Abstract
Leukocyte rolling has been postulated to be mandatory for subsequent leukocyte adhesion and tissue injury observed during ischemia/reperfusion. The objective of this study was to systematically assess this hypothesis at the microvascular level by examining the effects of various concentrations of a selectin-binding carbohydrate (fucoidin) on the increased rolling and adhesion of leukocytes in postischemic venules. The contribution of L-selectin and/or P-selectin to leukocyte rolling were also assessed in this model. Using intravital microscopy we observed that 60 min of ischemia followed by reperfusion caused a profound increase in leukocyte rolling and adhesion. A high dose of fucoidin (25 mg/kg) reduced leukocyte rolling by > 90% and significantly reduced leukocyte adhesion, whereas a lower dose of fucoidin still reduced leukocyte rolling by 60% but had no effect on leukocyte adhesion. Moreover, despite the profound reduction in leukocyte rolling with fucoidin, the remaining rolling cells were able to firmly adhere via a CD18-dependent mechanism, particularly in those postcapillary venules with reduced (30-50%) shear rates. The increased rolling was also reduced 60% by either an anti-P-selectin antibody, an anti-L-selectin antibody, or a combination of the two antibodies, but this reduction in rolling cells did not translate into significantly reduced leukocyte adhesion. Our data suggest that L-selectin, P-selectin, and a fucoidin-sensitive pathway contribute to the significant increase in reperfusion-induced leukocyte rolling. However, targeting leukocyte rolling as a form of therapy requires very significant efficacy (> 90%) to achieve reasonable (approximately 50%) attenuation in leukocyte adhesion in postischemic venules.
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Selected References
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- Arfors K. E., Ley K. Sulfated polysaccharides in inflammation. J Lab Clin Med. 1993 Feb;121(2):201–202. [PubMed] [Google Scholar]
- Asako H., Kurose I., Wolf R., DeFrees S., Zheng Z. L., Phillips M. L., Paulson J. C., Granger D. N. Role of H1 receptors and P-selectin in histamine-induced leukocyte rolling and adhesion in postcapillary venules. J Clin Invest. 1994 Apr;93(4):1508–1515. doi: 10.1172/JCI117129. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bevilacqua M. P., Nelson R. M. Selectins. J Clin Invest. 1993 Feb;91(2):379–387. doi: 10.1172/JCI116210. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bienvenu K., Granger D. N. Molecular determinants of shear rate-dependent leukocyte adhesion in postcapillary venules. Am J Physiol. 1993 May;264(5 Pt 2):H1504–H1508. doi: 10.1152/ajpheart.1993.264.5.H1504. [DOI] [PubMed] [Google Scholar]
- Bienvenu K., Russell J., Granger D. N. Platelet-activating factor promotes shear rate-dependent leukocyte adhesion in postcapillary venules. J Lipid Mediat. 1993 Oct;8(2):95–103. [PubMed] [Google Scholar]
- Carden D. L., Young J. A., Granger D. N. Pulmonary microvascular injury after intestinal ischemia-reperfusion: role of P-selectin. J Appl Physiol (1985) 1993 Dec;75(6):2529–2534. doi: 10.1152/jappl.1993.75.6.2529. [DOI] [PubMed] [Google Scholar]
- Cecconi O., Nelson R. M., Roberts W. G., Hanasaki K., Mannori G., Schultz C., Ulich T. R., Aruffo A., Bevilacqua M. P. Inositol polyanions. Noncarbohydrate inhibitors of L- and P-selectin that block inflammation. J Biol Chem. 1994 May 27;269(21):15060–15066. [PubMed] [Google Scholar]
- Del Maestro R. F., Planker M., Arfors K. E. Evidence for the participation of superoxide anion radical in altering the adhesive interaction between granulocytes and endothelium, in vivo. Int J Microcirc Clin Exp. 1982;1(2):105–120. [PubMed] [Google Scholar]
