Cell-Cell Interactions in the Regulation of Glomerular Inflammation by Arachidonate Lipoxygenase Products

  • Kamal F. Badr
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 314)


Deposition of antigen-antibody complexes is a common initiating mechanism in a wide variety of human glomerulopathies. While the site of formation of these complexes, the route(s) by which they gain access to the glomerulus, their localization, and the nature of the histopathologic reaction they elicit can vary considerably, the central role of the activated leukocyte in the subsequent pathogenesis is well-established (1). In most immune-mediated glomerulopathies, complement activation in the early phase of injury triggers a polymorphonuclear (PMN) leukocyte infiltrate, and activates resident glomerular macrophages (1–3). This is often followed by macrophage infiltration and proliferation, accompanied, at times, by a proliferative reaction of glomerular mesangial and/or epithelial cells (1). These leukocyte-dependent stages of injury frequently coexist within the same glomerulus, ultimately leading to its sclerosis. Even when an overt inflammatory reaction is absent (as in membranous nephropathy), there is convincing evidence to suggest that the activation of resident macrophages is a central component of the pathogenetic pathways which eventually result in the impairment of glomerular functions (3, 4).


Mesangial Cell Glomerular Injury Glomerular Cell Glomerular Function Lipoxygenase Product 
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  1. 1.
    Wilson, C.B and F.J Dixon. 1986. Renal response to immunological injury. In The Kidney. BM Brenner and FC Rector Jr., editors. Saunders, Philadelphia. 800–890.Google Scholar
  2. 2.
    Cochrane, C.G., E. Unanue and F.J. Dixon. 1965. A role of polymorphonuclear leukocytes and complement in nephrotoxic nephritis. J. Exp. Med. 122: 99–116.PubMedCrossRefGoogle Scholar
  3. 3.
    Schreiner, G.F, R.S. Cotran, and E.R. Unanue. 1984. Modulation of Ia and leukocyte common antigen expression in rat glomeruli during the course of glomerulonephritis and aminonucleoside nephrosis. Lab. Invest. 51: 524–533.PubMedGoogle Scholar
  4. 4.
    Cook, H.T., J. Smith, J.A. Salmon, and V. Cattell. 1989. Functional characteristics of macrophages in glomerulonephritis in the rat. Am J. Pathol. 134: 431–437.PubMedGoogle Scholar
  5. 5.
    Lewis, R.A. and K.F. Austen. 1984. The biologically active leukotrienes. J. Clin. Invest. 73: 889–897.PubMedCrossRefGoogle Scholar
  6. 6.
    Samuelsson, B., S.-E. Dahlén, J. Å. Lindren, C. A. Rouzer, and C. N. Serhan. 1987. Leukotrienes and lipoxins: Structures, biosynthesis and biological effects. Science 237: 1171–1176.PubMedCrossRefGoogle Scholar
  7. 7.
    Goldman, D. W., L. A. Gifford, T. Marotti, C. H. Koo, and E. J. Goetzl. 1987. Molecular and cellular properties of human polymorphonuclear leukocyte receptors for leukotriene B4. Fed. Proc. 46: 200–203.PubMedGoogle Scholar
  8. 8.
    Serhan, C. N., J. Fridovich, E. J. Goetzl, P. B. Dunham, and G. Weismann. 1982. Leukotriene B4 and phosphatidic acid are calcium ionophores. J. Biol. Chem. 257: 4746–4752.PubMedGoogle Scholar
  9. 9.
    Feinmark, S. J., J. Å. Lindgren, H.-E. Claesson, C. Malmsten, and B. Samuelsson. 1981. Stimulation of human leukocyte degranulation by leukotriene B4 and its w-oxidized metabolites. FEBS letters 136: 141–144.PubMedCrossRefGoogle Scholar
  10. 10.
    Palmblad, J., C. L. Malmsten, A.-M. Udén, O. Rädmark, L. Engstedt, and B. Samuelsson. 1981. Leukotriene B4 is a potent and stereospecific stimulator of neutrophil Chemotaxis and adherence. Blood 58: 658–661.PubMedGoogle Scholar
  11. 11.
