TNF-alpha causes reversible in vivo systemic vascular barrier dysfunction via NO-dependent and -independent mechanisms.
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.
Worrall
N K
NK
Department of Surgery, Washington University School of Medicine, St. Louis 63110, USA.
Chang
K
K
LeJeune
W S
WS
Misko
T P
TP
Sullivan
P M
PM
Ferguson
T B
TB
Williamson
J R
JR
D000818:Animals; D001921:Brain / Q000098:blood supply; D002199:Capillary Permeability / Q000187:drug effects* / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D006146:Guanidines / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology*; D007422:Intestines / Q000098:blood supply; D008099:Liver / Q000098:blood supply; D008168:Lung / Q000201:enzymology / Q000473:pathology; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011912:Rats, Inbred ACI; D011994:Recombinant Proteins / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D012710:Serum Albumin, Bovine / Q000493:pharmacokinetics; D012867:Skin / Q000098:blood supply; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D006146:Guanidines; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D012710:Serum Albumin, Bovine; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C004479:pimagedine