Leukotrienes as mediators in ischemia-reperfusion injury in a microcirculation model in the hamster (original) (raw)

Abstract

Leukotriene (LT)B4 promotes leukocyte chemotaxis and adhesion to the endothelium of postcapillary venules. The cysteinyl leukotrienes, LTC4, LTD4, and LTE4, elicit macromolecular leakage from this vessel segment. Both leukocyte adhesion to the endothelium and macromolecular leakage from postcapillary venules hallmark the microcirculatory failure after ischemia-reperfusion, suggesting a role of leukotrienes as mediators of ischemia-reperfusion injury. Using the dorsal skinfold chamber model for intravital fluorescence microscopy of the microcirculation in striated muscle in awake hamsters and sequential RP-HPLC and RIA for leukotrienes, we demonstrate in this study that (a) the leukotrienes (LT)B4 and LTD4 elicit leukocyte/endothelium interaction and macromolecular leakage from postcapillary venules, respectively, that (b) leukotrienes accumulate in the tissue after ischemia and reperfusion, and that (c) selective inhibition of leukotriene biosynthesis (by MK-886) prevents both postischemic leukotriene accumulation and the microcirculatory changes after ischemia-reperfusion, while blocking of LTD4/E4 receptors (by MK-571) inhibits postischemic macromolecular leakage. These results demonstrate a key role of leukotrienes in ischemia-reperfusion injury in striated muscle in vivo.

2036

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arfors K. E., Lundberg C., Lindbom L., Lundberg K., Beatty P. G., Harlan J. M. A monoclonal antibody to the membrane glycoprotein complex CD18 inhibits polymorphonuclear leukocyte accumulation and plasma leakage in vivo. Blood. 1987 Jan;69(1):338–340. [PubMed] [Google Scholar]
  2. Björk J., Hedqvist P., Arfors K. E. Increase in vascular permeability induced by leukotriene B4 and the role of polymorphonuclear leukocytes. Inflammation. 1982 Jun;6(2):189–200. doi: 10.1007/BF00916243. [DOI] [PubMed] [Google Scholar]
  3. Dahlén S. E., Björk J., Hedqvist P., Arfors K. E., Hammarström S., Lindgren J. A., Samuelsson B. Leukotrienes promote plasma leakage and leukocyte adhesion in postcapillary venules: in vivo effects with relevance to the acute inflammatory response. Proc Natl Acad Sci U S A. 1981 Jun;78(6):3887–3891. doi: 10.1073/pnas.78.6.3887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Denzlinger C., Guhlmann A., Scheuber P. H., Wilker D., Hammer D. K., Keppler D. Metabolism and analysis of cysteinyl leukotrienes in the monkey. J Biol Chem. 1986 Nov 25;261(33):15601–15606. [PubMed] [Google Scholar]
  5. Denzlinger C., Rapp S., Hagmann W., Keppler D. Leukotrienes as mediators in tissue trauma. Science. 1985 Oct 18;230(4723):330–332. doi: 10.1126/science.4048937. [DOI] [PubMed] [Google Scholar]
  6. Dixon R. A., Diehl R. E., Opas E., Rands E., Vickers P. J., Evans J. F., Gillard J. W., Miller D. K. Requirement of a 5-lipoxygenase-activating protein for leukotriene synthesis. Nature. 1990 Jan 18;343(6255):282–284. doi: 10.1038/343282a0. [DOI] [PubMed] [Google Scholar]
  7. Endrich B., Asaishi K., Götz A., Messmer K. Technical report--a new chamber technique for microvascular studies in unanesthetized hamsters. Res Exp Med (Berl) 1980;177(2):125–134. doi: 10.1007/BF01851841. [DOI] [PubMed] [Google Scholar]
  8. Feinmark S. J., Lindgren J. A., Claesson H. E., Malmsten C., Samuelsson B. Stimulation of human leukocyte degranulation by leukotriene B4 and its omega-oxidized metabolites. FEBS Lett. 1981 Dec 21;136(1):141–144. doi: 10.1016/0014-5793(81)81233-1. [DOI] [PubMed] [Google Scholar]
  9. Ford-Hutchinson A. W., Bray M. A., Doig M. V., Shipley M. E., Smith M. J. Leukotriene B, a potent chemokinetic and aggregating substance released from polymorphonuclear leukocytes. Nature. 1980 Jul 17;286(5770):264–265. doi: 10.1038/286264a0. [DOI] [PubMed] [Google Scholar]
