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 lung for the development of pulmonary vasoconstriction and edema by activating protein kinase C (PKC). Guinea pigs were injected with TNF (1.6 x 10(5) U/kg i.p.), and the lungs were isolated 4 h later. Compared with controls, TNF pretreatment resulted in greater increases in pulmonary vascular resistance and pressure and lung weight, in response to the thromboxane A2 mimetic, U-46619 (122 pmol/min). Treatment with TNF resulted in 1) pulmonary arterial endothelial PKC activation, 2) increased lung polymorphonuclear neutrophil (PMN) sequestration, 3) increased levels of superoxide radical (O2.) in lung effluent, and 4) decreased nitrite levels (NO2-, oxidation product of nitric oxide) in lung effluent. Intraperitoneal treatment with calphostin C (3 microM, 15 min prior to treatment with TNF) prevented the effects of TNF on 1) PKC activation, 2) the hemodynamic responses to U-46619, and 3) the levels of NO2- and O2(.). PKC activation does not mediate TNF-induced lung sequestration of PMN, since calphostin C had no effect on lung myeloperoxidase activity. The data suggest that PKC activation mediates TNF-induced 1) increases in O2., 2) decreases in NO2-, and 3) increases in vasoreactivity and edema in response to U-46619.
Serfilippi
G
G
Samuel S. Stratton Veterans Affairs Medical Center, Albany, New York.
Ferro
T J
TJ
Johnson
A
A
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D004789:Enzyme Activation; D006168:Guinea Pigs; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D009573:Nitrites / Q000037:antagonists & inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology*; D011654:Pulmonary Edema / Q000139:chemically induced; D013481:Superoxides / Q000378:metabolism; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014661:Vasoconstriction; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D009573:Nitrites; D011450:Prostaglandin Endoperoxides, Synthetic; D014409:Tumor Necrosis Factor-alpha; D014662:Vasoconstrictor Agents; D013481:Superoxides; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D011493:Protein Kinase C