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1 Department of Surgery and Pulmonary Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
2 Department of Surgery, Louisiana State University, Shreveport, Louisiana, USA
* To whom correspondence should be addressed. E-mail: fiemu.nwariaku{at}utsouthwestern.edu.
Objective: We previously demonstrated that mitogen-activated protein kinase (MAPK) activation is an important signal during cytokine-induced endothelial permeability. Since GTP-binding proteins have been implicated in MAPK activation, we now hypothesize that the GTP-binding protein, Rho is a mediator of TNF-induced MAPK activation and increased endothelial permeability. Methods: Trans-monolayer permeability was assessed in human lung microvascular cells (HLMEC) by measuring transmonolayer electrical resistance, TER. MAPK activity was assessed using a phospho-specific immunoprecipitation kinase assay and by comparing Western blots for phospho-MAPK with total MAPK. MAPK inhibitors used were SB202190 and PD098059, while Cl. botulinum C3 transferase was used as a Rho inactivator. Rho-associated coiled-coil kinase (ROCK) was inhibited using Y-27632. Results: TNF increased pulmonary endothelial permeability in-vitro and caused a rapid, sustained increase in endothelial p38 and Erk MAPK activity. Inhibition of p38 and Erk MAPK with SB202190 and PD098059 respectively, decreased TNF-induced endothelial permeability. C3 transferase attenuated TNF-induced MAPK activation, and blocked TNF - induced endothelial permeability. Finally, inhibition of ROCK with Y-27632 prevented both MAPK activation and TNF-induced decreases in trans-monolayer resistance. Conclusions: Rho acts upstream of mitogen-activated protein kinases in mediating TNF-induced pulmonary endothelial leak.
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