  10. Gillard J., Ford-Hutchinson A. W., Chan C., Charleson S., Denis D., Foster A., Fortin R., Leger S., McFarlane C. S., Morton H. L-663,536 (MK-886) (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2 - dimethylpropanoic acid), a novel, orally active leukotriene biosynthesis inhibitor. Can J Physiol Pharmacol. 1989 May;67(5):456–464. doi: 10.1139/y89-073. [DOI] [PubMed] [Google Scholar]
  11. Gimbrone M. A., Jr, Brock A. F., Schafer A. I. Leukotriene B4 stimulates polymorphonuclear leukocyte adhesion to cultured vascular endothelial cells. J Clin Invest. 1984 Oct;74(4):1552–1555. doi: 10.1172/JCI111570. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Goldman G., Welbourn R., Paterson I. S., Klausner J. M., Kobzik L., Valeri C. R., Shepro D., Hechtman H. B. Ischemia-induced neutrophil activation and diapedesis is lipoxygenase dependent. Surgery. 1990 Apr;107(4):428–433. [PubMed] [Google Scholar]
  13. Granger D. N., Benoit J. N., Suzuki M., Grisham M. B. Leukocyte adherence to venular endothelium during ischemia-reperfusion. Am J Physiol. 1989 Nov;257(5 Pt 1):G683–G688. doi: 10.1152/ajpgi.1989.257.5.G683. [DOI] [PubMed] [Google Scholar]
  14. Grisham M. B., Hernandez L. A., Granger D. N. Xanthine oxidase and neutrophil infiltration in intestinal ischemia. Am J Physiol. 1986 Oct;251(4 Pt 1):G567–G574. doi: 10.1152/ajpgi.1986.251.4.G567. [DOI] [PubMed] [Google Scholar]
  15. Guhlmann A., Keppler A., Kästner S., Krieter H., Brückner U. B., Messmer K., Keppler D. Prevention of endogenous leukotriene production during anaphylaxis in the guinea pig by an inhibitor of leukotriene biosynthesis (MK-886) but not by dexamethasone. J Exp Med. 1989 Dec 1;170(6):1905–1918. doi: 10.1084/jem.170.6.1905. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gyllenhammar H. Correlation between neutrophil superoxide formation, luminol-augmented chemiluminescence and intracellular Ca2+ levels upon stimulation with leukotriene B4, formylpeptide and phorbolester. Scand J Clin Lab Invest. 1989 Jun;49(4):317–322. doi: 10.3109/00365518909089103. [DOI] [PubMed] [Google Scholar]
  17. Hernandez L. A., Grisham M. B., Twohig B., Arfors K. E., Harlan J. M., Granger D. N. Role of neutrophils in ischemia-reperfusion-induced microvascular injury. Am J Physiol. 1987 Sep;253(3 Pt 2):H699–H703. doi: 10.1152/ajpheart.1987.253.3.H699. [DOI] [PubMed] [Google Scholar]
  18. Hua X. Y., Dahlén S. E., Lundberg J. M., Hammarström S., Hedqvist P. Leukotrienes C4, D4 and E4 cause widespread and extensive plasma extravasation in the guinea pig. Naunyn Schmiedebergs Arch Pharmacol. 1985 Aug;330(2):136–141. doi: 10.1007/BF00499906. [DOI] [PubMed] [Google Scholar]
  19. Jolly S. R., Lucchesi B. R. Effect of BW755C in an occlusion-reperfusion model of ischemic myocardial injury. Am Heart J. 1983 Jul;106(1 Pt 1):8–13. doi: 10.1016/0002-8703(83)90431-3. [DOI] [PubMed] [Google Scholar]
  20. Jones T. R., Zamboni R., Belley M., Champion E., Charette L., Ford-Hutchinson A. W., Frenette R., Gauthier J. Y., Leger S., Masson P. Pharmacology of L-660,711 (MK-571): a novel potent and selective leukotriene D4 receptor antagonist. Can J Physiol Pharmacol. 1989 Jan;67(1):17–28. doi: 10.1139/y89-004. [DOI] [PubMed] [Google Scholar]
  21. Joris I., Majno G., Corey E. J., Lewis R. A. The mechanism of vascular leakage induced by leukotriene E4. Endothelial contraction. Am J Pathol. 1987 Jan;126(1):19–24. [PMC free article] [PubMed] [Google Scholar]
  22. Klausner J. M., Paterson I. S., Goldman G., Kobzik L., Rodzen C., Lawrence R., Valeri C. R., Shepro D., Hechtman H. B. Postischemic renal injury is mediated by neutrophils and leukotrienes. Am J Physiol. 1989 May;256(5 Pt 2):F794–F802. doi: 10.1152/ajprenal.1989.256.5.F794. [DOI] [PubMed] [Google Scholar]
