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Title: TUMOR NECROSIS FACTOR-ALPHA-MEDIATED PULMONARY ENDOTHELIAL BARRIER DYSFUNCTION

Author
item ANGELINI, DANIEL - UNIVERSITY OF MARYLAND
item HASDAY, JEFFREY - UNIVERSITY OF MARYLAND
item GOLDBLUM, SIMEON - UNIVERSITY OF MARYLAND
item Bannerman, Douglas

Submitted to: Current Respiratory Medicine Reviews
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/24/2005
Publication Date: 11/1/2005
Citation: Angelini, D.J., Hasday, J.D., Goldblum, S.E., Bannerman, D.D. 2005. Tumor necrosis factor-alpha-mediated pulmonary endothelial barrier dysfunction. Current Respiratory Medicine Reviews. 1(3):233-246.

Interpretive Summary: Intramammary infection by bacterial pathogens remains the main cause of mastitis. During the course of bacterial infection, proteins known as cytokines are produced both locally and systemically and contribute to the inflammatory response. One key pro-inflammatory cytokine produced is tumor necrosis factor-alpha (TNF-alpha). During the course of mastitis, the bacterial pathogens and/or their products can gain systemic access resulting in the development of septic shock. Complications arising from septic shock include hemodynamic alterations, multi-organ failure, and acute respiratory distress. TNF-alpha is believed to contribute to the development of acute respiratory distress/lung injury via its effects on the pulmonary vasculature. Interestingly, bovine endothelial cells are exquisitely sensitive to the effects of TNF-alpha. Recent findings have elucidated the mechanisms by which TNF-alpha elicits endothelial activation and/or dysfunction and these findings are detailed in the present report.

Technical Abstract: 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 (EC) 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.