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

Abstract

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-a , IL-1b , 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.

Grape seed extract treatment reduces hepatic ischemia‐reperfusion injury in rats

“…In the study of Hato et al (2001) neutrophil accumulation and the content of cytokines, including TNF-α and IL-1β, were increased in the reperfused liver. Similarly, Tsuchihashi et al (2006) who studied the role of cytokines in I/R injury of the liver tissue, suggested that I/R led to the expression of TNF-α, IL-1β, IL-6 in the reperfused rat liver model, and the expressed cytokines are expected to aggravate I/R injury. In accordance with these findings, in the present study, the plasma levels of the pro-inflammatory cytokines TNF-α, and IL-1β, were significantly elevated in I/Rinduced hepatic injury, which was verified using both biochemical and histological assessments.…”

Molecular Mediators of Liver Ischemia and Reperfusion Injury: A Brief Review

“…Inhibition of iNOS may exert beneficial biological effects. Indeed, use of iNOS inhibitors, such as FK330 (FR260330), reduced leukocyte activation, hepatic apoptosis, and overall liver IRI in a rat liver transplant model (58). Another iNOS inhibitor, ONO-1714, similarly attenuated liver IRI (59).…”

Effects of Methylprednisolone and Its Liver-Targeted Dextran Prodrug on Ischemia–Reperfusion Injury in a Rat Liver Transplantation Model

“…Sprague-Dawley rats were used as both donors (240−280 g) and recipients (280−320 g) for the transplantation procedure. This syngeneic model, which is devoid of immunologic rejection, has been used before by other investigators to study IR damage (9,10). Donor rats were administered a single intravenous 5-mg/kg dose of MP or DMP via the penile vein 2−3 h before liver isolation.…”