- Doré M., Korthuis R. J., Granger D. N., Entman M. L., Smith C. W. P-selectin mediates spontaneous leukocyte rolling in vivo. Blood. 1993 Aug 15;82(4):1308–1316. [PubMed] [Google Scholar]
- Engler R. L., Schmid-Schönbein G. W., Pavelec R. S. Leukocyte capillary plugging in myocardial ischemia and reperfusion in the dog. Am J Pathol. 1983 Apr;111(1):98–111. [PMC free article] [PubMed] [Google Scholar]
- Fehr J., Dahinden C. Modulating influence of chemotactic factor-induced cell adhesiveness on granulocyte function. J Clin Invest. 1979 Jul;64(1):8–16. doi: 10.1172/JCI109466. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gaboury J. P., Anderson D. C., Kubes P. Molecular mechanisms involved in superoxide-induced leukocyte-endothelial cell interactions in vivo. Am J Physiol. 1994 Feb;266(2 Pt 2):H637–H642. doi: 10.1152/ajpheart.1994.266.2.H637. [DOI] [PubMed] [Google Scholar]
- Geng J. G., Bevilacqua M. P., Moore K. L., McIntyre T. M., Prescott S. M., Kim J. M., Bliss G. A., Zimmerman G. A., McEver R. P. Rapid neutrophil adhesion to activated endothelium mediated by GMP-140. Nature. 1990 Feb 22;343(6260):757–760. doi: 10.1038/343757a0. [DOI] [PubMed] [Google Scholar]
- 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]
- Granger D. N. Role of xanthine oxidase and granulocytes in ischemia-reperfusion injury. Am J Physiol. 1988 Dec;255(6 Pt 2):H1269–H1275. doi: 10.1152/ajpheart.1988.255.6.H1269. [DOI] [PubMed] [Google Scholar]
- Grisham M. B., Hernandez L. A., Granger D. N. Adenosine inhibits ischemia-reperfusion-induced leukocyte adherence and extravasation. Am J Physiol. 1989 Nov;257(5 Pt 2):H1334–H1339. doi: 10.1152/ajpheart.1989.257.5.H1334. [DOI] [PubMed] [Google Scholar]
- 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]
- House S. D., Lipowsky H. H. Leukocyte-endothelium adhesion: microhemodynamics in mesentery of the cat. Microvasc Res. 1987 Nov;34(3):363–379. doi: 10.1016/0026-2862(87)90068-9. [DOI] [PubMed] [Google Scholar]
- Jaeschke H., Farhood A., Smith C. W. Neutrophils contribute to ischemia/reperfusion injury in rat liver in vivo. FASEB J. 1990 Dec;4(15):3355–3359. [PubMed] [Google Scholar]
- Jones D. A., Abbassi O., McIntire L. V., McEver R. P., Smith C. W. P-selectin mediates neutrophil rolling on histamine-stimulated endothelial cells. Biophys J. 1993 Oct;65(4):1560–1569. doi: 10.1016/S0006-3495(93)81195-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kanwar S., Kubes P. Ischemia/reperfusion-induced granulocyte influx is a multistep process mediated by mast cells. Microcirculation. 1994 Oct;1(3):175–182. doi: 10.3109/10739689409148272. [DOI] [PubMed] [Google Scholar]
- Korthuis R. J., Grisham M. B., Granger D. N. Leukocyte depletion attenuates vascular injury in postischemic skeletal muscle. Am J Physiol. 1988 May;254(5 Pt 2):H823–H827. doi: 10.1152/ajpheart.1988.254.5.H823. [DOI] [PubMed] [Google Scholar]
- Kubes P., Grisham M. B., Barrowman J. A., Gaginella T., Granger D. N. Leukocyte-induced vascular protein leakage in cat mesentery. Am J Physiol. 1991 Dec;261(6 Pt 2):H1872–H1879. doi: 10.1152/ajpheart.1991.261.6.H1872. [DOI] [PubMed] [Google Scholar]
- 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]
- Kubes P., Kanwar S. Histamine induces leukocyte rolling in post-capillary venules. A P-selectin-mediated event. J Immunol. 1994 Apr 1;152(7):3570–3577. [PubMed] [Google Scholar]
- Kubes P., Kurose I., Granger D. N. NO donors prevent integrin-induced leukocyte adhesion but not P-selectin-dependent rolling in postischemic venules. Am J Physiol. 1994 Sep;267(3 Pt 2):H931–H937. doi: 10.1152/ajpheart.1994.267.3.H931. [DOI] [PubMed] [Google Scholar]
