Basic Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 7, 2015; 21(45): 12778-12786
Published online Dec 7, 2015. doi: 10.3748/wjg.v21.i45.12778
New drug delivery system for liver sinusoidal endothelial cells for ischemia-reperfusion injury
Naoki Sano, Takafumi Tamura, Naoyuki Toriyabe, Takeshi Nowatari, Ken Nakayama, Tomohito Tanoi, Soichiro Murata, Yu Sakurai, Mamoru Hyodo, Kiyoshi Fukunaga, Hideyoshi Harashima, Nobuhiro Ohkohchi
Naoki Sano, Takafumi Tamura, Takeshi Nowatari, Ken Nakayama, Tomohito Tanoi, Soichiro Murata, Kiyoshi Fukunaga, Nobuhiro Ohkohchi, Department of Surgery, Doctoral Program in Clinical Science, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba 305-8575, Japan
Naoyuki Toriyabe, Yu Sakurai, Mamoru Hyodo, Hideyoshi Harashima, Faculty of Pharmaceutical Sciences, Hokkaido University, Hokkaido 060-0812, Japan
Author contributions: Sano N performed the majority of experiments and analyzed the data; Toriyabe N, Sakurai Y and Hyodo M created the reagnt; Tamura T, Harashima H and Ohkohchi N designed and coordinated the research; Sano N, Tamura T, Toriyabe N, Nowatari T, Nakayama K, Tanoi T, Murata S, Sakurai Y, Hyodo M, Fukunaga K, Harashima H and Ohkohchi N wrote the paper.
Supported by Ministry of Education, Culture, Sports, Science, and Technology of Japan, KAKENHI, No. 23390319.
Institutional review board statement: Animal experiments were performed in accordance with the university’s Regulations for Animal Experiments and Fundamental Guidelines for Proper Conduct of Animal Experiment and Related Activities in Academic Research Institutions, under the jurisdiction of the Japanese Ministry of Education, Culture, Sports, Science, and Technology.
Institutional animal care and use committee statement: Animal experiments were performed in a humane manner after receiving approval from the Institutional University Experiment Committee of the University of Tsukuba.
Conflict-of-interest statement: We have no financial relationships to disclose.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Nobuhiro Ohkohchi, MD, PhD, Professor, Department of Surgery, Doctoral Program in Clinical Science, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan. nokochi3@md.tsukuba.ac.jp
Telephone: +81-29-8533221 Fax: +81-29-8533222
Received: June 16, 2015
Peer-review started: June 19, 2015
First decision: July 10, 2015
Revised: July 22, 2015
Accepted: September 15, 2015
Article in press: September 15, 2015
Published online: December 7, 2015
Abstract

AIM: To investigate the cytoprotective effects in hepatic ischemia-reperfusion injury, we developed a new formulation of hyaluronic acid (HA) and sphingosine 1-phophate.

METHODS: We divided Sprague-Dawley rats into 4 groups: control, HA, sphingosine 1-phosphate (S1P), and HA-S1P. After the administration of each agent, we subjected the rat livers to total ischemia followed by reperfusion. After reperfusion, we performed the following investigations: alanine aminotransferase (ALT), histological findings, TdT-mediated dUTP-biotin nick end labeling (TUNEL) staining, and transmission electron microscopy (TEM). We also investigated the expression of proteins associated with apoptosis, hepatoprotection, and S1P accumulation.

RESULTS: S1P accumulated in the HA-S1P group livers more than S1P group livers. Serum ALT levels, TUNEL-positive hepatocytes, and expression of cleaved caspase-3 expression, were significantly decreased in the HA-S1P group. TEM revealed that the liver sinusoidal endothelial cell (LSEC) lining was preserved in the HA-S1P group. Moreover, the HA-S1P group showed a greater increase in the HO-1 protein levels compared to the S1P group.

CONCLUSION: Our results suggest that HA-S1P exhibits cytoprotective effects in the liver through the inhibition of LSEC apoptosis. HA-S1P is an effective agent for hepatic ischemia/reperfusion injury.

Keywords: Hyaluronic acid, Sphingosine 1-phosphate, Liver sinusoidal endothelial cell, Drug delivery system, Heme oxygenase-1, Stabilin-2

Core tip: We have developed a new formulation by directly combining hyaluronic acid and sphingosine 1-phosphate (HA-S1P), which targets liver sinusoidal endothelial cell (LSEC) by binding specifically to HA and HA receptors. This study demonstrated that HA-S1P protects the liver from hepatic ischemia/reperfusion (I/R) injury in rats. The strong protective effect of HA-S1P may be mediated by the anti-apoptotic effect of S1P on LSECs. These data indicate that HA-S1P is an effective agent for preventing hepatic I/R injury.