Phosphodiesterase III inhibitor attenuates rat sinusoidal
obstruction syndrome through inhibition of platelet
aggregation in Disse’s space
Takashi Miyata,* Hidehiro Tajima,* Miki Hirata,* Shin-ichi Nakanuma,* Isamu Makino,* Hironori Hayashi,*
Katsunobu Oyama,* Tomoharu Miyashita,* Hiroyuki Takamura,* Itasu Ninomiya,* Sachio Fushida,*
and Tetsuo Ohta*
*Department of Gastroenterological Surgery, Division of Cancer Medicine,
Department of Histology and Embryology, Division of Cancer Medicine,
for Biomedical Research, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, and
Department of Histology, Faculty of Life Sciences,
Kumamoto University, Kumamoto, Japan
cilostazol, extravasated platelet aggregation,
plasminogen activator inhibitor-1, platelets,
sinusoidal obstruction syndrome.
Accepted for publication 13 September 2017.
Hidehiro Tajima, Department of
Gastroenterological Surgery, Division of Cancer
Medicine, Graduate School of Medicine,
Kanazawa University, 13-1 Takaramachi,
Kanazawa, Ishikawa 920-8641, Japan.
Declaration of conflict of interest: We have no
ﬁnancial conﬂicts of interest to disclose
concerning the study.
Background and Aim: Sinusoidal obstruction syndrome (SOS) is a serious drug-induced
liver injury. However, the pathophysiology of the disease remains unclear. This study in-
vestigated the effects of cilostazol (CZ), a phosphodiesterase III inhibitor, in a monocrota-
line (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 an-
alyzed. Plasminogen activator inhibitor-1 (PAI-1) in hepatocytes was analyzed using west-
ern blotting and polymerase chain reaction.
Results: In the MCT group, macroscopic ﬁndings showed a dark-red liver surface. Histo-
logical ﬁndings showed sinusoidal dilatation, coagulative necrosis of hepatocytes, and en-
dothelial 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 plate-
let aggregation, and suppressed hepatocyte apoptosis around the central vein. CZ attenu-
ated hepatic PAI-1 protein and mRNA levels.
Conclusions: Cilostazol attenuated MCT-induced SOS by preventing damage to liver si-
nusoidal endothelial cells and extravasated platelet aggregation. Hepatic PAI-1 levels were
suppressed with CZ treatment.
Sinusoidal obstruction syndrome (SOS), previously called veno-
is a fatal drug-induced liver injury. Drugs such
as busulfan in hematopoietic stem cell transplantation,
cyclophosphamide in immunosuppression therapy and bone mar-
and oxaliplatin in chemotherapy
known to cause SOS. The clinical features of SOS include
hyperbilirubinemia, painful hepatomegaly, and weight gain due
These features decrease the hepatic functional re-
Prevention and treatment of SOS are necessary to improve
complications following liver surgery; however, an effective strat-
egy for SOS remains to be determined.
Several studies have reported that initial pathophysiological
changes in SOS are possibly the result of drug-induced injury to
liver sinusoidal endothelial cells (LSEC),
after LSEC damage remain unclear. We previously immuno-
stained for CD42b, a platelet surface marker, and observed plate-
lets in contact with hepatocytes, especially in zone 3, in the liver
tissue of a liver transplant recipient with severe SOS. It was sug-
gested that platelets exist in the extravascular space, the space of
Disse, and destruction of hepatocytes were observed.
of a lack of nuclei, platelets are invisible on histological analysis
using hematoxylin and eosin (HE) staining.
We considered that LSEC are injured in the liver of SOS pa-
tients, and platelets that aggregate in the extravascular space,
the space of Disse, play an important role in processes resulting
in SOS. We termed platelet aggregation in the extravascular
space as extravasated platelet aggregation (EPA).
In the cur-
rent study, we hypothesized that to prevent LSEC damage and in-
stead of antiplatelet therapy, anti-EPA therapy is beneﬁcial for
SOS and results in the promotion of liver regeneration. To this
Journal of Gastroenterology and Hepatology 33 (2018) 950–957
© 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd