HYPOCHLOROUS ACID AND CHLORAMINES INCREASE ENDOTHELIAL PERMEABILITY - POSSIBLE INVOLVEMENT OF CELLULAR ZINC

The migration of neutrophils through the endothelium at sites of inflammation may be facilitated by oxidant-mediated disruption of cellular junetions. The present study examined the effects of noncytotoxic concentrations of the membrane-penetrating neutrophil oxidants hypochlorous acid (HOCl) and monochloramine (NH2Cl), or the membrane-impermeant taurine chloramine (taurine NCI), on cultured bovine aorta endothelial monolayers. HOCl (25 mu M) or NH2Cl (10 mu M), but not taurine NCl (100 mu M), caused a reversible shortening of the cytoskeletal actin microfilaments, cell retraction, and increased permeability within 2 min. These effects were accompanied by an increase in intracellular zinc concentration as well as the oxidation of intracellular glutathione and protein sulfhydryls. The zinc ionophore pyrithione also increased permeability. HOCl or NH2Cl, but not taurine NCl, also rapidly increased microvascular permeability in isolated perfused rat lungs. The data suggest that HOCl and NH2Cl can increase endothelial permeability by causing very rapid cytoskeletal shortening and cell retraction, possibly as a result of the oxidation of intracellular sulfhydryls and mobilization of zinc.