Phosphodiesterase III inhibitor attenuates rat sinusoidal obstruction syndrome through inhibition of platelet aggregation in Disse's space

• Published in: Journal of gastroenterology and hepatology 2018-04, Vol.33 (4), p.950-957
• Main Authors: Miyata, Takashi, Tajima, Hidehiro, Hirata, Miki, Nakanuma, Shin‐ichi, Makino, Isamu, Hayashi, Hironori, Oyama, Katsunobu, Miyashita, Tomoharu, Takamura, Hiroyuki, Ninomiya, Itasu, Fushida, Sachio, Iseki, Shoichi, Harada, Shin‐ichi, Wakayama, Tomohiko, Ohta, Tetsuo
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD34 - metabolism; Apoptosis; Capillaries - cytology; Capillaries - pathology; Caspase; CD34 antigen; cilostazol; Disease Models, Animal; Endothelial cells; Epithelial Cells - pathology; extravasated platelet aggregation; Hepatic Veno-Occlusive Disease - chemically induced; Hepatic Veno-Occlusive Disease - drug therapy; Hepatic Veno-Occlusive Disease - metabolism; Hepatic Veno-Occlusive Disease - pathology; Hepatocytes; Liver; Liver - blood supply; Liver - metabolism; Liver - pathology; Male; Monocrotaline; Monocrotaline - adverse effects; mRNA; Phosphodiesterase; Phosphodiesterase 3 Inhibitors - administration & dosage; Phosphodiesterase 3 Inhibitors - pharmacology; Plasminogen Activator Inhibitor 1 - metabolism; Plasminogen activator inhibitors; plasminogen activator inhibitor‐1; Platelet aggregation; Platelet Aggregation - drug effects; Platelet Membrane Glycoprotein IIb - metabolism; platelets; Polymerase chain reaction; Rats, Wistar; Rodents; sinusoidal obstruction syndrome; Tetrazoles - administration & dosage; Tetrazoles - pharmacology; Time Factors; Transaminase; Western blotting
• ISSN: 0815-9319; 1440-1746
• DOI: 10.1111/jgh.14004

Background and Aim Sinusoidal obstruction syndrome (SOS) is a serious drug‐induced liver injury. However, the pathophysiology of the disease remains unclear. This study investigated the effects of cilostazol (CZ), a phosphodiesterase III inhibitor, in a monocrotaline (MCT)‐induced rat model of SOS. Methods Male Wistar rats were administrated MCT to induce SOS. Rats were divided into control, MCT, and MCT + CZ groups. In the MCT + CZ group, CZ was administered at 48 h, 24 h, and 30 min prior to and 8 h and 24 h after MCT administration. The MCT group was treated with water instead of CZ. At 48 h after MCT administration, blood and liver samples were collected to assess biochemistry and liver histology. Expression of rat endothelial cell antigen, CD34, CD41, P‐selectin, and caspase‐3 in the liver were analyzed. Plasminogen activator inhibitor‐1 (PAI‐1) in hepatocytes was analyzed using western blotting and polymerase chain reaction. Results In the MCT group, macroscopic findings showed a dark‐red liver surface. Histological findings showed sinusoidal dilatation, coagulative necrosis of hepatocytes, and endothelial damage of the central vein. These changes were attenuated in the MCT + CZ group. Elevated serum transaminase and decreased platelet counts were observed in the MCT + CZ group compared with those in the MCT group. Treatment with CZ reduced MCT‐induced damage to the liver sinusoidal endothelial cells, inhibited extravasated platelet aggregation, and suppressed hepatocyte apoptosis around the central vein. CZ attenuated hepatic PAI‐1 protein and mRNA levels. Conclusions Cilostazol attenuated MCT‐induced SOS by preventing damage to liver sinusoidal endothelial cells and extravasated platelet aggregation. Hepatic PAI‐1 levels were suppressed with CZ treatment.