  23. Korthuis R. J., Granger D. N., Townsley M. I., Taylor A. E. The role of oxygen-derived free radicals in ischemia-induced increases in canine skeletal muscle vascular permeability. Circ Res. 1985 Oct;57(4):599–609. doi: 10.1161/01.res.57.4.599. [DOI] [PubMed] [Google Scholar]
  24. Kubes P., Ibbotson G., Russell J., Wallace J. L., Granger D. N. Role of platelet-activating factor in ischemia/reperfusion-induced leukocyte adherence. Am J Physiol. 1990 Aug;259(2 Pt 1):G300–G305. doi: 10.1152/ajpgi.1990.259.2.G300. [DOI] [PubMed] [Google Scholar]
  25. Lehr H. A., Guhlmann A., Nolte D., Keppler D., Messmer K. Preservation of postischemic capillary perfusion by selective inhibition of leukotriene biosynthesis. Transplant Proc. 1991 Feb;23(1 Pt 1):833–834. [PubMed] [Google Scholar]
  26. Leng W., Kuo C. G., Qureshi R., Jakschik B. A. Role of leukotrienes in vascular changes in the rat mesentery and skin in anaphylaxis. J Immunol. 1988 Apr 1;140(7):2361–2368. [PubMed] [Google Scholar]
  27. Ley K., Arfors K. E. Changes in macromolecular permeability by intravascular generation of oxygen-derived free radicals. Microvasc Res. 1982 Jul;24(1):25–33. doi: 10.1016/0026-2862(82)90039-5. [DOI] [PubMed] [Google Scholar]
  28. Lindström P., Lerner R., Palmblad J., Patarroyo M. Rapid adhesive responses of endothelial cells and of neutrophils induced by leukotriene B4 are mediated by leucocytic adhesion protein CD18. Scand J Immunol. 1990 Jun;31(6):737–744. doi: 10.1111/j.1365-3083.1990.tb02825.x. [DOI] [PubMed] [Google Scholar]
  29. Mangino M. J., Anderson C. B., Murphy M. K., Brunt E., Turk J. Mucosal arachidonate metabolism and intestinal ischemia-reperfusion injury. Am J Physiol. 1989 Aug;257(2 Pt 1):G299–G307. doi: 10.1152/ajpgi.1989.257.2.G299. [DOI] [PubMed] [Google Scholar]
  30. Menger M. D., Sack F. U., Barker J. H., Feifel G., Messmer K. Quantitative analysis of microcirculatory disorders after prolonged ischemia in skeletal muscle. Therapeutic effects of prophylactic isovolemic hemodilution. Res Exp Med (Berl) 1988;188(3):151–165. doi: 10.1007/BF01852316. [DOI] [PubMed] [Google Scholar]
  31. Miller D. K., Gillard J. W., Vickers P. J., Sadowski S., Léveillé C., Mancini J. A., Charleson P., Dixon R. A., Ford-Hutchinson A. W., Fortin R. Identification and isolation of a membrane protein necessary for leukotriene production. Nature. 1990 Jan 18;343(6255):278–281. doi: 10.1038/343278a0. [DOI] [PubMed] [Google Scholar]
  32. Moskowitz M. A., Kiwak K. J., Hekimian K., Levine L. Synthesis of compounds with properties of leukotrienes C4 and D4 in gerbil brains after ischemia and reperfusion. Science. 1984 May 25;224(4651):886–889. doi: 10.1126/science.6719118. [DOI] [PubMed] [Google Scholar]
  33. Mullane K. M., Salmon J. A., Kraemer R. Leukocyte-derived metabolites of arachidonic acid in ischemia-induced myocardial injury. Fed Proc. 1987 May 15;46(7):2422–2433. [PubMed] [Google Scholar]
  34. Nourshargh S., Rampart M., Hellewell P. G., Jose P. J., Harlan J. M., Edwards A. J., Williams T. J. Accumulation of 111In-neutrophils in rabbit skin in allergic and non-allergic inflammatory reactions in vivo. Inhibition by neutrophil pretreatment in vitro with a monoclonal antibody recognizing the CD18 antigen. J Immunol. 1989 May 1;142(9):3193–3198. [PubMed] [Google Scholar]
  35. Palmblad J., Malmsten C. L., Udén A. M., Rådmark O., Engstedt L., Samuelsson B. Leukotriene B4 is a potent and stereospecific stimulator of neutrophil chemotaxis and adherence. Blood. 1981 Sep;58(3):658–661. [PubMed] [Google Scholar]
  36. Parks D. A., Bulkley G. B., Granger D. N., Hamilton S. R., McCord J. M. Ischemic injury in the cat small intestine: role of superoxide radicals. Gastroenterology. 1982 Jan;82(1):9–15. [PubMed] [Google Scholar]
  37. Rae S. A., Smith M. J. The stimulation of lysosomal enzyme secretion from human polymorphonuclear leucocytes by leukotriene B4. J Pharm Pharmacol. 1981 Sep;33(9):616–617. doi: 10.1111/j.2042-7158.1981.tb13884.x. [DOI] [PubMed] [Google Scholar]
