Tumor Necrosis Factor-alpha-Mediated Pulmonary Endothelial Barrier Dysfunction

The multifunctional cytokine, tumor necrosis factor-alpha (TNF-alpha), is released from host cells in response to diverse injurious stimuli and is elevated during acute lung injury. Increased levels of TNF-alpha are found in both the bloodstream and bronchoalveolar lavage fluid of experimental and clinical settings of acute lung injury. TNF-alpha administration to experimental animals increases pulmonary leukostasis, microvascular permeability and edema formation. Further, TNF-alpha can directly open the pulmonary vascular endothelial paracellular pathway in vitro. TNF-alpha opens the pulmonary endothelial paracellular pathway in both a dose- and time-dependent manner independent of endothelial cell injury/apoptosis. A prolonged stimulus-to-response lag time between the TNF-alpha stimulus and altered barrier function exists (>= 2h) and this delayed response cannot be ascribed to a requirement for de novo protein synthesis. TNF-alpha activates one or more protein tyrosine kinase(s), increases tyrosine phosphorylation of adherens junction proteins, and induces actin disassembly temporally coincident with opening of the paracellular pathway; the increased protein tyrosine phosphorylation and actin reorganization are both prerequisites to TNF-alpha-induced loss of endothelial barrier function. Febrile range hyperthermia further enhances TNF-alpha levels and its biological effects. All of these data implicate TNF-alpha in the pathogenesis of acute lung injury. Understanding the mechanisms through which TNF-alpha regulates the pulmonary microvascular paracellular pathway should provide targets for future clinical interventions.