TUMOR-NECROSIS-FACTOR-ALPHA ALTERS PULMONARY VASOREACTIVITY VIA NEUTROPHIL-DERIVED OXIDANTS

We postulated that tumor necrosis factor-alpha (TNF) ''primes'' the lu ng for the development of pulmonary vasoconstriction and edema by indu cing 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) ca using 50% of maximal dilation (EC50). The vascular effects of TNF were associated with 1) decreased lung effluent nitrite (NO2-, oxidation p roduct 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 response s to U-46619 and ACh and 2) the TNF-induced decrease in NO2-. The effe cts of TNF on lung MPO and effluent 02- were prevented using cyclophos phamide intraperitoneally (100 mg/kg 5 days before, and 50 mg/kg 1 day before, treatment with TNF or control). The data suggest that ROS gen erated from PMN mediate the decrease in nitric oxide and altered pulmo nary vasoreactivity induced by TNF.