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Am J Physiol Heart Circ Physiol 273: H2565-H2574, 1997;
0363-6135/97 $5.00
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Vol. 273, Issue 6, H2565-H2574, December 1997

TNF-alpha causes reversible in vivo systemic vascular barrier dysfunction via NO-dependent and -independent mechanisms

Neil K. Worrall1, Kathy Chang2, Wanda S. Lejeune2, Thomas P. Misko3, Patrick M. Sullivan4, T. Bruce Ferguson Jr.1, and Joseph R. Williamson2

Departments of 1 Surgery and 2 Pathology, Washington University School of Medicine, St. Louis 63110; and Departments of 3 Molecular Pharmacology and 4 Molecular and Cellular Biology, Searle Research and Development, Monsanto Company, St. Louis, MO 63167

Tumor necrosis factor (TNF-alpha ) and nitric oxide (NO) are important vasoactive mediators of septic shock. This study used a well-characterized quantitative permeation method to examine the effect of TNF-alpha and NO on systemic vascular barrier function in vivo, without confounding endotoxemia, hypotension, or organ damage. Our results showed 1) TNF-alpha reversibly increased albumin permeation in the systemic vasculature (e.g., lung, liver, brain, etc.); 2) TNF-alpha did not affect hemodynamics or blood flow or cause significant tissue injury; 3) pulmonary vascular barrier dysfunction was associated with increased lung water content and impaired oxygenation; 4) TNF-alpha caused inducible nitric oxide synthase (iNOS) mRNA expression in the lung and increased in vivo NO production; 5) selective inhibition of iNOS with aminoguanidine prevented TNF-alpha -induced lung and liver vascular barrier dysfunction; 6) aminoguanidine prevented increased tissue water content in TNF-alpha -treated lungs and improved oxygenation; and 7) nonselective inhibition of NOS with NG-monomethly-L-arginine increased vascular permeation in control lungs and caused severe lung injury in TNF-alpha -treated animals. We conclude that 1) TNF-alpha reversibly impairs vascular barrier integrity through NO-dependent and -independent mechanisms; 2) nonselective NOS inhibition increased vascular barrier dysfunction and caused severe lung injury, whereas selective inhibition of iNOS prevented impaired endothelial barrier integrity and pulmonary dysfunction; and 3) selective inhibition of iNOS may be beneficial in treating increased vascular permeability that complicates endotoxemia and cytokine immunotherapy.

blood-brain barrier; capillary permeability; cytokines; endothelium; lung; nitric oxide


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