    Naccache, P. H., N. Faucher, S. Therrien, and P. Borgeat. 1988. Calcium mobilization, actin polymerization and right-angle light scatter responses to leukotriene B4, 12(R)-and 12(S)-hydroxyeicosatetraenoic acid in human neutrophils. Life Sciences 42: 727–733.PubMedCrossRefGoogle Scholar
  12. 12.
    Andersson, T., W. Schlegel, A. Monod, K.-H. Krause, O. Stendahl, and D. P. Lew. 1986. Leukotriene B4 stimulation of phagocytes results in the formation of inositol 1, 4, 5-trisphosphate. A second messenger for Ca2+ mobilization. Biochem. J. 240: 333–340.PubMedGoogle Scholar
  13. 13.
    Mong, S., G. Chi-Rosso, J. Miller, K. Hoffman, K. A. Razgaitis, P. Bender, and S. T. Crooke. 1986. Leukotriene B4 induces formation of inositol phosphates in rat peritoneal polymorphonuclear leukocytes. Mol. Pharmacol. 30: 235–242.PubMedGoogle Scholar
  14. 14.
    Mclntyre, T. M., S. L. Reinhold, S. M. Prescott, and G. A. Zimmerman. 1987. Protein kinase C activity appears to be required for the synthesis of platelet-activating factor and leukotriene B4 by human neutrophils. J. Biol. Chem. 262: 15370–15376.Google Scholar
  15. 15.
    Lee, T,H., Horton, CE., Kyan-Aung, U., Haskard, D., Crea, A.E.G., and Spur, B.W. 1989 Lipoxin A4 and lipoxin B4 inhibit chemotactic responses of human neutrophils stimulated by leukotriene B4 and N-formyl-L-methionyl-L-leucyl-L-phenylalanine. Clin. Sci. 77: 195–203.PubMedGoogle Scholar
  16. 16.
    Hedqvist, P, J. Raud, U. Palmertz, J Haeggstrom, K.C. Nicolau, and S-E Dahlen. 1989. Lipoxin A4 inhibits leukotriene B4-induced inflammation in the hamster cheek pouch. Acta. Physiol. Scand. 137: 571–572.PubMedCrossRefGoogle Scholar
  17. 17.
    Badr, KF, DeBoer, D, Schwartzberg, M, and Serhan, CN. 1989. Lipoxin A4 antagonizes cellular and in vivo actions of leukotriene D4 in rat glomerular mesangial cells: Evidence for competition at a common receptor. Proc. Nat’1. Acad. Science. U.S.A. 86: 3438–3442.CrossRefGoogle Scholar
  18. 18.
    Lefer, A.M., G.L Stahl, D. J. Lefer, M.E. Brezinski, K.C. Nicolau, C.A. Veale, Y. Abe, and J. Bryan Smith. 1988. Lipoxins A4 and B4: comparison of icosanoids having bronchoconstrictor and vasodilator actions but lacking lacking platelet aggregatory activity. Proc. Nat’1 Acad. Sci, USA. 85: 8340–8344.CrossRefGoogle Scholar
  19. 19.
    Badr, KF, Serhan, CN, Nicolau, KC, and Samuelsson, B. 1987. The Action of Lipoxin A on Glomerular Microcirculatory Dynamics in the Rat. Biochem. Biophys. Res.Commun. 145: 408–414.CrossRefGoogle Scholar
  20. 20.
    Dahlen, E-E, J. Raud, C.N. Serhan, J. Bjork, and B Samuelsson. 1987. Biological activities of lipoxin A include lung strip contraction and dilation of arterioles in vivo. Acta. Physiol. Scand. 130: 643–647.PubMedCrossRefGoogle Scholar
  21. 21.
