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The Role of the Microtubules in Tumor Necrosis Factor-–Induced Endothelial Cell Permeability

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland

Address correspondence to: Alexander D. Verin, M.D., Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Room 4B.72, Baltimore, MD 21224-6801. E-mail: averin{at}jhmi.edu

Tumor necrosis factor (TNF)-, a major proinflammatory cytokine, triggers endothelial cell activation and barrier dysfunction which are implicated in the pathogenesis of pulmonary edema associated with acute lung injury syndromes. The mechanisms of TNF-–induced vascular permeability are not completely understood. Our initial experiments demonstrated that TNF-–induced decreases in transendothelial electrical resistance across human pulmonary artery endothelial cells are independent of myosin light chain phosphorylation catalyzed by either myosin light chain kinase or Rho kinase. We next assessed the involvement of another cytoskeletal component, the tubulin-based microtubule network, and found TNF- to induce a decrease in stable tubulin content and partial dissolution of peripheral microtubule network as evidenced by anti-acetylated tubulin and anti–ß-tubulin immunofluorescent staining, respectively. Microtubule-stabilizing agents, paclitaxel and epothilone B, significantly attenuated TNF-–induced decreases in transendothelial electrical resistance, inhibited the cytokine-induced increases in actin stress fibers, formation of intercellular gap, and restored the TNF-–compromised vascular endothelial (VE)-cadherin–based cell–cell junctions. Importantly, neither TNF- nor paclitaxel treatment was associated with endothelial cell apoptosis. Inhibition of p38 mitogen-activated protein kinase by SB203580 significantly attenuated TNF-–induced microtubule destabilization, actin rearrangement, and endothelial barrier dysfunction. These results strongly suggest the involvement of microtubule rearrangement in TNF-–induced endothelial cell permeability via p38 mitogen-activated protein kinase activation.

Abbreviations: enhanced chemiluminescence, ECL • heat shock protein-27, HSP-27 • mitogen-activated protein kinase, MAPK • myosin light chain kinase, MLCK • transendothelial electrical resistance, TER • tumor necrosis factor-, TNF- • vascular endothelial, VE • vascular endothelial growth factor, VEGF

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