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

Tumor necrosis factor (TNF)-, a major proinflammatory cyto- filaments, intermediate filaments, and microtubules (3). Tu-kine, triggers endothelial cell activation and barrier dysfunction mor necrosis factor (TNF)-, a proinflammatory cytokine which are implicated in the pathogenesis of pulmonary edema secreted by macrophages and endothelial cells, has been associated with acute lung injury syndromes. The mechanisms implicated in endothelial cell activation, increased endothe-of TNF-–induced vascular permeability are not completely un- lial cell permeability, and pulmonary edema formation (4, 5). derstood. Our initial experiments demonstrated that TNF-– However, the exact mechanisms by which TNF- triggersinduced decreases in transendothelial electrical resistance across vascular barrier dysfunction are not precisely defined. Wehuman pulmonary artery endothelial cells are independent of and others have noted that TNF- induces endothelial actinmyosin light chain phosphorylation catalyzed by either myosin microfilament rearrangement and intercellular gap forma-light chain kinase or Rho kinase. We next assessed the involve-ment of another cytoskeletal component, the tubulin-based micro- tion that parallel the development of transendothelial per-tubule network, and found TNF- to induce a decrease in stable meability (5, 6). It is less clear which signaling pathways tubulin content and partial dissolution of peripheral micro- are orchestrating these morphologic changes of endothelial tubule network as evidenced by anti-acetylated tubulin and cells and their relative direct contribution to the vascular anti–-tubulin immunofluorescent staining, respectively. Micro- barrier dysfunction. We have previously shown that TNF