Two Structurally Unrelated PAF Antagonists, BN 52021 and BN 52111, Partially Inhibit TNF-Induced Superoxide Release by Human Neutrophils
The normal bactericidal response of human neutrophils (PMN) involves cell stimulation, followed by a respiratory burst which results from the activation of NADPH oxidase. This multicomponent electron transport chain transfers electrons from intracellular NADPH to extra-cellular oxygen, reducing molecular oxygen to superoxide. This latter product is rapidly converted to hydrogen peroxide and toxic free radicals (1). Activated PMN also release lysosomal proteases and adhere to the endothelial surface, the cells of which can be severely damaged by the secretion of these toxic products if the local cytotoxic response escalates into a systemic process. Indeed, the microvascular collapse, characterisic of pathologies such as shock, asthma, ischemia and graft rejection, may be partially mediated by dysregulation of PMN functions.
Unable to display preview. Download preview PDF.
- 2.P. Braquet, L. Touqui, T.S. Shen, and B.B. Vargaftig, 1987, Perspectives in platelet-activating factor research. Pharmacol Reviews. 39:97.Google Scholar
- 4.K.J. Tracey, B. Beutler, S.F. Lowry, J. Merryweather, S. Wolpe, I.W. Milsark, R.J. Hariri, T.J. Fahey, A. Zentella, J.D. Albert, T. Shires, and A. Cerami, 1986, Shock and tissue injury induced by recombinant human cachectin. Science. 234: 4704.Google Scholar
- 5.Y. Ozaki, T. Ohashi, Y. Niwa, and S. Kume, S., 1988, Effect of recombinant DNA-produced tumour necrosis factor on various parameters of neutrophil function. Inflammation. 12: 297.Google Scholar
- 8.G.M. Vercellotti, H.Q. Yin, K.S. Gustafson, P.O. Nelson, H.S. Jacob, 1988, Platelet activating factor primes neutrophil responses to agonists: role in promoting neutrophil-mediated endothelial damage. Blood. 71: 1100.Google Scholar
- 9.R.L. Berkow, D. Wang, J.W. Larrich, R.W. Dodson, and T.H. Howard, 1987, Enhancement of human neutrophil superoxide production by preincubation with recombinant tumour necrosis factor. J. Immunol. 139:3783.Google Scholar
- 10.P. Braquet, 1987, The Ginkgolides: potent platelet-activating factor antagonists isolated from Ginkgo Biloba L. Drugs of the Future 12: 643.Google Scholar
- 11.C. Broquet, and P. Braquet, 1988, Compositions thérapeutiques à base de nouveaux aminoacylates d’acétal du glycerol. Fr. Patent. N° 2.616.326.Google Scholar
- 12.F.H. Valone, and L.B. Epstein, 1988, Biphasic platelet-activating factor synthesis by human monocytes stimulated with interleukin 1 beta (IL 1), tumor necrosis factor (TNF) or gamma interferon (IFN). J. Immunol. 11:3945.Google Scholar
- 13.M. Rola-Pleszczynski, 1988, Priming of human monocytes with PAF augments their production of tumour necrosis factor in response to interleukin 1. J. Lipid Mediators. in press.Google Scholar
- 15.M.L. Blank, T.C. Lee, V. Fitzgerald, and F. Snyder, 1981, Anti-hypertensive activity of an alkyl ether analog of phosphatidylcholine. Biochem. Biophys. Res. Commun. 29: 2472.Google Scholar
- 16.H. Heuer, and G. Letts, 1989, Priming of effects of PAF in vivo by tumor necrosis factor and endotoxin. J. Lipid Mediators. in press.Google Scholar