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Current Respiratory Medicine Reviews


ISSN (Print): 1573-398X
ISSN (Online): 1875-6387

Tumor Necrosis Factor-α-Mediated Pulmonary Endothelial Barrier Dysfunction

Author(s): Daniel J. Angelini, Jeffrey D. Hasday, Simeon E. Goldblum and Douglas D. Bannerman

Volume 1, Issue 3, 2005

Page: [233 - 246] Pages: 14

DOI: 10.2174/157339805774598063

Price: $65


The multifunctional cytokine, tumor necrosis factor-alpha (TNF-α), is released from host cells in response to diverse injurious stimuli and is elevated during acute lung injury. Increased levels of TNF-α are found in both the bloodstream and bronchoalveolar lavage fluid of experimental and clinical settings of acute lung injury. TNF-α administration to experimental animals increases pulmonary leukostasis, microvascular permeability and edema formation. Further, TNF-α can directly open the pulmonary vascular endothelial paracellular pathway in vitro. TNF-α 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-α stimulus and altered barrier function exists (≥2h) and this delayed response cannot be ascribed to a requirement for de novo protein synthesis. TNF-α 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-α-induced loss of endothelial barrier function. Febrile range hyperthermia further enhances TNF-α levels and its biological effects. All of these data implicate TNF-α in the pathogenesis of acute lung injury. Understanding the mechanisms through which TNF-α regulates the pulmonary microvascular paracellular pathway should provide targets for future clinical interventions.

Keywords: Acute respiratory distress syndrome (ARDS), cytokine, endothelial, sepsis, tumor necrosis factor-α (TNF-α)

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