BioDrugs

, Volume 15, Issue 6, pp 395–404 | Cite as

The Potential of Monoclonal Antibodies to Reduce Reperfusion Injury in Myocardial Infarction

Review Article

Abstract

Reperfusion injury is mediated, in part, by the accumulation of platelets and leucocytes in the microvasculature after reflow. These components of the blood pool form aggregates that can obstruct flow in small vessels. In addition, mediators released from leucocytes and platelets further damage the reperfused myocardium. A strategy to limit reperfusion injury exploits the important role of membrane-bound adhesion molecules that attach platelets and leucocytes to themselves and to the vascular endothelium. Monoclonal antibodies against specific adhesion receptors effectively eliminate the function of the receptor. The most widely investigated receptors are P-selectin, present on platelets and the endothelium, CD11/CD18, present on leucocytes, and the fibrinogen receptor on platelets. Numerous animal studies have strongly supported the use of these monoclonal antibodies to block adhesion receptors as adjunctive reperfusion therapy. However, recent human trials have yielded disappointing results.

Keywords

Infarct Size Reperfusion Injury Abciximab Alteplase Left Bundle Branch Block 

References

  1. 1.
    Hill GE. Cardiopulmonary bypass-induced inflammation: is it important? J Cardiothorac Vasc Anesth 1998; 12 (2 Suppl. 1): 21–5PubMedGoogle Scholar
  2. 2.
    Weman SM, Karhunen PJ, Penttila A, et al. Reperfusion injury associated with one-fourth of deaths after coronary artery bypass grafting. Ann Thorac Surg 2000; 70(2): 807–12PubMedCrossRefGoogle Scholar
  3. 3.
    Kloner RA. Does reperfusion injury exist in humans? J Am Coll Cardiol 1993; 21(2): 537–45PubMedCrossRefGoogle Scholar
  4. 4.
    McCord JM. Free radicals and myocardial ischemia: overview and outlook. Free Radic Biol Med 1998; 4: 9–14CrossRefGoogle Scholar
  5. 5.
    Zweier JL, Rayburn BK, Flaherty JT, et al. Recombinant superoxide dismutase reduces oxygen free radical concentrations in reperfused myocardium. J Clin Invest 1987; 80: 1728–34PubMedCrossRefGoogle Scholar
  6. 6.
    Schaper W, Schaper J. Problems associated with reperfusion of ischemic myocardium. Pathophysiol Severe Myocard Injury 1990; 41: 269CrossRefGoogle Scholar
  7. 7.
    Becker LC, Ambrosio G. Myocardial consequences of reperfusion. Prog Cardiovasc Dis 1987; 30: 23–44PubMedCrossRefGoogle Scholar
  8. 8.
    Lucchesi BR, Mullane KM. Leukocytes and ischemia induced myocardial injury. Annu Rev Pharmacol Toxicol 1988; 26: 201–24CrossRefGoogle Scholar
  9. 9.
    Reilly MP, Delanty N, Roy L, et al. Increased formation of the isoprostanes IPF2alpha-I and 8-epi-prostaglandin F2alpha in acute coronary angioplasty: evidence for oxidant stress during coronary reperfusion in humans. Circulation 1997; 96(10): 3314–20PubMedCrossRefGoogle Scholar
  10. 10.
    Ross GD, Vetvicka V. CR3 (CD11b, CD18): a phagocyte and NK cell membrane receptor with multiple ligand specificities and functions. Clin Exp Immunol 1993; 92(2): 181–4PubMedCrossRefGoogle Scholar
  11. 11.
    Simon DI, Chen Z, Xu H, et al. Platelet glycoprotein Ib alpha is a counterreceptor for the leukocyte integrin Mac-1 (CD11b/CD18). J Exp Med 2000; 192(2): 193–240PubMedCrossRefGoogle Scholar
  12. 12.
    De Servi S, Mazzone A, Ricevuti G, et al. Clinical and angiographic correlates of leukocyte activation in unstable angina. J Am Coll Cardiol 1995; 26(5): 1146–50PubMedCrossRefGoogle Scholar
  13. 13.
    Neumann FJ, Ott I, Gawaz M, et al. Cardiac release of cytokines and inflammatory responses in acute myocardial infarction. Circulation 1995; 92(4): 748–55PubMedCrossRefGoogle Scholar
  14. 14.
    Gurbel PA, Kolodgie F, Serebruany V, et al. Myocardial cell injury during ischemia and reflow. In: Bittar E, Bittar N, editors. Principles of medical biology. Stamford, CT: JAI Press, 1998: 127–66Google Scholar
  15. 15.
