NOX 100, a nitric oxide scavenger, enhances cardiac allograft survival and promotes long-term graft acceptance. Transplantation 2000 Jan 27;69(2):227-31
Date
02/12/2000Pubmed ID
10670631DOI
10.1097/00007890-200001270-00006Scopus ID
2-s2.0-0034719350 (requires institutional sign-in at Scopus site) 44 CitationsAbstract
BACKGROUND: We examined the role of nitrosative stress in allograft destruction.
METHODS: Rats undergoing cardiac transplants received NOX-100, a water-soluble nitric oxide (NO) scavenger with antioxidant properties, with or without low-dose cyclosporine (CsA). Graft survival, NO production, and nuclear factor kappa B (NF-kappaB) activity were studied.
RESULT: Using NOX-100 daily until rejection prolonged graft survival (11.6+/-0.6 vs. 7.4+/-0.2 days; P<0.05). Daily low-dose CsA (2.5 mg/kg im) for 7 days or until rejection also prolonged survival (12.6+/-0.5 and 21.6+/-1.6 days, respectively; P<0.01 vs. Controls). Low-dose CsA for 7 days and NOX-100 for 30 days prolonged graft survival (45.0+/-4.7 days; P<0.01 vs. all groups.). NOX-100 had no effect on whole blood CsA levels. Combination therapy until Day 100 resulted in 1 graft loss at Day 116 and indefinite survival in 3 animals (>300 days), which accepted a second WF strain heart without further immunosuppressive therapy but promptly rejected a third party (ACI) cardiac allograft. NOX-100 and CsA reduced nitrate and nitrite, and combination therapy completely normalized NO through to Day 30. Electron paramagnetic resonance spectroscopic analysis demonstrated reduction of signals for nitrosylmyoglobin and nitrosyl-heme with NOX-100 and elimination of signals with CsA alone or combination therapy. Activity of myocardial NF-kappaB decreased with monotherapy vs. untreated allografts. Combination therapy resulted in further inhibition of NF-kappaB up to Day 30. The extent of graft survival correlated with the extent of NO scavenging and NF-kappaB inhibition. Short-term combination therapy had no effect on graft lymphocytic infiltrate on Days 15, 20, and 30.
CONCLUSION: These data support a role for both oxidative and nitrosative stress in rejection and the immunoregulatory potential of antioxidant therapy after transplantation.
Author List
Roza AM, Cooper M, Pieper G, Hilton G, Dembny K, Lai CS, Lindholm P, Komorowski R, Felix C, Johnson C, Adams MAuthor
Matthew Cooper MD Chief, Director, Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBiopsy
Cyclosporine
Free Radical Scavengers
Graft Survival
Heart Transplantation
Myocardium
NF-kappa B
Nitric Oxide
Rats
Rats, Inbred Lew
Rats, Inbred WF
Sorbitol
