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Published ahead of print on July 29, 2004, doi:10.1165/rcmb.2003-0432OC

Am. J. Respir. Cell Mol. Biol., Volume 31, Number 5, November 2004, 517-527

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Submitted on December 2, 2003
Revised on July 26, 2004

Differential Regulation of Human Lung Epithelial and Endothelial Barrier Function by Thrombin

Kamon Kawkitinarong1, Laura Linz-McGillem2, Konstantin G Birukov2, and Joe G. N. Garcia2*

1 Department of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, United States; Department of Medicine, Chulalongkorn University, Bangkok, Thailand, Thailand, 2 Department of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, United States

* To whom correspondence should be addressed. E-mail: drgarcia{at}jhmi.edu.

Lung epithelial and endothelial barrier dysfunction is critical to the physiologic derangement observed in acute lung injury, but remains poorly understood. We utilized human alveolar epithelial (A549) and endothelial cells to study cytoskeletal remodeling, myosin light chain (MLC) phosphorylation and barrier regulation evoked by the edemagenic agent, thrombin. Thrombin-challenged human endothelial cell monolayers demonstrated increased MLC phosphorylation, actin stress fiber formation and loss of barrier integrity reflected by decreased transmonolayer electrical resistance (TER). In contrast, thrombin produced prominent circumferential localization of actin fibers, increased MLC phosphorylation and increased TER across epithelial monolayers, consistent with barrier protection. Reductions in MLC phosphorylation induced by cell pretreatment with pharmacological inhibitors of MLC kinase (ML-7) and Rho kinase (Y-27632) significantly attenuated thrombin-mediated TER changes and MLC phosphorylation in both lung cell types. Thrombin produced time-dependent activation of Rho GTPase in both epithelial and endothelial cells, whereas Rac GTPase activation was observed only in A549 cells. Molecular inhibition of Rac activity by adenoviral transfer of dominant negative Rac mutant abolished thrombin-induced TER increases in alveolar epithelial cells. Finally, A549 cells, but not endothelium, demonstrated increased levels of tight junction proteins (ZO-1 and occludin) after thrombin at the cell-cell interface areas linked to thrombin-elicited barrier protection. These results demonstrate differential pulmonary endothelial and alveolar epithelial barrier regulation via unique actomyosin remodeling and cytoskeletal interactions with tight junction complexes, which confer selective barrier responses to edemagenic stimuli.




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