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Am J Physiol Lung Cell Mol Physiol (August 4, 2006). doi:10.1152/ajplung.00109.2006
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Submitted on March 23, 2006
Accepted on July 25, 2006

TNF{alpha} Increases Tyrosine Phosphorylation of Vascular Endothelial-Cadherin and Opens the Paracellular Pathway Through Fyn Activation in Human Lung Endothelia

Daniel J Angelini1, Sang-Won Hyun1, Dmitry N Grigoryev1, Pallavi Garg1, Ping Gong1, Ishwar S Singh2, Antonino Passaniti3, Jeffrey D Hasday2, and Simeon E Goldblum4*

1 Division of Infectious Diseases, University of Maryland School of Medicine, Baltimore, Maryland, United States
2 Pulmonary and Critical Care Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States
3 Department of Medicine and Pathology, University of Maryland School of Medicine, Baltimore, Maryland, United States
4 The Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore, Maryland, United States

* To whom correspondence should be addressed. E-mail: sgoldblu{at}mbrc.umaryland.edu.

Tumor necrosis factor alpha (TNF{alpha}) 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{alpha}-induced pulmonary vascular permeability. Postconfluent human lung microvascular and pulmonary artery endothelial cell (EC) monolayers exposed to human recombinant TNF{alpha} displayed a dose- and time-dependent increase in transendothelial 14C-albumin flux in the absence of EC injury. TNF{alpha} also increased tyrosine phosphorylation of EC proteins and several substrates were identified as the zonula adherens (ZA) proteins vascular endothelial (VE)-cadherin, {beta}-, {gamma}-, and p120 catenins. Prior protein tyrosine kinase (PTK) inhibition protected against the TNF{alpha} effect. TNF{alpha} 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{alpha}-induced increment in 14C-albumin flux. PP2 also blocked TNF{alpha}-induced tyrosine phosphorylation of VE-cadherin, {gamma}-catenin, and p120ctn. To identify which src family kinase(s) was required for TNF{alpha}-induced vascular permeability, siRNA targeting each of the 3 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{alpha} effect, whereas the c-src and yes siRNA's did not. These combined data suggest that TNF{alpha} regulates the pulmonary vascular endothelial paracellular pathway, in part, through fyn activation.




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