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Updated: Oct 2, 2026
Murine Cervical Heart Transplantation Model Using a Modified Cuff Technique
Published on: October 12, 2014
Prolonging organ allograft survival: potential role of nitric oxide scavengers
Galen M Pieper1, Ashwani K Khanna, Allan M Roza
1Division of Transplant Surgery, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA. gmpieper@mcw.edu
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).
Insights
New metal-based nitric oxide (NO) scavengers show promise in preventing organ transplant rejection by neutralizing excess NO. These compounds may enhance graft survival, even with reduced immunosuppression.
Area of Science:
- Immunology
- Transplantation Biology
- Biochemistry
Background:
- Inducible nitric oxide synthase (iNOS) produces nitric oxide (NO), a key mediator in acute organ transplant rejection.
- NO can lead to protein nitrosylation/nitration, enzyme dysfunction, and apoptosis, contributing to graft failure.
- Gene expression of iNOS and nitrotyrosine are found in human graft biopsies, confirming NO's role.
Purpose of the Study:
- To review evidence for novel NO scavengers/neutralizers as an alternative strategy to iNOS inhibitors for preventing transplant rejection.
- To evaluate the potential of these agents to prolong allograft survival by scavenging excess NO.
- To explore the immunosuppressive and anti-inflammatory properties of these NO-scavenging compounds.
Main Methods:
- Review of recent laboratory evidence on metal-based NO scavenging compounds.
- Assessment of effects on cardiac allograft survival in experimental models.
- Evaluation of synergistic effects with low-dose cyclosporin.
- Analysis of anti-inflammatory and immunosuppressive mechanisms, including effects on cell infiltration, NF-kappaB activation, cyclin D3 expression, and autoimmune responses.
Main Results:
- Metal-based NO scavengers enhanced cardiac allograft survival without immunosuppression.
- Combination therapy with low-dose cyclosporin showed synergistic effects, leading to prolonged or permanent graft survival.
- These compounds demonstrated in vivo immunosuppressive and anti-inflammatory activities.
- Mechanisms included attenuated cell infiltration, NF-kappaB activation, cyclin D3 expression, and autoimmune responses.
Conclusions:
- Experimental NO scavengers represent a promising therapeutic strategy to mitigate organ transplant rejection.
- These agents offer a potential alternative or adjunct to traditional immunosuppression.
- The observed anti-inflammatory and immunosuppressive properties contribute to enhanced graft survival.
