent to an increase in permeability. The development of inflammatory edema is primarily attributable to the increase in protein efflux, which decreases the lymph-to-plasma total-protein ratio (L/P ratio), virtually eliminating the transmural colloid osmotic pressure gradient. Hence, fluid filtration is increased at almost any level of Pmv. Noninflammatory vasodilators and venous occlusion produce increases in Pmv and protein clearance, but fail to increase the L/P ratio. The increase in protein efflux and L/P ratio is attributable to a nonhemodynamic action of the inflammatory mediators, an increase in microvascular permeability to macromolecules. The increase in protein efflux, CFC, and net fluid filtration produced by various inflammatory mediators is largely inhibited by cooling, treatment with endothelial cell stabilizers, or perfusion with blood from hemorrhaged animals. This inhibition is independent of changes in hemodynamics and must be ascribed to a direct effect on the microvascular membrane, providing evidence for a variable macromolecular transport pathway. In contrast, increases in protein clearance produced by increasing Pmv are not inhibited by these maneuvers, which provides evidence for a static macromolecular transport pathway. These findings correlate well with those from microscopic studies supporting the concept that macromolecular permeability may be directly regulated at the level of the venular endothelial cell subsequent to the modulation of interendothelial cell junction gap size.