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. 1997 Sep 1;100(5):1150–1158. doi: 10.1172/JCI119626

Modulation of eicosanoid metabolism in endothelial cells in a xenograft model. Role of cyclooxygenase-2.

M Bustos 1, T M Coffman 1, S Saadi 1, J L Platt 1
PMCID: PMC508290  PMID: 9276732

Abstract

Lipid inflammatory mediators are thought to play a critical role in the pathogenesis of vascular injury. Among the events which might cause the synthesis of eicosanoids in blood vessels is activation of the complement. To evaluate how complement might influence eicosanoid metabolism, we investigated endothelial cells exposed to xenoreactive antibodies and complement, as might occur in rejecting xenografts where severe vascular injury is a typical feature. While resting porcine aortic endothelial cells released only prostaglandin (PG) I2, endothelial cells stimulated with xenoreactive antibodies and complement released PGE2 and thromboxane A2 (TXA2), in addition to increased amounts of PGI2. This alteration in eicosanoid metabolism was associated with induction of cyclooxygenase (Cox)-2 and thromboxane synthase, but not Cox-1. Unlike results seen in other systems, the upregulation of Cox-2 and the subsequent release of eicosanoids by endothelial cells was not directly induced by complement but rather required production of IL-1alpha, which acted on endothelial cells as an autocrine factor. Since eicosanoids have a potent effect on inflammation, vascular tone and platelet aggregation, we postulated that the abnormalities in eicosanoid release induced by xenoreactive antibodies and complement might provide one explanation for the vascular injury, focal ischemia, and thrombosis observed in acute vascular rejection and other vasculitides mediated by complement.

