TNF-ALPHA CAUSES REVERSIBLE IN-VIVO SYSTEMIC VASCULAR BARRIER DYSFUNCTION VIA NO-DEPENDENT AND NO-INDEPENDENT MECHANISMS

Tumor necrosis factor (TNF-alpha) and nitric oxide (NO) are important vasoactive mediators of septic shock. This study used a well-character ized quantitative permeation method to examine the-effect of TNF-alpha and NO on systemic vascular barrier function in vivo, without confoun ding endotoxemia, hypotension, or organ damage. Our results showed 1) TNF-alpha reversibly increased albumin permeation in the systemic vasc ulature (e.g., lung, liver, brain, etc.); 2) TNF-alpha did not affect hemodynamics or blood flow or cause significant tissue injury; 3) pulm onary 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 aminoguan idine prevented TNF-alpha-induced lung and liver vascular barrier dysf unction; 6) aminoguanidine prevented increased tissue water content in TNF-alpha-treated lungs and improved oxygenation; and 7) nonselective inhibition of NOS with N-G-monomethly-L-arginine increased vascular p ermeation in control lungs and caused severe lung injury in TNF-alpha- treated animals. We conclude that 1) TNF-alpha reversibly impairs vasc ular barrier integrity through NO-dependent and -independent mechanism s; 2) nonselective NOS inhibition increased vascular barrier dysfuncti on and caused severe lung injury, whereas selective inhibition of iNOS prevented impaired endothelial barrier integrity and pulmonary dysfun ction; and 3) selective inhibition of iNOS may be beneficial in treati ng increased vascular permeability that complicates endotoxemia and cy tokine immunotherapy.