Ann Thorac Surg 2002;74:2070-2071
© 2002 The Society of Thoracic Surgeons
Original article: cardiovascular
Invited Commentary
Yoshifumi Naka, MD, PhDa
a Division of Cardiothoracic Surgery, Department of Surgery, New York Presbyterian Hospital, Columbia Presbyterian Center, MHB 7-435, 177 Fort Washington Avenue, New York, NY 10032, USA
e-mail: yn33{at}columbia.edu
There have been numerous papers addressing the positive correlation between neutrophil infiltration and post ischemia-reperfusion tissue/organ injury. Neutrophil is rolling and decelerated by the selectins, trapped on the endothelium by the integrins and egress through the endothelium that is being helped by other adhesion molecules. P-selectin, preformed and stored in the endothelial subplasmalemmal storage sites, is exposed to the blood stream by rapid exocytosis of the Weibel–Palade body upon the reperfusion after a period of ischemia. P-selectin is also expressed on the endothelium even during a period of hypothermic preservation. These characteristics of P-selectin cause rapid leukostasis in reperfused organs and subsequent dysfunction [1]. On the other hand, E- and L-selectins require de novo protein synthesis, including the transcription of mRNA and translation to protein production (proteome) as seen in ICAM-1 activation and leukostasis in reperfused organs [2]. The transcription of mRNA may be upregulated even during hypothermic preservation which primes exaggerated proteome upon reperfusion, resulting in leukostasis and tissue/organ damage. This feature can be attenuated by suppressing transcription and/or proteome during periods of preservation and/or reperfusion [3].
The study by Dr Carter and colleagues has assessed the effect of a unique monoclonal antibody given locally in the coronary to block both E- and L-selectin on neutrophil infiltration after a period of hypothermic global ischemia during cardiac transplantation. The authors demonstrate that the posttransplant neutrophil infiltration into the allografts was reduced by the intracoronary administration of the blocking monoclonal antibody given immediately prior to reperfusion, and conclude that prohibiting neutrophil-endothelial adhesion and transmission may be useful by decreasing neutrophil dependent postreperfusion injury in both transplantation and routine cardiac surgery.
As mentioned above, it is critical that the antibody should be administered to the milieu in an appropriate timing to block the interaction between neutrophils and the endothelium. E-selectin may be already primed during the ischemic period (upregulated mRNA transcription) and rapidly produced upon the reperfusion. The paper lacks data regarding the time course of E-selectin mRNA transcription, subsequent proteome, and expression on the endothelium. Such data can be evaluated by Northern and Western plotting, in situ hybridization, immunostaining, etc. The paper simply demonstrates that a bolus of a small amount of the blocking antibody reduces leukostasis in the allografts at 24 hours after reperfusion. To achieve the maximal blocking effect with the minimal dose, it is essential to know the best timing to give the antibody. There is also lack of insight into the mechanism whereby the antibody attenuates organ damage. The paper simply demonstrates the entrance and exit of the black box, which is the significant attenuation of neutrophil infiltration into the allograft 24 hours after transplantation by a monoclonal antibody to block E- and L-selectins. No evidence of impaired allograft function is shown.
Nevertheless, these authors convincingly demonstrate the attenuation of neutrophil infiltration by simply giving a monoclonal antibody into the coronary artery immediately prior to reperfusion of the preserved allografts. They importantly open a potential and promising therapeutic option to treat primary cardiac allograft failure, as well as to improve routine cardiac surgery. Further investigations are required to warrant this therapy.
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- Pinsky D.J., Naka Y., Liao H., Oz M.C., Wagner D.D., Tanya N.M., Johnson R.C., Heath M., Lawson C.A., Stern D.S. Hypoxia-induced exocytosis of endothelial cell Weibel–Palade bodies: A, mechanism for rapid neutrophil recruitment following cardiac preservation. J Clin Invest 1996;97:493-500.[Medline]
- Toda K., Naka Y., Kayano K., Karimova A., Wang C.Y., Pinsky D.J. Antisense intracellular adhesion molecule 1 (ICAM-1) oligodeoxyribonucleotides delivered during organ preservation inhibits posttransplant ICAM-1 expression and reduces primary lung isograft failure. Circ Res 2000;86:166-174.[Abstract/Free Full Text]
- Minamoto K., Pinsky D.J., Fujita T., Naka Y. Timing of nitric oxide donor supplementation determines endothelin-1 regulation and quality of lung preservation for transplantation. Am J Respir Cell Mol Biol 2002;26:14-21.[Abstract/Free Full Text]
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