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Journal of Lipid Research, Vol. 42, 587-596, April 2001
Copyright © 2001 by Lipid Research, Inc.

Original Article

Identification of platelet-activating factor as the inflammatory lipid mediator in CCl₄-metabolizing rat liver

Correspondence to: Thomas M. McIntyre, at 4130 Eccles Institute of Human Genetics, 2030 E. 15 N., University of Utah, Salt Lake City, UT 84112-5330., tom.mcintyre{at}hmbg.utah.edu (E-mail)

Unmitigated oxidative stress is deleterious, as epitomized by CCl₄ intoxication. In this well-characterized model of free radical-initiated damage, liver metabolism of CCl₄ to CCl₃. causes lipid peroxidation, F-ring isoprostane formation, and pathologic leukocyte activation. The nature of the mediator that couples oxidation to the hepatotoxic inflammatory response is uncharacterized. We found that oxidatively modified phosphatidylcholines were present in the livers of CCl₄-exposed rats and not in livers from control animals, that CCl₄ metabolism generated lipids that activated 293 cells stably transfected with the human platelet-activating factor (PAF) receptor, and that this PAF-like activity was formed as rapidly as isoprostane-containing phosphatidylcholine (iPC) during oxidation. iPC and the PAF-like activity also had similar chromatographic properties. The potential for iPC activation of the PAF receptor has been unexplored, but we conclude that iPC themselves did not activate the PAF receptor, as phospholipase A₁ hydrolysis completely destroyed iPC, but none of the PAF-like bioactivity. Oxidatively fragmented phospholipids are potent agonists of the PAF receptor, but mass spectrometry characterized PAF as the major inflammatory component coeluting with iPC.

Oxidatively fragmented phospholipids and iPC are markers of free radical generation in CCl₄-intoxicated liver, but PAF generation by activated hepatic cells generated the inflammatory agent. — Marathe, G. K., K. A. Harrison, L. J. Roberts II, J. D. Morrow, R. C. Murphy, L. W. Tjoelker, S. M. Prescott, G. A. Zimmerman, and T. M. McIntyre. Identification of platelet-activating factor as the inflammatory lipid mediator in CCl₄-metabolizing rat liver. J. Lipid Res. 2001. 42: 587;–596.

Supplementary key words: PAF, inflammation, liver, isoprostane, oxidation

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