Effect of fenofibrate on the experimentally induced hepatic ischemia/reperfusion injury in rats: biochemical, light, and electron microscopic studies

ABSTRACT

Liver ischemia/reperfusion [I/R] injury is a serious clinical problem. It is one of the main causes of hepatic failure after liver surgery. It was proved that reactive oxygen species and tumor necrosis factor-alpha [TNF-alpha] are important mediators in liver I/R injury. This study was designed to investigate the effect of preischemic treatment with fenofibrate [peroxisome proliferator-activated receptor-alpha activator] on the oxidative stress and inflammatory response to hepatic I/R injury in rats. Forty-eight male rats were equally divided into four groups group 1 [sham group], group 2 [fenofibrate-treated sham group], group 3 [hepatic I/R group; hepatic I/R was induced by clamping the blood supply of the left lateral and median lobes of the liver for 60 min, followed by reperfusion for 4 h], and group 4 [fenofibrate-treated hepatic I/R group; the animals were pretreated with a single dose of fenofibrate [50mg/kg body weight, intraperitoneally] 1 h before ischemia]. After 4 h of reperfusion, blood samples were obtained to assess serum alanine aminotransferase and TNF-alpha. Then liver tissues were obtained to assess hepatic malondialdehyde and superoxide dismutase activity. In addition, liver specimens from each group were obtained and processed for light and electron microscopic studies. Hepatic I/R induced a significant elevation of serum alanine aminotransferase, TNF-alpha, and malondialdehyde. However, superoxide dismutase activity in the hepatic tissues showed significant reduction. Light microscopic examination of group 3 showed a disorganized hepatic architecture with congestion, multiple areas of hemorrhage, and focal necrosis. In addition, mononuclear cellular infiltrate was observed in the portal tract. The hepatocytes showed necrosis, apoptosis, and vacuolated cytoplasm. Moreover, there was a significant increase in the mean diameter of the central veins, blood sinusoids, portal vessels, and bile ducts [P<0.001]. Scanning electron micrographs showed dilated blood sinusoids packed with red blood cells and leukocytes. Ultrastructural study showed hepatocytes containing multiple cytoplasmic vacuoles and lysosomes. The mitochondria appeared swollen with cristolysis or with an electron-dense matrix. Moreover, Kupffer cells showed apoptotic bodies and multiple lysosomes in their cytoplasm. In addition, the hepatic stellate cells appeared surrounded by wide areas containing collagen fibers. In group 4, preischemic treatment with fenofibrate significantly attenuated the biochemical and histological alterations of I/R-induced liver injury. Fenofibrate could be promising as an adjuvant therapy before hepatic surgery for rescuing the liver from I/R injury