  38. Rosengren S., Björk J., Smedegård G. Oxygen radicals are not a prerequisite for neutrophil-mediated increased vascular permeability. Lab Invest. 1988 May;58(5):559–564. [PubMed] [Google Scholar]
  39. Rouzer C. A., Ford-Hutchinson A. W., Morton H. E., Gillard J. W. MK886, a potent and specific leukotriene biosynthesis inhibitor blocks and reverses the membrane association of 5-lipoxygenase in ionophore-challenged leukocytes. J Biol Chem. 1990 Jan 25;265(3):1436–1442. [PubMed] [Google Scholar]
  40. Sasaki K., Ueno A., Katori M., Kikawada R. Detection of leukotriene B4 in cardiac tissue and its role in infarct extension through leucocyte migration. Cardiovasc Res. 1988 Feb;22(2):142–148. doi: 10.1093/cvr/22.2.142. [DOI] [PubMed] [Google Scholar]
  41. Schmid-Schönbein G. W. Capillary plugging by granulocytes and the no-reflow phenomenon in the microcirculation. Fed Proc. 1987 May 15;46(7):2397–2401. [PubMed] [Google Scholar]
  42. Serhan C. N., Radin A., Smolen J. E., Korchak H., Samuelsson B., Weissmann G. Leukotriene B4 is a complete secretagogue in human neutrophils: a kinetic analysis. Biochem Biophys Res Commun. 1982 Aug;107(3):1006–1012. doi: 10.1016/0006-291x(82)90622-2. [DOI] [PubMed] [Google Scholar]
  43. Shappell S. B., Taylor A. A., Hughes H., Mitchell J. R., Anderson D. C., Smith C. W. Comparison of antioxidant and nonantioxidant lipoxygenase inhibitors on neutrophil function. Implications for pathogenesis of myocardial reperfusion injury. J Pharmacol Exp Ther. 1990 Feb;252(2):531–538. [PubMed] [Google Scholar]
  44. Simpson P. J., Todd R. F., 3rd, Fantone J. C., Mickelson J. K., Griffin J. D., Lucchesi B. R. Reduction of experimental canine myocardial reperfusion injury by a monoclonal antibody (anti-Mo1, anti-CD11b) that inhibits leukocyte adhesion. J Clin Invest. 1988 Feb;81(2):624–629. doi: 10.1172/JCI113364. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Suzuki M., Inauen W., Kvietys P. R., Grisham M. B., Meininger C., Schelling M. E., Granger H. J., Granger D. N. Superoxide mediates reperfusion-induced leukocyte-endothelial cell interactions. Am J Physiol. 1989 Nov;257(5 Pt 2):H1740–H1745. doi: 10.1152/ajpheart.1989.257.5.H1740. [DOI] [PubMed] [Google Scholar]
  46. Tateson J. E., Randall R. W., Reynolds C. H., Jackson W. P., Bhattacherjee P., Salmon J. A., Garland L. G. Selective inhibition of arachidonate 5-lipoxygenase by novel acetohydroxamic acids: biochemical assessment in vitro and ex vivo. Br J Pharmacol. 1988 Jun;94(2):528–539. doi: 10.1111/j.1476-5381.1988.tb11557.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Tonnesen M. G., Anderson D. C., Springer T. A., Knedler A., Avdi N., Henson P. M. Adherence of neutrophils to cultured human microvascular endothelial cells. Stimulation by chemotactic peptides and lipid mediators and dependence upon the Mac-1, LFA-1, p150,95 glycoprotein family. J Clin Invest. 1989 Feb;83(2):637–646. doi: 10.1172/JCI113928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Vedder N. B., Winn R. K., Rice C. L., Chi E. Y., Arfors K. E., Harlan J. M. A monoclonal antibody to the adherence-promoting leukocyte glycoprotein, CD18, reduces organ injury and improves survival from hemorrhagic shock and resuscitation in rabbits. J Clin Invest. 1988 Mar;81(3):939–944. doi: 10.1172/JCI113407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Wallis W. J., Hickstein D. D., Schwartz B. R., June C. H., Ochs H. D., Beatty P. G., Klebanoff S. J., Harlan J. M. Monoclonal antibody-defined functional epitopes on the adhesion-promoting glycoprotein complex (CDw18) of human neutrophils. Blood. 1986 Apr;67(4):1007–1013. [PubMed] [Google Scholar]
  50. Zeintl H., Sack F. U., Intaglietta M., Messmer K. Computer assisted leukocyte adhesion measurement in intravital microscopy. Int J Microcirc Clin Exp. 1989 Jul;8(3):293–302. [PubMed] [Google Scholar]