title: New drug delivery system for liver sinusoidal endothelial cells for ischemia-reperfusion injury.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Naoki
authors.initials: N
authors.lastname: Sano
authors.affiliation: 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.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Tamura
authors.affiliation: 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.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Toriyabe
authors.affiliation: 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.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nowatari
authors.affiliation: 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.
authors.forename: Ken
authors.initials: K
authors.lastname: Nakayama
authors.affiliation: 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.
authors.forename: Tomohito
authors.initials: T
authors.lastname: Tanoi
authors.affiliation: 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.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Murata
authors.affiliation: 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.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sakurai
authors.affiliation: 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.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Hyodo
authors.affiliation: 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.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Fukunaga
authors.affiliation: 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.
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Harashima
authors.affiliation: 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.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Ohkohchi
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000097:blood; D002626:Chemistry, Pharmaceutical; D019610:Cytoprotection; D004195:Disease Models, Animal; D004338:Drug Combinations; D016503:Drug Delivery Systems; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006820:Hyaluronic Acid / Q000008:administration & dosage* / Q000737:chemistry; D020287:In Situ Nick-End Labeling; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008107:Liver Diseases / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D008246:Lysophospholipids / Q000008:administration & dosage* / Q000737:chemistry; D008297:Male; D046529:Microscopy, Electron, Transmission; D020011:Protective Agents / Q000008:administration & dosage* / Q000737:chemistry; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D015415:Biomarkers; D004338:Drug Combinations; D008246:Lysophospholipids; D020011:Protective Agents; C060506:sphingosine 1-phosphate; D006820:Hyaluronic Acid; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D000410:Alanine Transaminase; D013110:Sphingosine
keywords: Drug delivery system; Heme oxygenase-1; Hyaluronic acid; Liver sinusoidal endothelial cell; Sphingosine 1-phosphate; Stabilin-2