Abe Y.

Chang S.

Cobb J. P.

Edwards M. J.

Joseph R. Williamson

Kathy Chang

Kim K. S.

Kubes P.

Mayhan W. G.

Mier J. W.

Moncada S.

Neil K. Worrall

Patrick M. Sullivan

Remich D. G.

Rosenstein M.

Royall J. A.

Stolpen A. H.

T. Bruce Ferguson

Thomas P. Misko

Tilton R. G.

Wanda S. Lejeune

Yi E. S.

Yuan Y.

 Tumor necrosis factor (TNF-α) 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-α and NO on systemic vascular barrier function in vivo, without confounding endotoxemia, hypotension, or organ damage. Our results showed 1) TNF-α reversibly increased albumin permeation in the systemic vasculature (e.g., lung, liver, brain, etc.); 2) TNF-α 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-α 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-α-induced lung and liver vascular barrier dysfunction; 6) aminoguanidine prevented increased tissue water content in TNF-α-treated lungs and improved oxygenation; and 7) nonselective inhibition of NOS with N G-monomethly-l-arginine increased vascular permeation in control lungs and caused severe lung injury in TNF-α-treated animals. We conclude that 1) TNF-α 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. </jats:p

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AJP Heart and Circulatory Physiology

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

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

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