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Selected References

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  1. Carreras L. O., Maclouf J. The lupus anticoagulant and eicosanoids. Prostaglandins Leukot Essent Fatty Acids. 1993 Jul;49(1):483–488. doi: 10.1016/0952-3278(93)90035-u. [DOI] [PubMed] [Google Scholar]
  2. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  3. Crowl R. M., Stoller T. J., Conroy R. R., Stoner C. R. Induction of phospholipase A2 gene expression in human hepatoma cells by mediators of the acute phase response. J Biol Chem. 1991 Feb 5;266(4):2647–2651. [PubMed] [Google Scholar]
  4. DeWitt D. L. Prostaglandin endoperoxide synthase: regulation of enzyme expression. Biochim Biophys Acta. 1991 May 8;1083(2):121–134. doi: 10.1016/0005-2760(91)90032-d. [DOI] [PubMed] [Google Scholar]
  5. Forman B. M., Tontonoz P., Chen J., Brun R. P., Spiegelman B. M., Evans R. M. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell. 1995 Dec 1;83(5):803–812. doi: 10.1016/0092-8674(95)90193-0. [DOI] [PubMed] [Google Scholar]
  6. Habib A., Martinuzzo M. E., Carreras L. O., Lévy-Toledano S., Maclouf J. Increased expression of inducible cyclooxygenase-2 in human endothelial cells by antiphospholipid antibodies. Thromb Haemost. 1995 Aug;74(2):770–777. [PubMed] [Google Scholar]
  7. Imagawa D. K., Osifchin N. E., Ramm L. E., Koga P. G., Hammer C. H., Shin H. S., Mayer M. M. Release of arachidonic acid and formation of oxygenated derivatives after complement attack on macrophages: role of channel formation. J Immunol. 1986 Jun 15;136(12):4637–4643. [PubMed] [Google Scholar]
  8. Karim S., Habib A., Lévy-Toledano S., Maclouf J. Cyclooxygenase-1 and -2 of endothelial cells utilize exogenous or endogenous arachidonic acid for transcellular production of thromboxane. J Biol Chem. 1996 May 17;271(20):12042–12048. doi: 10.1074/jbc.271.20.12042. [DOI] [PubMed] [Google Scholar]
  9. Lawson J. H., Platt J. L. Molecular barriers to xenotransplantation. Transplantation. 1996 Aug 15;62(3):303–310. doi: 10.1097/00007890-199608150-00001. [DOI] [PubMed] [Google Scholar]
  10. Leung D. Y., Moake J. L., Havens P. L., Kim M., Pober J. S. Lytic anti-endothelial cell antibodies in haemolytic-uraemic syndrome. Lancet. 1988 Jul 23;2(8604):183–186. doi: 10.1016/s0140-6736(88)92287-8. [DOI] [PubMed] [Google Scholar]
  11. Lin L. L., Lin A. Y., DeWitt D. L. Interleukin-1 alpha induces the accumulation of cytosolic phospholipase A2 and the release of prostaglandin E2 in human fibroblasts. J Biol Chem. 1992 Nov 25;267(33):23451–23454. [PubMed] [Google Scholar]
  12. Masferrer J. L., Zweifel B. S., Manning P. T., Hauser S. D., Leahy K. M., Smith W. G., Isakson P. C., Seibert K. Selective inhibition of inducible cyclooxygenase 2 in vivo is antiinflammatory and nonulcerogenic. Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3228–3232. doi: 10.1073/pnas.91.8.3228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Needleman P., Moncada S., Bunting S., Vane J. R., Hamberg M., Samuelsson B. Identification of an enzyme in platelet microsomes which generates thromboxane A2 from prostaglandin endoperoxides. Nature. 1976 Jun 17;261(5561):558–560. doi: 10.1038/261558a0. [DOI] [PubMed] [Google Scholar]
  14. Oka S., Arita H. Inflammatory factors stimulate expression of group II phospholipase A2 in rat cultured astrocytes. Two distinct pathways of the gene expression. J Biol Chem. 1991 May 25;266(15):9956–9960. [PubMed] [Google Scholar]
  15. Parker W., Bruno D., Holzknecht Z. E., Platt J. L. Characterization and affinity isolation of xenoreactive human natural antibodies. J Immunol. 1994 Oct 15;153(8):3791–3803. [PubMed] [Google Scholar]
  16. Parker W., Saadi S., Lin S. S., Holzknecht Z. E., Bustos M., Platt J. L. Transplantation of discordant xenografts: a challenge revisited. Immunol Today. 1996 Aug;17(8):373–378. doi: 10.1016/0167-5699(96)10028-1. [DOI] [PubMed] [Google Scholar]
  17. Platt J. L. A perspective on xenograft rejection and accommodation. Immunol Rev. 1994 Oct;141:127–149. doi: 10.1111/j.1600-065x.1994.tb00875.x. [DOI] [PubMed] [Google Scholar]
  18. Platt J. L., Lindman B. J., Geller R. L., Noreen H. J., Swanson J. L., Dalmasso A. P., Bach F. H. The role of natural antibodies in the activation of xenogenic endothelial cells. Transplantation. 1991 Dec;52(6):1037–1043. doi: 10.1097/00007890-199112000-00019. [DOI] [PubMed] [Google Scholar]
  19. Platt J. L., Vercellotti G. M., Dalmasso A. P., Matas A. J., Bolman R. M., Najarian J. S., Bach F. H. Transplantation of discordant xenografts: a review of progress. Immunol Today. 1990 Dec;11(12):450–457. doi: 10.1016/0167-5699(90)90174-8. [DOI] [PubMed] [Google Scholar]
  20. Platt J. L., Vercellotti G. M., Lindman B. J., Oegema T. R., Jr, Bach F. H., Dalmasso A. P. Release of heparan sulfate from endothelial cells. Implications for pathogenesis of hyperacute rejection. J Exp Med. 1990 Apr 1;171(4):1363–1368. doi: 10.1084/jem.171.4.1363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Ramadan F. M., Upchurch G. R., Jr, Keagy B. A., Johnson G., Jr Endothelial cell thromboxane production and its inhibition by a calcium-channel blocker. Ann Thorac Surg. 1990 Jun;49(6):916–919. doi: 10.1016/0003-4975(90)90865-4. [DOI] [PubMed] [Google Scholar]
  22. Ristimäki A., Garfinkel S., Wessendorf J., Maciag T., Hla T. Induction of cyclooxygenase-2 by interleukin-1 alpha. Evidence for post-transcriptional regulation. J Biol Chem. 1994 Apr 22;269(16):11769–11775. [PubMed] [Google Scholar]
  23. Ristimäki A., Viinikka L. Modulation of prostacyclin production by cytokines in vascular endothelial cells. Prostaglandins Leukot Essent Fatty Acids. 1992 Oct;47(2):93–99. doi: 10.1016/0952-3278(92)90143-7. [DOI] [PubMed] [Google Scholar]
  24. Saadi S., Holzknecht R. A., Patte C. P., Stern D. M., Platt J. L. Complement-mediated regulation of tissue factor activity in endothelium. J Exp Med. 1995 Dec 1;182(6):1807–1814. doi: 10.1084/jem.182.6.1807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Saadi S., Platt J. L. Transient perturbation of endothelial integrity induced by natural antibodies and complement. J Exp Med. 1995 Jan 1;181(1):21–31. doi: 10.1084/jem.181.1.21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Smith W. L., Marnett L. J. Prostaglandin endoperoxide synthase: structure and catalysis. Biochim Biophys Acta. 1991 Apr 24;1083(1):1–17. doi: 10.1016/0005-2760(91)90119-3. [DOI] [PubMed] [Google Scholar]
  27. Smith W. L. Prostaglandin biosynthesis and its compartmentation in vascular smooth muscle and endothelial cells. Annu Rev Physiol. 1986;48:251–262. doi: 10.1146/annurev.ph.48.030186.001343. [DOI] [PubMed] [Google Scholar]
  28. Vane J. R., Anggård E. E., Botting R. M. Regulatory functions of the vascular endothelium. N Engl J Med. 1990 Jul 5;323(1):27–36. doi: 10.1056/NEJM199007053230106. [DOI] [PubMed] [Google Scholar]
  29. Wrenshall L. E., Cerra F. B., Carlson A., Bach F. H., Platt J. L. Regulation of murine splenocyte responses by heparan sulfate. J Immunol. 1991 Jul 15;147(2):455–459. [PubMed] [Google Scholar]
  30. Wrenshall L. E., Cerra F. B., Singh R. K., Platt J. L. Heparan sulfate initiates signals in murine macrophages leading to divergent biologic outcomes. J Immunol. 1995 Jan 15;154(2):871–880. [PubMed] [Google Scholar]

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