    Simpson PJ, Todd RD, Fantone JC, et al. Reduction of experimental canine myocardial reperfusion injury by a monoclonal antibody (anti-Mo1, anti-CD11b) that inhibits leukocyte adhesion. J Clin Invest 1988; 81(2): 624–9PubMedCrossRefGoogle Scholar
  16. 16.
    Ma XL, Tsao PS, Lefer AM. Antibody to CD-18 exerts endothelial and cardiac protective effects in myocardial ischemia and reperfusion. J Clin Invest 1991; 88(4): 1237–43PubMedCrossRefGoogle Scholar
  17. 17.
    Dreyer WJ, Michael LH, West MS, et al. Neutrophil accumulation in ischemic canine myocardium. Insights into time course, distribution, and mechanism of localization during early reperfusion. Circulation 1991; 84(1): 400–11PubMedCrossRefGoogle Scholar
  18. 18.
    Arai M, Lefer DJ, So T, et al. An anti-CD 18 antibody limits infarct size and preserves left ventricular function in dogs with ischemia and 48-hour reperfusion. J Am Coll Cardiol 1996; 27(5): 1278–85PubMedCrossRefGoogle Scholar
  19. 19.
    Lefer DJ, Shanelya SM, Serrano Jr CV, et al. Cardioprotective actions of a monoclonal antibody against CD-18 in myocardial ischemia-reperfusion injury. Circulation 1993; 88 (4 Pt 1): 1779–87PubMedCrossRefGoogle Scholar
  20. 20.
    Aversano T, Zhou W, Nedelman M, et al. A chimeric IgG4 monoclonal antibody directed against CD 18 reduces infarct size in a primate model of myocardial ischemia and reperfusion. J Am Coll Cardiol 1995; 25(3): 781–8PubMedCrossRefGoogle Scholar
  21. 21.
    Faxon DP, Gibbons RJ, Chronos NAF, et al. The effect of a CD11/CD18 inhibitor (Hu23F2G) on infarct size following direct angioplasty: the HALT MI study [abstract]. Circulation 1999; 100(18): I–791Google Scholar
  22. 22.
    Baran K. LIMIT AMI trial [oral presentation]. Presented at the Congress of the European Society of Cardiology; 2000 Aug 26-30: San FranciscoGoogle Scholar
  23. 23.
    Pinsky DJ, Naka Y, Liao H, et al. Hypoxia-induced exocytosis of endothelial cell Weibel-Palade bodies. A mechanism for rapid neutrophil recruitment after cardiac preservation. J Clin Invest 1996; 97: 493PubMedCrossRefGoogle Scholar
  24. 24.
    Evangelista V, Manarini S, Sideri R, et al. Platelet/polymorphonuclear leukocyte interaction: P-selectin triggers proteintyrosin phosphorylation-dependent CD11b/CD18 adhesion: role of PSGL-1 as a signaling molecule. Blood 1999; 93(3): 876–85PubMedGoogle Scholar
  25. 25.
    Moore KL, Stults NL, Diaz S, et al. Identification of a specific glycoprotein ligand for P-selectin (CD62) on myeloid cells. J Cell Biol 1992; 118:445–56PubMedCrossRefGoogle Scholar
  26. 26.
    Sako D, Chang XJ, Barone KM, et al. Expression cloning of a functional glycoprotein ligand for P-selectin. Cell 1993; 75: 1179–86PubMedCrossRefGoogle Scholar
  27. 27.
    Austrup F, Vestweber D, Borges E, et al. P- and E-selectin mediate recruitment of T-helper-1 but not T-helper-2 cells into inflamed tissues. Nature 1997; 385(6611): 81–3PubMedCrossRefGoogle Scholar
  28. 28.
    Kitayama J, Fuhlbrigge RC, Puri KD, et al. P-selectin, L-selectin, and alpha 4 integrin have distinct roles in eosinophil tethering and arrest on vascular endothelial cells under physiological flow conditions. J Immunol 1997; 159(8): 3929–39PubMedGoogle Scholar
  29. 29.
    Lim YC, Snapp K, Kansas GS, et al. Important contributions of P-selectin glycoprotein ligand-1-mediated secondary capture to human monocyte adhesion to P-selectin, E-selectin, and TNF-alpha-activated endothelium under flow in vitro. J Immunol 1998; 161(5): 2501–8PubMedGoogle Scholar
  30. 30.
    Massberg S, Enders G, Leiderer R, et al. Platelet-endothelial cell interactions during ischemia/reperfusion: the role of P-selectin. Blood 1998; 92(2): 507–15PubMedGoogle Scholar
  31. 31.
    Lefer AM, Campbell B, Scalia R, et al. Synergism between platelets and neutrophils in provoking cardiac dysfunction after ischemia and reperfusion: role of selectins. Circulation 1998; 98(13): 1322–8PubMedCrossRefGoogle Scholar
  32. 32.
