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TNF- increases tyrosine phosphorylation of vascular endothelial cadherin and opens the paracellular pathway through fyn activation in human lung endothelia

Divisions of Infectious Disease and Pulmonary and Critical Care Medicine, Departments of Medicine and Pathology, and Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore, Maryland

Submitted 25 March 2006 ; accepted in final form 25 July 2006

Tumor necrosis factor (TNF)- is a key mediator of sepsis-associated multiorgan failure, including the acute respiratory distress syndrome. We examined the role of protein tyrosine phosphorylation in TNF--induced pulmonary vascular permeability. Postconfluent human lung microvascular and pulmonary artery endothelial cell (EC) monolayers exposed to human recombinant TNF- displayed a dose- and time-dependent increase in transendothelial [¹⁴C]albumin flux in the absence of EC injury. TNF- also increased tyrosine phosphorylation of EC proteins, and several substrates were identified as the zonula adherens proteins vascular endothelial (VE)-cadherin, and -catenin, -catenin, and p120 catenin (p120^ctn). Prior protein tyrosine kinase (PTK) inhibition protected against the TNF- effect. TNF- activated multiple PTKs, including src family PTKs. Prior PTK inhibition with the src-selective agents PP1 and PP2 each protected against 60% of the TNF--induced increment in [¹⁴C]albumin flux. PP2 also blocked TNF--induced tyrosine phosphorylation of VE-cadherin, -catenin, and p120^ctn. To identify which src family kinase(s) was required for TNF--induced vascular permeability, small interfering RNA (siRNA) targeting each of the three src family PTKs expressed in human EC, c-src, fyn, and yes, were introduced into the barrier function assay. Only fyn siRNA protected against the TNF- effect, whereas the c-src and yes siRNAs did not. These combined data suggest that TNF- regulates the pulmonary vascular endothelial paracellular pathway, in part, through fyn activation.

acute respiratory distress syndrome; endothelial barrier function; zonula adherens; src

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