Protecting liver sinusoidal endothelial cells suppresses apoptosis in acute liver damage.
OBJECTIVE
Apoptosis is associated with various types of hepatic disorders. We have developed a novel cell-transfer drug delivery system (DDS) using a multifunctional envelope-type nano device that targets liver sinusoidal endothelial cells (LSECs). The purpose of this study was to determine the efficacy of the novel DDS containing siRNA at suppressing apoptosis in LSECs.


METHODS
Bax siRNA was transfected into a sinusoidal endothelial cell line (M1) to suppress apoptosis induced by an anti-Fas antibody and staurosporine. C57BL/6J mice were divided into three groups: (i) a control group, only intravenous saline; (ii) a nonselective group, injections of siRNA sealed in the nonselective DDS; and (iii) an LSEC-transfer efficient group, injections of siRNA sealed in an LSEC-transfer efficient DDS. Hepatic cell apoptosis was induced by an anti-Fas antibody.


RESULTS
Bax siRNA had an anti-apoptotic effect on M1 cells. Serum alanine aminotransferase was reduced in the LSEC-transfer efficient group, as were cleaved caspase-3 and the number of terminal deoxynucleotidyl transferase dUTP nick end labeling positive hepatocytes. Silver impregnation staining indicated that the sinusoidal space was maintained in the LSEC-transfer efficient group but not in the other groups. Electron microscopy showed that the LSECs were slightly impaired, although the sinusoidal structure was maintained in the LSEC-transfer efficient group.


CONCLUSIONS
Hepatocyte apoptosis was reduced by the efficient suppression of LSEC apoptosis with a novel DDS. Protecting the sinusoidal structure by suppressing LSEC damage will be an effective treatment for acute liver failure.
Department of Surgery, Division of Gastroenterological and Hepatobiliary Surgery and Organ Transplantation, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Tomohito
T
Tanoi
Department of Surgery, Division of Gastroenterological and Hepatobiliary Surgery and Organ Transplantation, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Takafumi
T
Tamura
Department of Surgery, Division of Gastroenterological and Hepatobiliary Surgery and Organ Transplantation, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Naoki
N
Sano
Department of Surgery, Division of Gastroenterological and Hepatobiliary Surgery and Organ Transplantation, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Ken
K
Nakayama
Department of Surgery, Division of Gastroenterological and Hepatobiliary Surgery and Organ Transplantation, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Kiyoshi
K
Fukunaga
Department of Surgery, Division of Gastroenterological and Hepatobiliary Surgery and Organ Transplantation, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Yun-Wen
YW
Zheng
Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Afsana
A
Akhter
Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Yu
Y
Sakurai
Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Yasuhiro
Y
Hayashi
Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Hideyoshi
H
Harashima
Department of Surgery, Division of Gastroenterological and Hepatobiliary Surgery and Organ Transplantation, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Nobuhiro
N
Ohkohchi
Bax; acute liver failure; apoptosis; drug delivery system; liver sinusoidal endothelial cell; siRNA