    Badr, KF, C. Baylis, J.M. Pfeffer, M.A. Pfeffer, R.J. Soberman, R.A. Lewis, K.F. Austen, E.J. Corey and B.M. Brenner. 1984. Renal and systemic hemodynamic responses to intravenous infusion of leukotriene C4 in the rat. Circ. Res. 54: 492–499.PubMedGoogle Scholar
  22. 22.
    Sun, F.F., Chau, L.Y., and Austen, K.F. 1987. Binding of leukotriene C4 by glutathione transferase: a reassessment of biochemical and functional criteria for leukotriene receptors. Fed, Proc. 46: 204–207.Google Scholar
  23. 23.
    Badr, K.F., Brenner, B.M., and Ichikawa, I. 1987. Effects of leukotriene D4 on glomerular dynamics in the rat. Am. J. Physiol. 22: F239–F243.Google Scholar
  24. 24.
    Barnett, R, P. Goldwasser, L.A. Scharschmidt and D. Schlondorff. 1986. Effects of leukotrienes on isolated rat glomeruli and cultured mesangial cells. Am. J. Physiol. 19: F838–F844.Google Scholar
  25. 25.
    Simonson, M.S. and M.J. Dunn. 1986. Leukotriene C4 and D4 contract rat glomerular mesangial cells. Kidney Int. 30: 524–531.PubMedCrossRefGoogle Scholar
  26. 26.
    Badr, KF, Hoover, RL, Mong, S, Ebert, J, Schwartzberg, M., Jacobson, HR, and Harris, RC. 1989. Leukotriene D4 Binding and Signal Transduction in Rat Glomerular Mesangial Cells. Am. J. Physiol. (Renal Fluid and Electrolyte Physiol. 26) F280–F287.Google Scholar
  27. 27.
    Simonson, M. S., Mene, P., Dubyak, G.R., and Dunn, M.J. 1988. Identification and transmembrane signaling of leukotriene D4 receptors in human mesangial cells. Am. J. Physiol. 255: C771–C780.PubMedGoogle Scholar
  28. 28.
    Cattell, V., H. T. Cook, J. Smith, J. A. Salmon, and S. Moncada. 1987. Leukotriene B4 production in normal rat glomeruli. Nephrol. Dial. Transplant 2: 154–157.PubMedGoogle Scholar
  29. 29.
    Lianos, E. A. 1988. Synthesis of hydroxyeicosatetraenoic acids and leukotrienes in rat nephrotoxic serum glomerulonephritis: Role of anti-glomerular basement membrane antibody dose, complement, and neutrophiles. J. Clin. Invest. 82: 427–435.PubMedCrossRefGoogle Scholar
  30. 30.
    Fauler, J., A. Wiemeyer, K.-H. Marx, K. Kühn, K. M. Koch, and J. C. Fröhlich. 1989. LTB4 in nephrotoxic serum nephritis in rats. Kidney Int. 36: 46–50.PubMedCrossRefGoogle Scholar
  31. 31.
    Rahman, M.A., M. Nakazawa, S. N. Emancipator, and M. J. Dunn. 1988. Increased leukotriene B4 synthesis in immune injured rat glomeruli. J. Clin. Invest. 81: 1945–1952.PubMedCrossRefGoogle Scholar
  32. 32.
    Schreiner, G. F., B. Rovin, and J. B. Lefkowith. 1989. The antiinflammatory effects of essential fatty acid deficiency in experimental glomerulonephritis: The modulation of macrophage migration and eicosanoid metabolism. J. Immunol. 143: 3192–3199.PubMedGoogle Scholar
  33. 33.
    Lianos, E. A., and B. A. Bresnahan. 1990. Origin of leukotrienes and HETE in glomerular epithelial and mesangial cell immune injury. Kidney Int. 37: 421. (Abstr.)CrossRefGoogle Scholar
  34. 34.
    Lianos, E. A., B. Noble, and B. Hucke. 1989. Glomerular leukotriene synthesis in Heymann nephritis. Kidney Int. 36: 998–1002.PubMedCrossRefGoogle Scholar
  35. 35.
