Tumor necrosis factor-alpha alters pulmonary vasoreactivity via neutrophil-derived oxidants.
We postulated that tumor necrosis factor-alpha (TNF) "primes" the lung for the development of pulmonary vasoconstriction and edema by inducing the release of polymorphonuclear leukocyte (PMN)-derived reactive oxidant species (ROS). Guinea pigs were injected with TNF (1.6 x 10(5) U/kg ip), and the lungs isolated 18 h later. Compared with controls, TNF pretreatment resulted in 1) greater increases in lung weight and capillary pressure in response to the thromboxane A2 mimetic U-46619 (365 pmol/min) and 2) an increase in the dose of acetylcholine (ACh) causing 50% of maximal dilation (EC50). The vascular effects of TNF were associated with 1) decreased lung effluent nitrite (NO2-, oxidation product of nitric oxide), 2) increased lung effluent superoxide (O2-), and 3) increased lung myeloperoxidase (MPO). Superoxide dismutase (SOD, 10 U/ml) prevented 1) the effects of TNF on the hemodynamic responses to U-46619 and ACh and 2) the TNF-induced decrease in NO2-. The effects of TNF on lung MPO and effluent O2- were prevented using cyclophosphamide intraperitoneally (100 mg/kg 5 days before, and 50 mg/kg 1 day before, treatment with TNF or control). The data suggest that ROS generated from PMN mediate the decrease in nitric oxide and altered pulmonary vasoreactivity induced by TNF.
Ferro
T J
TJ
Research Service, Samuel S. Stratton Veterans Affairs Medical Center, Albany, New York.
Hocking
D C
DC
Johnson
A
A
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002196:Capillaries / Q000187:drug effects / Q000502:physiology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008168:Lung / Q000187:drug effects / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009504:Neutrophils / Q000502:physiology*; D009599:Nitroprusside / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D016877:Oxidants / Q000494:pharmacology*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology*; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology*; D011667:Pulmonary Veins / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
D016877:Oxidants; D011450:Prostaglandin Endoperoxides, Synthetic; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D014662:Vasoconstrictor Agents; D009599:Nitroprusside; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D013482:Superoxide Dismutase; D000109:Acetylcholine