AJP - Lung Cellular and Molecular Physiology, Vol 265, Issue 5 462-L471, Copyright © 1993 by American Physiological Society

ARTICLES

Tumor necrosis factor-alpha alters pulmonary vasoreactivity via neutrophil-derived oxidants

T. J. Ferro, D. C. Hocking and A. Johnson
Research Service, Samuel S. Stratton Veterans Affairs Medical Center, Albany, New York.

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.

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