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1 Anesthesiology & Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
2 Department of Veterans Affairs Medical Center, Boston, MA, USA
3 Division of Biological Engineering, Harvard-Massachusetts Institute of Technology Division of Health Science and Technology, Cambridge, MA, USA
4 Division of Pulmonary & Critical Care, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MA, USA
* To whom correspondence should be addressed. E-mail: Rdull1{at}jhmi.edu.
The endothelial glycocalyx is believed to play a major role in microvascular permeability. We tested the hypothesis that specific components of the glycocalyx, via cytoskeletal-mediated signaling, actively participate in barrier regulation. Using polymers of arginine and lysine as models of neutrophil-derived inflammatory cationic proteins, we determined size- and dose-dependent responses of cultured bovine lung microvascular endothelial cell permeability as assessed by transendothelial electrical resistance (TER). Polymers of arginine and lysine greater than 11kDa produced maximal barrier dysfunction as demonstrated by a 70% decrease in TER. Monomers of L-arginine and L-lysine did not alter barrier function suggesting a cross-linking requirement of cell surface "receptors". To test the hypothesis that glycosaminoglycans (GAGS) are candidate "receptors" for this response, we used highly selective enzymes to remove specific GAGs prior to polyarginine (PA) treatment and examined the effect on TER. Heparanase III attenuated PA-induced barrier dysfunction by 50% whereas heparinase I had no effect. To link changes in barrier function with structural alterations, we examined actin organization and syndecan localization after PA. PA- induced actin stress fiber formation and clustering of syndecan-1 and syndecan-4 which was significantly attenuated by heparanase III. PA-induced cytoskeletal rearrangement and barrier function did not involve myosin light chain kinase or p38 MAP kinase, as ML-7, a selective MLCK inhibitor, or SB20358, a p38 MAP kinase inhibitor did not alter PA-induced barrier dysfunction. In summary, lung endothelial cell heparan sulfate proteoglycans are key participants in inflammatory cationic peptide-induced signaling that links cytoskeletal re-organization with subsequent barrier dysfunction.
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