    Funk, C.D., Radmark, O., Fu, J.Y., Matsumoto, T., Jornvall, H. Shimizu, T., and Samuelsson, B. 1987. Molecular cloning and amino acid sequence of leukotriene A4 hydrolase. Proc. Nat’1. Acad. Sci. USA 84: 6677–6681.CrossRefGoogle Scholar
  36. 36.
    Matsumoto, T., Funk, CD., Radmark, O., Hoog, J-O, Jornvall, H., and Samuelsson, B. 1988. Molecular cloning and amino acid sequence of human 5-lipoxygenase. Proc. Nat’l Acad. Sci. USA 85: 26–30.CrossRefGoogle Scholar
  37. 37.
    Sigal, E., C.S. Craik, E. Highland, D. Grunberger, L.L. Costello, R.A.F. Dixon, and J.A. Nadel. 1988. Molecular cloning and primary structure of human 15-lipoxygenase. Biochem. bophys. Res. Commun. 157: 457–464.CrossRefGoogle Scholar
  38. 38.
    Imai, E, Hoover, RL, Makita, N, Funk, CD and Badr, KF. 1990. Localization and relative abundance of 5-lipoxygenase, 15-lipoxygenase, 12-lipoxygenase and leukotriene A4-hydrolase gene expression in cultured glomerular cells. J. Am. Soc. Nephrol. 1: 751.Google Scholar
  39. 39.
    Badr, KF, Frazer, M, Hoover, RL, Imai, E and Funk, CD. 1990. Leukotriene A4 hydrolase gene expression and catalytic activity in cultured glomerular cells: implications for glomerular immune injury. J. Am. Soc. Nephrol. 1: 437.Google Scholar
  40. 40.
    Hoover, RL, Imai, E., Makita, N, Funk, CD, and Badr, KF. 1990. Neutrophil adhesion suppresses leukotriene A4 hydrolase gene expression in human renal microvascular endothelial cells: potential mechanism for the arrest of PMN infiltration during inflammation. J. Am. Soc. Nephrol. 1: 443.Google Scholar
  41. 41.
    Feinmark, S. J., and P. J. Cannon. 1986. Endothelial cell leukotriene C4 synthesis results from intercellular transfer of leukotriene A4 synthesized by polymorphonuclear leukocytes. J. Biol. Chem. 261: 16466–16472.PubMedGoogle Scholar
  42. 42.
    Fitzpatrick, F., Ligget, W., McGee J., Bunting, S., Morton, D., and Samuelsson, B. 1984. Metabolism of leukotriene A4 by human erythrocytes. J. Biol. Chem. 259: 11403–11407.PubMedGoogle Scholar
  43. 43.
    Maclouf, J. A., and R. C Murphy. 1988. Transcellular metabolism of neutrophil-derived leukotriene A4 by human platelets. A potential cellular source of leukotriene C4. J. Biol. Chem. 263: 174–181PubMedGoogle Scholar
  44. 44.
    Marcus, A., Broekman, M., Safier, M.L., Ullman, H., and Islam, N. Formation of leukotrienes and other hydroxy acids during platelet-neutrophil interactions in vitro. Biochem. Biophys. Res. Commun. 109: 130–137, 1982.PubMedCrossRefGoogle Scholar
  45. 45.
    Edenius, C, J. Haeggstrom, and J. A. Lindgren. 1988. Transcellular conversion of endogenous archidonic acid to lipoxins in mixed human platelet-granulocyte suspensions. Biochem. Biophys. Res. Commun. 157: 801–807.PubMedCrossRefGoogle Scholar
  46. 46.
    Serhan, C.N. and K-A Sheppard. Lipoxin formation during human neutrophil-platelet interactions. Evidence for the transformation of leukotriene A4 by platelet 12-lipoxygenase in vitro. 1990. J. Clin. Invest. 85: 772–780.PubMedCrossRefGoogle Scholar
  47. 47.
