ACTIVATION OF PROTEIN-KINASE-C MEDIATES ALTERED PULMONARY VASOREACTIVITY INDUCED BY TUMOR-NECROSIS-FACTOR-ALPHA

We postulated that tumor necrosis factor-alpha (TNF) ''primes'' the lu ng for the development of pulmonary vasoconstriction and edema by acti vating protein kinase C (PKC). Guinea pigs were injected with TNF (1.6 x 10(5) U/kg ip), and the lungs were isolated 4 h later. Compared wit h controls, TNF pretreatment resulted in greater increases in pulmonar y vascular resistance and pressure and lung weight, in response to the thromboxane A(2) mimetic, U-46619 (122 pmol/min). Treatment with TNF resulted in 1) pulmonary arterial endothelial PKC activation, 2) incre ased lung polymorphonuclear neutrophil (PMN) sequestration, 3) increas ed levels of superoxide radical (O-2.) in lung effluent, and 4) decrea sed nitrite levels (NO2-, oxidation product of nitric oxide) in lung e ffluent. Intraperitoneal treatment with calphostin C (3 mu M, 15 min p rior to treatment with TNF) prevented the effects of TNF on 1) PKC act ivation, 2) the hemodynamic responses to U-46619, and 3) the levels of NO2- and O-2.. PKC activation does not mediate TNF-induced lung seque stration of PMN, since calphostin C had no effect on lung myeloperoxid ase activity. The data suggest that PKC activation mediates TNF-induce d 1) increases in O-2., 2) decreases in NO2-, and 3) increases in vaso reactivity and edema in response to U-46619.