Nox 100, a Nitric Oxide Scavenger, Enhances Cardiac Allograft Survival and Promotes Long-Term Graft Acceptance 1

Roza, Allan M.; Cooper, Matthew M.; Pieper, Galen M.; Hilton, Gail; Dembny, Ken; Lai, Ching San; Lindholm, Paul F.; Komorowski, Richard; Felix, Christopher C.; Johnson, Christopher P.; Adams, Mark B.

doi:10.1097/00007890-200001270-00006

Cited by 46 publications

(34 citation statements)

References 20 publications

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“…The EPR signals in red blood cells and grafts were attributable to immune activation as they were absent in cardiac isografts and blocked by treatment of allograft recipients with FK506. Similar conclusions were obtained using cyclosporine [50].…”

Section: No Interaction With Metalloproteins In Cardiac Rejectionsupporting

confidence: 85%

“…In combination with low-dose cyclosporine, both agents dramatically improved graft survival beyond that achieved by either agent used alone. In addition, in a long-term combination treatment strategy, retransplantation of a 2 nd donor heart several weeks after cessation of treatment resulted in permanent graft acceptance [50]. This finding suggests latent drug-induced effects of alloimmune activation.…”

Section: Evidence Using No Neutralizing Agentsmentioning

confidence: 93%

“…These studies were followed by evaluation of two related compounds, NOX-100 and NOX-700 developed by Medinox, Inc., San Diego, CA. These compounds were shown to be able to scavenge NO in vivo and to significantly improve graft survival [50][51][52]. In combination with low-dose cyclosporine, both agents dramatically improved graft survival beyond that achieved by either agent used alone.…”

Section: Evidence Using No Neutralizing Agentsmentioning

confidence: 99%

“…This notion should be a consideration for understanding a role of NO in acute allograft rejection. Traditional measurements in a plethora of studies of experimental cardiac transplant rejection have shown increased levels of plasma or serum or urinary NO metabolites, nitrate plus nitrite [35,37,50]. The fact that these NO metabolites were increased in allografts but not isografts excludes any increases due to complications of surgery.…”

Section: Issues Of Inos Expression Vs Inos-derived No Bioactivitymentioning

confidence: 99%

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The complex role of iNOS in acutely rejecting cardiac transplants

Pieper

Roza

2008

Free Radical Biology and Medicine

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This review summarizes the evidence for a detrimental role of nitric oxide (NO) derived from inducible NO synthase (iNOS) and/or reactive nitrogen species such as peroxynitrite in acutelyrejecting cardiac transplants. In chronic cardiac transplant rejection, iNOS may have an opposing beneficial component. The purpose of this review is primarily to address issues related to acute rejection which is a recognized risk factor for chronic rejection. The evidence for a detrimental role is based upon strategies involving non-selective NOS inhibitors, NO neutralizers, selective iNOS inhibitors and iNOS gene deletion in rodent models of cardiac rejection. The review is discussed in the context of the impact on various components including graft survival, histological rejection and cardiac function which may contribute in toto to the process of graft rejection. Possible limitations of each strategy are discussed in order to understand better the variance in published findings including issues related to the potential importance of cell localization of iNOS expression. Finally, the concept of a dual role of NO and its down-stream product, peroxynitrite, in rejection vs. immune regulation is discussed.

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Section: No Interaction With Metalloproteins In Cardiac Rejectionsupporting

confidence: 85%

Section: Evidence Using No Neutralizing Agentsmentioning

confidence: 93%

Section: Evidence Using No Neutralizing Agentsmentioning

confidence: 99%

Section: Issues Of Inos Expression Vs Inos-derived No Bioactivitymentioning

confidence: 99%

See 2 more Smart Citations

The complex role of iNOS in acutely rejecting cardiac transplants

Pieper

Roza

2008

Free Radical Biology and Medicine

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“…Also in a rat renal transplant model, liposomal clodronate administration 1 d posttransplantation, which depletes the majority of MΦ, reduces allograft damage (Jose et al, 2003), although liposomal clodronate also depletes other subsets of monocytes and DC thus complicating interpretation of the data. The production of iNOS in particular seems important for allograft rejection, as its neutralization prolongs cardiac allograft survival in mice (Roza et al, 2000;Worrall et al, 1995).…”