- Kubes P., Suzuki M., Granger D. N. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4651–4655. doi: 10.1073/pnas.88.11.4651. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lawrence M. B., Bainton D. F., Springer T. A. Neutrophil tethering to and rolling on E-selectin are separable by requirement for L-selectin. Immunity. 1994 May;1(2):137–145. doi: 10.1016/1074-7613(94)90107-4. [DOI] [PubMed] [Google Scholar]
- Lawrence M. B., Springer T. A. Leukocytes roll on a selectin at physiologic flow rates: distinction from and prerequisite for adhesion through integrins. Cell. 1991 May 31;65(5):859–873. doi: 10.1016/0092-8674(91)90393-d. [DOI] [PubMed] [Google Scholar]
- Lawrence M. B., Springer T. A. Neutrophils roll on E-selectin. J Immunol. 1993 Dec 1;151(11):6338–6346. [PubMed] [Google Scholar]
- Lehr H. A., Kress E., Menger M. D., Friedl H. P., Hübner C., Arfors K. E., Messmer K. Cigarette smoke elicits leukocyte adhesion to endothelium in hamsters: inhibition by CuZn-SOD. Free Radic Biol Med. 1993 Jun;14(6):573–581. doi: 10.1016/0891-5849(93)90138-k. [DOI] [PubMed] [Google Scholar]
- Ley K., Cerrito M., Arfors K. E. Sulfated polysaccharides inhibit leukocyte rolling in rabbit mesentery venules. Am J Physiol. 1991 May;260(5 Pt 2):H1667–H1673. doi: 10.1152/ajpheart.1991.260.5.H1667. [DOI] [PubMed] [Google Scholar]
- Ley K., Gaehtgens P., Fennie C., Singer M. S., Lasky L. A., Rosen S. D. Lectin-like cell adhesion molecule 1 mediates leukocyte rolling in mesenteric venules in vivo. Blood. 1991 Jun 15;77(12):2553–2555. [PubMed] [Google Scholar]
- Ley K., Linnemann G., Meinen M., Stoolman L. M., Gaehtgens P. Fucoidin, but not yeast polyphosphomannan PPME, inhibits leukocyte rolling in venules of the rat mesentery. Blood. 1993 Jan 1;81(1):177–185. [PubMed] [Google Scholar]
- Lindbom L., Xie X., Raud J., Hedqvist P. Chemoattractant-induced firm adhesion of leukocytes to vascular endothelium in vivo is critically dependent on initial leukocyte rolling. Acta Physiol Scand. 1992 Dec;146(4):415–421. doi: 10.1111/j.1748-1716.1992.tb09442.x. [DOI] [PubMed] [Google Scholar]
- Ma X. L., Tsao P. S., Lefer A. M. Antibody to CD-18 exerts endothelial and cardiac protective effects in myocardial ischemia and reperfusion. J Clin Invest. 1991 Oct;88(4):1237–1243. doi: 10.1172/JCI115427. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ma X. L., Weyrich A. S., Lefer D. J., Buerke M., Albertine K. H., Kishimoto T. K., Lefer A. M. Monoclonal antibody to L-selectin attenuates neutrophil accumulation and protects ischemic reperfused cat myocardium. Circulation. 1993 Aug;88(2):649–658. doi: 10.1161/01.cir.88.2.649. [DOI] [PubMed] [Google Scholar]
- Mayadas T. N., Johnson R. C., Rayburn H., Hynes R. O., Wagner D. D. Leukocyte rolling and extravasation are severely compromised in P selectin-deficient mice. Cell. 1993 Aug 13;74(3):541–554. doi: 10.1016/0092-8674(93)80055-j. [DOI] [PubMed] [Google Scholar]
- Mayrovitz H. N. Leukocyte rolling: a prominent feature of venules in intact skin of anesthetized hairless mice. Am J Physiol. 1992 Jan;262(1 Pt 2):H157–H161. doi: 10.1152/ajpheart.1992.262.1.H157. [DOI] [PubMed] [Google Scholar]
- Mori E., del Zoppo G. J., Chambers J. D., Copeland B. R., Arfors K. E. Inhibition of polymorphonuclear leukocyte adherence suppresses no-reflow after focal cerebral ischemia in baboons. Stroke. 1992 May;23(5):712–718. doi: 10.1161/01.str.23.5.712. [DOI] [PubMed] [Google Scholar]
- Mori E., del Zoppo G. J., Chambers J. D., Copeland B. R., Arfors K. E. Inhibition of polymorphonuclear leukocyte adherence suppresses no-reflow after focal cerebral ischemia in baboons. Stroke. 1992 May;23(5):712–718. doi: 10.1161/01.str.23.5.712. [DOI] [PubMed] [Google Scholar]
