We examined the effects of activation of endothelial protein kinase C (PKC) of the endothelial barrier function. Exposure of confluent bovine pulmonary artery endothelial cell monolayers to phorbol 12-myristate 13-acetate (PMA) resulted in concentration-dependent (10-s-10-6 M) increases in PKC activity and in the transendothelial flux of 25I-albumin. Exposure of the endothelium to 1-oleoyl 2-acetyl glycerol (OAG) also increased the transendothelial flux of 11I-albumin in a concentration-dependent manner. Neither 4a-phorbol didecanoate nor 1-mono-oleoyl glycerol, which do not activate PKC, altered permeability. The increase in '25I-albumin permeability induced by PMA was inhibited by 25 gM H7 (a PKC inhibitor), but not by the control compound HA1004 (25 MM). After 16 h of exposure to PMA, '25I-albumin permeability returned to baseline and a significant reduction in cytosolic PKC activity was noted. Further challenge with PMA at this time resulted in no significant increase in PKC activity indicating downregulation of the enzyme; moreover, this PMA challenge did not increase endothelial permeability. Exposure of endothelial monolayers to phospholipase C (PLC), which increases membrane phosphatidylinositide turnover, or to a-thrombin also induced concentration-dependent activation of PKC and increases in "5I-albumin endothelial permeability. The thrombin-and PLC-induced permeability increases were inhibited by H7, but not by HA1004. The activation of endothelial PKC directly by PMA or OAG and by PLC and a-thrombin increases the transendothelial albumin permeability, indicating that PKC activation is an important signal transduction pathway by which extracellular mediators increase endothelial macromolecular transport. (J.
We examined the selectivity of the bovine pulmonary artery endothelial monolayer in vitro to molecules of different sizes. The cultured bovine pulmonary endothelial monolayer was grown on a gelatinized filter and the transendothelial transport was studied by determining the permeability of molecules ranging from 182 to 340,000 daltons under diffusion conditions. The permeabilities across the cultured bovine endothelium were modeled according to cylindrical pore theory. The data were best fit by a two-pore model with radii 65 A and 304 A and a ratio of small to large pores of 160:1. The results indicate that the cultured endothelial monolayer is a selective barrier to molecules of different sizes and that the molecular selectivity is consistent with a diffusional pathway through endothelial pore equivalents. The cultured endothelial monolayer is a useful system for studying the permeability characteristics of the endothelial barrier.
Human opsonic alpha2-surface binding glyoprotein (alphs2SB-glycoprotein), a molecule having immunologic identity with an amino acid composition similar to cold-insoluble globulin, is concentrated in a cryoprecipitate of plasma. Septic surgical and trauma patients manifesting opsonic alpha2SB-glycoprotein deficiency and associated reticuloendothelial system dysfunction were treated by intravenous infusion of cryoprecipitate. This therapy restored circulating bioreactive and immunoreactive opsonin and improved their septicemia, pulmonary insufficiency, and duration of recovery. Cryoprecipitate infusion may offer a new approach to the treatment of septic injured patients in preventing multiple organ failure; measurement of immuno-reactive serum opsonic alpha2SB-glycoprotein may provide a noninvasive index of reticuloendothelial system function and patient status during servere sepsis that follows trauma.
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