Section: Ischemia-reperfusion Injurymentioning

confidence: 99%

Cell-Based Therapies in the Prevention of Solid Organ Transplant Rejection

Morelli¹,

Divito²

2012

American Journal of Immunology

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Problem statement:Organ transplantation is a life-saving and increasingly common procedure, as it often serves as the only treatment available for end-stage organ disease. Although the constant development of new and more effective immunosuppressive drugs has revolutionized the prevention and treatment of acute graft rejection, these drugs have significant toxicity, greatly increase patient susceptibility to neoplasms and infection and exert little impact on chronic rejection. Approach: The literature was reviewed to illuminate the mechanisms by which the anti-donor immune response is initiated and how cellular therapies impact this response. Results: Data show that Donor Specific Transfusion, Apoptotic Cell therapies and Dendritic Cell therapies all function as a source of alloantigen to suppress the anti-donor T cell response. Conclusion: Cellular therapies hold promise in the prevention of solid organ allograft rejection, but require optimization and study in large animal models before clinical implementation.

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Nitrogen Monoxide (Nitric Oxide): Bioinorganic Chemistry

Fricker¹

2019

Encyclopedia of Inorganic and Bioinorganic Chemistry

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The discovery of nitrogen monoxide (nitric oxide, NO) as the vasodilator molecule endothelium‐derived relaxing factor revealed a major physiological role for this simple diatomic molecule. We now know that NO regulates cardiovascular function, is a neurotransmitter, and is a component of the innate immune response to infection and cancer. The physiological effects of NO are mediated by its varied chemistry which includes redox chemistry and interaction with transition metals. NO can interact with iron‐heme‐containing proteins including hemoglobin and cytochrome c oxidase, and nonheme iron proteins such as aconitase and bacterial transcription regulatory proteins. NO reacts with superoxide to form the highly reactive peroxynitrite which decomposes to give the hydroxyl radical. Nitrosothiols, thiol adducts of NO, act to control NO release, and to shuttle NO between proteins and transport NO across cell membranes. NO is produced by one of three nitric oxide synthase (NOS) enzymes, endothelial NOS, neuronal NOS, and inducible NOS. Signaling functions are mediated via interaction with the heme‐containing protein soluble guanylate cyclase (GC), which produces the cell signaling molecule cyclic guanosine monophosphate (cGMP). This, in turn, is hydrolyzed by phosphodiesterase 5 (PDE5), which turns off NO signaling. Perturbation in NO function contributes to the pathophysiology of many disease states. Endothelial dysfunction and subsequent reduced NO production contribute to hypertension and atherosclerosis. Excess NO is a mediator of inflammatory disease, and neurodegenerative disease, due in part to the production of peroxynitrite. The cardiovascular collapse observed in septic shock is caused by the vasodilator action of NO. Targeting the NO pathway theoretically provides many opportunities for therapeutic intervention. The NO donor drugs glyceryl trinitrate, isosorbide mononitrate, isosorbide dinitrate, and amyl nitrate are used to treat acute angina; and inhaled NO is used to treat persistent pulmonary hypertension in new born infants. Conversely, NOS inhibitors and NO scavengers have been explored to counteract NO as a mediator of disease. Though promising results have been obtained in animal models of disease these latter approaches have had little clinical success. However, targeting downstream of NO has been more successful with new clinically approved classes of drugs such as the inhibitors of PDE5 sildenafil, tadalafil, and vardenafil; and the stimulator of the NO receptor soluble GC, riociguat. It has become apparent that the biological actions, and biological chemistry, of NO are very complex. New opportunities for drug discovery could result from an improved understanding of the biology of NO.

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Nox 100, a Nitric Oxide Scavenger, Enhances Cardiac Allograft Survival and Promotes Long-Term Graft Acceptance 1

Abstract: These data support a role for both oxidative and nitrosative stress in rejection and the immunoregulatory potential of antioxidant therapy after transplantation.

Cited by 46 publications

References 20 publications

The complex role of iNOS in acutely rejecting cardiac transplants

The complex role of iNOS in acutely rejecting cardiac transplants

Cell-Based Therapies in the Prevention of Solid Organ Transplant Rejection

Nitrogen Monoxide (Nitric Oxide): Bioinorganic Chemistry

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