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PERSPECTIVES |
Medical Faculty of the Charité, Franz Volhard Clinic HELIOS Klinikum-Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany
Email: luft{at}fvk-berlin.de
The so-called ‘reperfusion injury’ continues to dog students of shock, acute renal failure, acute coronary syndromes and transplantation medicine. In these conditions, a marked but transient diminution of blood supply sets off a train of events resulting in severe organ damage. The consequences may be long term despite complete recovery of blood flow. Thus, renal transplants with delayed function attributable to reperfusion injury have a much worse long-term result compared to organs that function immediately. The mechanisms appear to be initiated at the blood vessel surface, namely the interface between the flowing blood and the capillary endothelium. The processes responsible for reperfusion injury are too numerous to be discussed in detail here and largely still unknown. Suffice it to say, the local production of reactive oxygen species is a common feature that is associated with leucocyte infiltration into capillaries resulting in a subsequent inflammation and apoptosis.
The leucocytes receive their marching orders through a highly regulated chain of cell surface adhesion signalling molecules. The selectins mediate the rolling of leucocytes on activated endothelial cells through the recognition of the carbohydrate epitope sialyl Lewis(x) (Kaila & Thomas, 2002). E-selectin is synthesized after stimulation by cytokines such as tumour necrosis factor-
and interleukin-1 or by histamine and thrombin. P-selectin is constitutively present on granule membranes in endothelial cells and platelets. The selectin targets are neutrophils and monocytes. The counter-receptors on leucocytes are carbohydrate structures on membrane glycoproteins. Firm leucocyte adhesion is mediated by immunoglobulin gene superfamily receptors. The ß2 integrins share a common ß chain and three distinct chains. Their surface expression is increased by TNF- and after binding to E-selectin. Particularly important for firm adhesion and transmigration are LFA-1, binding partner for ICAM-1 and ICAM-2, and the very late antigen-2 (VLA-4), the binding partner of VCAM-1 (Frijns & Kappelle, 2002). Five molecules expressed by endothelial cells are pivotal to adherence, namely the intercellular adhesion molecules-1 and 2 (ICAM-1 and ICAM-2), the vascular cell adhesion molecule-1 (VCAM-1), platelet-endothelial cell adhesion molecule-1 (PECAM-1) and the mucosal addressin (MAdCAM-1). These cell adhesion molecules (CAMs) cause a stronger attachment to the endothelium than do the selectins.
Interfering with CAMs might be a successful strategy to ameliorate or avoid reperfusion injury. In a paper in this issue of The Journal of Physiology, Kiew et al. (2004) used an antisense oligodeoxynucleotide (ODN) for ICAM-1. Rats were exposed to a 30 min renal artery occlusion. The ischaemic insult decreased renal blood flow and glomerular filtration rate (GFR) in the control groups. The control groups also exhibited a marked increase in sodium and water excretion, compared to the antisense group. In the antisense group ICAM-1 levels were reduced, particularly in the medullary area of the kidney. The ischaemic changes were also markedly reduced. The authors' findings support earlier observations indicating that ICAM-1 antisense can ameliorate acute renal reperfusion injury in the renal artery occlusion model (Haller et al. 1996). New in their study is the role of ICAM-1 in the medullary area of the kidney. Presumably, the extremely hypoxaemic capillaries here are exquisitely sensitive to reperfusion injury, a state of affairs recognized clinically over 50 years ago and termed ‘lower nephron nephrosis’. Alwall (1950) was one of the first to employ acute haemodialysis in patients whom he diagnosed as having lower nephron nephrosis. The treatment of acute renal failure beyond technical improvements has changed little since Alwall's time. What Alwall (1950) might have preferred is a method to avoid renal failure.
Antisense technology is moving into the clinical arena. AIDS-related cytomegalovirus retinitis, inflammatory bowel disease, and cancer are three examples (Holmlund, 2003). However, antisense ODN delivery continues to be a major problem. Efficacy in human trials has not yet been shown (Yacyshyn et al. 2002). Intact ODNs must bypass membrane barriers and access the cytosol and nucleus to be effective. Kiew et al. (2004) and we (Haller et al. 1996) used lipofectin in rat studies. However, for humans, more efficient delivery strategies are necessary. Even if the ODNs penetrate the cell membrane, they may not be effective because of compartmentalization within vesicles.
Recently, Mathew et al. (2003) reported on a liposome-based formulation utilizing listeriolysin O, the endosomolytic haemolysin from Listeria monocytogenes, to mediate ODN escape from endocytic cellular compartments to the cytosol. The investigators used as their target protein murine ICAM-1. The listeriolysin greatly facilitated the antisense effect. Finally, antisense is not the only technique to block the action of mRNA. Post-transcriptional gene silencing via RNA interference is a powerful tool to silence gene expression. The interference is triggered by the introduction of small double-stranded RNA into mammalian cells as a tool to knock down gene expression in a specific fashion. The technology clearly has pharmaceutical prospects (Schiffelers et al. 2004). CAMs will be important therapeutic targets for many human diseases.
References
Alwall N (1950). Acta Med Scand Suppl 239, 33–34.[Medline]
Frijns CJM & Kappelle LJ (2002). Stroke 33, 2115–2122.
Haller H, Dragun D, Miethke A, Park JK, Weiss A, Lippoldt A, Groß V & Luft FC (1996). Kidney Int 50, 473–480.[Medline]
Holmlund JT (2003). Ann N Y Acad Sci 1002, 244–251.
Kaila N & Thomas BE IV (2002). Med Res Rev 22, 566–601.[CrossRef][Medline]
Kiew LV, Munavvar AS, Law CH, Nor Azizan A, Nazarina AR, Sidik K & Johns EJ (2004). J Physiol 557, 981–989.
Mathew E, Hardee GE, Bennett CF & Lee KD (2003). Gene Ther 10, 1105–1115.[CrossRef][Medline]
Schiffelers RM, Woodle MC & Scaria P (2004). Pharm Res 21, 1–7.[CrossRef][Medline]
Yacyshyn BR, Chey WY, Goff J, Salzberg B, Baerg R, Buchman AL, Tami J, YuR.Gibiansky E, Shanahan WR; ISIS 2302-CS9 Investigators (2002). Gut 51, 30–36.
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