FK330, a Novel Inducible Nitric Oxide Synthase Inhibitor, Prevents Ischemia and Reperfusion Injury in Rat Liver Transplantation

• Published in: American journal of transplantation Vol. 6; no. 9; pp. 2013 - 2022
• Main Authors: Tsuchihashi, S., Kaldas, F., Chida, N., Sudo, Y., Tamura, K., Zhai, Y., Qiao, B., Busuttil, R. W., Kupiec‐Weglinski, J. W.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.09.2006; Blackwell
• Subjects: Animals; Apoptosis - drug effects; Biological and medical sciences; Blotting, Western; Cytokines - metabolism; Enzyme Inhibitors - pharmacology; Graft Survival - drug effects; Immunoenzyme Techniques; Ischemia/reperfusion; liver; Liver - drug effects; Liver Transplantation; Male; Medical sciences; nitric oxide; Nitric Oxide Synthase Type II - antagonists & inhibitors; Piperidines - pharmacology; Rats; Rats, Sprague-Dawley; Reperfusion Injury - prevention & control; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Survival Rate; transplant; Graft(material); Rat; Digestive system; Nitric oxide synthase inhibitor; Liver; Ischemia reperfusion; Rodentia; Transplantation; Homotransplantation; Ischemia/reperfusion; Prevention; Vertebrata; Mammalia; Reperfusion; Treatment; Surgery; Animal; Nitric oxide; Graft; transplant
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/j.1600-6143.2006.01435.x

Nitric oxide (NO), produced via inducible NO synthase (iNOS), is implicated in the pathophysiology of liver ischemia/reperfusion injury (IRI). We examined the effects of a novel iNOS inhibitor, FK330 (FR260330), in well‐defined rat liver IRI models. In a model of liver cold ischemia followed by ex vivo reperfusion, treatment with FK330 improved portal venous flow, increased bile production and decreased hepatocellular damage. FK330 prevented IRI in rat model of 40‐h cold ischemia followed by syngeneic orthotopic liver transplantation (OLT), as evidenced by: (1) increased OLT survival (from 20% to 80%); (2) decreased hepatocellular damage (serum glutamic oxaloacetic transaminase/glutamic pyruvic transaminase levels); (3) improved histological features of IRI; (4) reduced intrahepatic leukocyte infiltration, as evidenced by decreased expression of P‐selectin/intracellular adhesion molecule 1, ED‐1/CD3 cells and neutrophils; (5) depressed lymphocyte activation, as evidenced by expression of pro‐inflammatory cytokine (TNF‐α, IL‐1β, IL‐6) and chemokine (IP‐10, MCP‐1, MIP‐2) programs; (6) prevented hepatic apoptosis and down‐regulated Bax/Bcl‐2 ratio. Thus, by modulating leukocyte trafficking and cell activation patterns, treatment of rats with FK330, a specific iNOS inhibitor, prevented liver IRI. These results provide the rationale for novel therapeutic approaches to maximize organ donor pool through the safer use of liver grafts despite prolonged periods of cold ischemia. Treatment of rats with FK330, a specific inhibitor of inducible nitric oxide synthase, resulted in a number of improved measurements of early and late liver transplant outcomes, with decreases in lymphocyte activation and inflammation markers.