Prolonging organ allograft survival: potential role of nitric oxide scavengers.

Abstract

A growing number of studies suggest a key role of nitric oxide (NO) derived from the inducible NO synthase (iNOS) isoform as a signalling molecule leading to acute organ transplant rejection. Current theory suggests that NO targets certain tissue proteins for nitrosylation or nitration leading to inhibition of enzyme/protein function and to cell death via apoptosis. Gene expression of iNOS and formation of nitrotyrosine residues have been confirmed in biopsies of rejecting grafts in humans. Experimental attempts to delay graft rejection by treatment with iNOS enzyme inhibitors have yielded conflicting results. An alternative strategy to alter rejection mediated by NO is to scavenge and/or neutralise the actions of excess NO, thereby by-passing the inhibition of iNOS enzyme activity. This review summarises recent laboratory evidence that new experimental NO scavengers/neutralisers have potential value to prolong graft survival. To date, various metal-based NO scavenging/neutralising compounds have been shown to enhance cardiac allograft survival in the absence of immunosuppression. When used in combination with low-dose cyclosporin, these agents produce a synergistic action to enhance graft survival or even to produce "permanent graft survival" under certain prolonged drug regimens. A portion of this benefit may be accounted for by the property of some of these compounds to display immunosuppressant and anti-inflammatory activity in vivo. These properties are based on findings including the following: (i) attenuating cell infiltration into the graft; (ii) attenuating activation of NFkappaB (a transcription factor important for upregulation of various inflammatory genes); (iii) attenuating cyclin D3 gene expression (a marker of cell proliferation; (iv) antagonising autoimmune activation (as determined by attenuated cytokine gene expression in splenocytes isolated from treated animals but stimulated for several days ex vivo in mixed lymphocyte cultures).