    Kubes P, Jutila M, Payne D. Therapeutic potential of inhibiting leukocyte rolling in ischemia/reperfusion. J Clin Invest 1995; 95(6): 2510–9PubMedCrossRefGoogle Scholar
  33. 33.
    Minamino T, Kitakaze M, Asanuma H, et al. Endogenous adenosine inhibits P-selectin-dependent formation of coronary thromboemboli during hypoperfusion in dogs. J Clin Invest 1998; 101(8): 1643–53PubMedCrossRefGoogle Scholar
  34. 34.
    Park IY, Lee DS, Song MH, et al. Cylexin: a P-selectin inhibitor prolongs heart allograft survival in hypersensitized rat recipients. Transplant Proc 1998; 30(7): 2927–8PubMedCrossRefGoogle Scholar
  35. 35.
    Nagashima M, Shin’oka T, Nollert G, et al. Effects of a monoclonal antibody to P-selectin on recovery of neonatal lamb hearts after cold cardioplegic ischemia. Circulation 1998; 98 (19 Suppl.): II391–7, discussion II397-8PubMedGoogle Scholar
  36. 36.
    Arai M, Masui Y, Goldschmidt-Clermont P, et al. P-selectin inhibition prevents early neutrophil activation but provides only modest protection against myocardial injury in dogs with ischemia and forty-eight hours reperfusion. J Am Coll Cardiol 1999; (34) 1:280–8CrossRefGoogle Scholar
  37. 37.
    Weyrich AS, Ma XY, Lefer DJ, et al. In vivo neutralization of P-selectin protects feline heart and endothelium in myocardial ischemia and reperfusion injury. J Clin Invest 1993; 91(6): 2620–9PubMedCrossRefGoogle Scholar
  38. 38.
    Kumar A, Villani MP, Keith Jr JC, et al. Recombinant soluble form of PSGL-1 accelerates thrombolysis and prevents reocclusion in a porcine model. Circulation 1999; 99(10): 1363–9PubMedCrossRefGoogle Scholar
  39. 39.
    He XY, Xu Z, Melrose J, et al. Humanization and pharmacokinetics of a monoclonal antibody with specificity for both E-and P-selectin. J Immunol 1998; 160(2): 1029–35PubMedGoogle Scholar
  40. 40.
    Altavilla D, Squadrito F, Ioculano M, et al. E-selectin in the pathogenesis of experimental myocardial ischemia-reperfusion injury. Eur J Pharmacol 1994; 270(1): 45–51PubMedGoogle Scholar
  41. 41.
    Coller BS. Binding of abciximab to alphaVbeta3 and activated alphaMbeta2 receptors: with a review of platelet-leukocyte interaction. Thromb Haemost 1999; 82(2): 326–36PubMedGoogle Scholar
  42. 42.
    Neumann FJ, Blasini R, Schmitt C, et al. Effect of glycoprotein IIb/IIIa receptor blockade on recovery of coronary flow and left ventricular function after the placement of coronary-artery stents in acute myocardial infarction. Circulation 1998; 98(24): 2695–701PubMedCrossRefGoogle Scholar
  43. 43.
    Coller BS. Potential non-glycoprotein IIb/IIIa effects of abciximab. Am Heart J 1999; 138 (1 Pt 2): S1–5PubMedCrossRefGoogle Scholar
  44. 44.
    Neumann FJ, Zohlnhofer D, Fakhoury L, et al. Effect of glycoprotein IIb/IIIa receptor blockade on platelet-leukocyte interaction and surface expression of the leukocyte integrin Mac-1 in acute myocardial infarction. J Am Coll Cardiol 1999; 34(5): 1420–6PubMedCrossRefGoogle Scholar
  45. 45.
    Mickelson J, Ali N, Kleiman NS, et al. Chimeric 7E3 Fab (ReoPro) decreases detectable CD11b on neutrophils from patients undergoing coronary angioplasty. J Am Coll Cardiol 1999; 33(1): 97–106PubMedCrossRefGoogle Scholar
  46. 46.
    Campbell B, Chuhran CM, Lefer DJ, et al. Cardioprotective effects of abciximab (ReoPro) in an isolated perfused rat heart model of ischemia and reperfusion. Methods Find Exp Clin Pharmacol 1999; 21(8): 529–34PubMedCrossRefGoogle Scholar
  47. 47.
    Murohara T, Delyani JA, Albelda SM, et al. Blockade of platelet endothelial cell adhesion molecule-1 protects against myocardial ischemia and reperfusion injury in cats. J Immunol 1996; 15(6): 3550–7Google Scholar
  48. 48.
    Buerke M, Weyrich AS, Zheng Z, et al. Sialyl Lewisx-containing oligosaccharide attenuates myocardial reperfusion injury in cats. J Clin Invest 1994; 93(3): 1140–8PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2001

Authors and Affiliations

  1. 1.Sinai Center for Thrombosis ResearchBaltimoreUSA

Personalised recommendations