- Nelson R. M., Dolich S., Aruffo A., Cecconi O., Bevilacqua M. P. Higher-affinity oligosaccharide ligands for E-selectin. J Clin Invest. 1993 Mar;91(3):1157–1166. doi: 10.1172/JCI116275. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Picker L. J., Warnock R. A., Burns A. R., Doerschuk C. M., Berg E. L., Butcher E. C. The neutrophil selectin LECAM-1 presents carbohydrate ligands to the vascular selectins ELAM-1 and GMP-140. Cell. 1991 Sep 6;66(5):921–933. doi: 10.1016/0092-8674(91)90438-5. [DOI] [PubMed] [Google Scholar]
- Romson J. L., Hook B. G., Kunkel S. L., Abrams G. D., Schork M. A., Lucchesi B. R. Reduction of the extent of ischemic myocardial injury by neutrophil depletion in the dog. Circulation. 1983 May;67(5):1016–1023. doi: 10.1161/01.cir.67.5.1016. [DOI] [PubMed] [Google Scholar]
- Seekamp A., Till G. O., Mulligan M. S., Paulson J. C., Anderson D. C., Miyasaka M., Ward P. A. Role of selectins in local and remote tissue injury following ischemia and reperfusion. Am J Pathol. 1994 Mar;144(3):592–598. [PMC free article] [PubMed] [Google Scholar]
- Smith C. W., Kishimoto T. K., Abbassi O., Hughes B., Rothlein R., McIntire L. V., Butcher E., Anderson D. C., Abbass O. Chemotactic factors regulate lectin adhesion molecule 1 (LECAM-1)-dependent neutrophil adhesion to cytokine-stimulated endothelial cells in vitro. J Clin Invest. 1991 Feb;87(2):609–618. doi: 10.1172/JCI115037. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Springer T. A. Adhesion receptors of the immune system. Nature. 1990 Aug 2;346(6283):425–434. doi: 10.1038/346425a0. [DOI] [PubMed] [Google Scholar]
- Tangelder G. J., Arfors K. E. Inhibition of leukocyte rolling in venules by protamine and sulfated polysaccharides. Blood. 1991 Apr 1;77(7):1565–1571. [PubMed] [Google Scholar]
- Von Andrian U. H., Hansell P., Chambers J. D., Berger E. M., Torres Filho I., Butcher E. C., Arfors K. E. L-selectin function is required for beta 2-integrin-mediated neutrophil adhesion at physiological shear rates in vivo. Am J Physiol. 1992 Oct;263(4 Pt 2):H1034–H1044. doi: 10.1152/ajpheart.1992.263.4.H1034. [DOI] [PubMed] [Google Scholar]
- Welbourn C. R., Goldman G., Paterson I. S., Valeri C. R., Shepro D., Hechtman H. B. Neutrophil elastase and oxygen radicals: synergism in lung injury after hindlimb ischemia. Am J Physiol. 1991 Jun;260(6 Pt 2):H1852–H1856. doi: 10.1152/ajpheart.1991.260.6.H1852. [DOI] [PubMed] [Google Scholar]
- Weyrich A. S., Ma X. Y., Lefer D. J., Albertine K. H., Lefer A. M. In vivo neutralization of P-selectin protects feline heart and endothelium in myocardial ischemia and reperfusion injury. J Clin Invest. 1993 Jun;91(6):2620–2629. doi: 10.1172/JCI116501. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Winn R. K., Liggitt D., Vedder N. B., Paulson J. C., Harlan J. M. Anti-P-selectin monoclonal antibody attenuates reperfusion injury to the rabbit ear. J Clin Invest. 1993 Oct;92(4):2042–2047. doi: 10.1172/JCI116799. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zimmerman G. A., Prescott S. M., McIntyre T. M. Endothelial cell interactions with granulocytes: tethering and signaling molecules. Immunol Today. 1992 Mar;13(3):93–100. doi: 10.1016/0167-5699(92)90149-2. [DOI] [PubMed] [Google Scholar]
- von Andrian U. H., Chambers J. D., McEvoy L. M., Bargatze R. F., Arfors K. E., Butcher E. C. Two-step model of leukocyte-endothelial cell interaction in inflammation: distinct roles for LECAM-1 and the leukocyte beta 2 integrins in vivo. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7538–7542. doi: 10.1073/pnas.88.17.7538. [DOI] [PMC free article] [PubMed] [Google Scholar]