    Garrick, R, Shen, S-Y, Ogunc, S., and Wong, P Y-K. 1989. Transformation of leukotriene A4 to lipoxins by rta kidney mesangial cell. Biochem. Biophys. Res. Commun. 162:62 6–633.Google Scholar
  48. 48.
    Baud, L., Hagege, J., Sraer, J., Rondeau, E., Perez, J., and Ardaillou, R. 1983. Reactive oxygen production by cultured rat glomerular mesangial cell during phagocytosis is associated with stimulation of lipoxygenase activity. J Exp Med. 158: 1836–1852.PubMedCrossRefGoogle Scholar
  49. 49.
    Badr, KF, Schreiner, GF, Wasserman, M, and Ichikawa, I. 1988. Preservation of the Glomerular Capillary Ultrafiltration Coefficient During Rat Nephrotoxic Serum Nephritis by a Specific Leukotriene D4 Receptor Antagonist. J. Clin. Invest. 81: 1702–1709.PubMedCrossRefGoogle Scholar
  50. 50.
    Spurney, R.F., P. Ruiz, D.S. Pisetsy, and T. M. Coffman. 1991. Enhanced renal leukotriene production in murine lupus: Role of lipoxygenase metabolites. Kidney. Int’l. 39: 95–102.CrossRefGoogle Scholar
  51. 51.
    Badr, KF. 1989. Leukotriene D4/leukotriene B4 interactions in the pathophysiology of experimental glomerulonephritis. In Advances in Prostaglandin, Thromboxane, and Leukotriene Research. Vol. 18. Wong, P. K-Y, Samuelsson, B., and Sun, F.F., eds. Raven Press, N.Y. pp 233–236.Google Scholar
  52. 52.
    Takahashi, K., Schreiner, GF, Yamashita, K., Christman, B, Blair, I., and Badr, KF. 1990. Predominant functional roles for thromboxane A2 and prostaglandin E2 during chronic mesangioproliferative glomerulonephritis in the rat. 1990. J. Clin. Invest. 85: 1974–1982.PubMedCrossRefGoogle Scholar
  53. 53.
    Fischer, D., Takahashi, K, Ebert, J, and Badr, KF. 1990. Limited early therapy with a novel 5-lipoxygenase (5-LO) activating protein (FLAP) antagonist, MK 886, during heterologous rat nephrotoxic serum (NTS) nephritis totally prevents proteinuria in the autologous phase. J. Am. Soc. Nephrol. 1: 628.Google Scholar
  54. 54.
    Serhan, C.N. 1989. On the relationship between leukotriene and lipoxin production by human neutrophils: evidence for differential metabolism of 15-HETE and 5-HETE. Biochem. Biophys. Acta. 1004: 158–168.PubMedGoogle Scholar
  55. 55.
    Brady, H.R., U Persson, B. M. Brenner, and C. N. Serhan. 1990. Leukotrienes and lipoxins modulate neutrophil-mesangial cell adhesion: role of CD18/CD11 complex. Clin. Res. 38: 275A.Google Scholar
  56. 56.
    Nicolau, K.C., Marron, B.E., Veale, CA., Webber, S.E., Dahlen, S-E, Samuelsson, B., and Serhan, C. N. 1989. Identification of a vovel 7-cis-11-trans-lipxin A4 generated by human neutrophils total synthesis, spasmogenic activities, and comparison with other geometric isomers of lipoxin A4 and B4. Biochem, Biophys. Acta. 1003: 44–53.Google Scholar
  57. 57.
    Marron, B.E., R.A. Spanecello, M.E. Elisseou, C.N. Serhan, and K.C. Nicolau. 1989. Synthesis of 19, 19, 20, 20, 20,-pentadeuterlipoxin A4 methyl ester and 19, 19, 20, 20 20,-pentadeuterioarachidonic acid. Agents for use in the quantitative detection of naturally occurring eicosanoids, J. Org. Chem. 54: 5522–5534.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Kamal F. Badr
    • 1
  1. 1.Division of Nephrology, Department of MedicineVanderbilt UniversityNashvilleUSA

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