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Ann Thorac Surg 2001;71:629-630
© 2001 The Society of Thoracic Surgeons

Invited commentary

^a Division of Cardiothoracic Surgery, Box 356310, University of Washington, Seattle, WA 98195, USA

Organ preservation during transplantation provides a unique and potentially effective method for the use of viral vectors to attenuate reperfusion injury. Sakaguchi and coworkers have used a liposomal viral vector to target a specific cellular transcription factor, nuclear factor–kappa B (NF–B). NF–B is a central mediator in signal transduction pathways for inflammatory and hypoxic stress. Numerous investigators have demonstrated that blocking NF–B favorably modulates ischemia–reperfusion injury. Hypothermia and circulatory arrest, both associated with organ preservation, may present a novel opportunity to block this central transcription factor using viral vectors.

There are some difficulties with the use of viral vectors related to transfection efficiency, duration of activity and long term effects. The authors demonstrate transfection of the endothelial cell, a key cellular mediator of reperfusion injury, at 16 hours. What percentage of the total number of endothelial cells were transfected? Most investigators report transfection in 1–7% of target cells using liposomes. Although the efficiency of transfection is poor, these vectors are potentially safer than their adenoviral counterparts and they may not require high transfection rates to demonstrate clinical effects. Viral incorporation into donor endothelial cells was evident at 16 hours, but were any of the liposomes effectively transfected at clinically relavant intervals (2–8 hours)? Liposomes diffuse across the cell membrane and therefore their cellular uptake is facilitated by the ample time provided at the cell surface by the non–circulating preservation solution. Despite this potentially ideal situation, liposomes may not be efficiently transfected during donor organ preservation for cardiac transplantation.

The authors present convincing physiologic and biochemical evidence that cardiac function is better preserved with the NF–B decoy at one hour of reperfusion. This preservation of cardiac function probably reflects the effects of the decoy on the promoter sequence during the hypothermic period. The production of downstream effectors, like IL–8 and ICAM–1, requires transcription of DNA and subsequent translation of protein. This process takes several hours and is most convincingly linked to reperfusion and not hypoxia alone. Therefore, the effects of NF–B blockade may be even more dramatic later during reperfusion.

The short–term clinical sequelae of NF-B blockade are clinically unknown but of potential concern since NF–B is a very ubiquitous transcription factor not only modulating inflammatory processes but many other critical immunologic processes. The long–term sequelae of NF–B blockade are also unknown. Because this protein is a central transcription factor for inflammatory stress, long term blockade may impair the host’s ability to fight infection. Aternatively, NF–B blockade may diminish the severity and onset of rejection episodes or more likely the late sequelae of transplant vasculopathy. Recent evidence suggests that NF–B is not only associated with a proinflammatory cellular phenotype, but that in certain circumstances it also results in cytoprotection. The cytoprotective effects of NF–B have been convincingly linked to ischemic preconditioning, where activation of this transcription factor results in the expression of proteins that protect the cells from further ischemic damage. Further research into non–specific NF–B blockade will need to consider the breadth of activity mediated by this critical central transcription factor.

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A novel strategy of decoy transfection against nuclear factor-B in myocardial preservation

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Ann. Thorac. Surg. 2001 71: 624-629. [Abstract] [Full Text] [PDF]

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This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Edward D. Verrier Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Krishnadasan, B. Articles by Verrier, E. D. Search for Related Content PubMed Articles by Krishnadasan, B. Articles by Verrier, E. D. Related Collections Myocardial protection Related Article