Polythiol-containing, recombinant mannosylated-albumin is a superior CD68+/CD206+ Kupffer cell-targeted nanoantioxidant for treatment of two acute hepatitis models

Hitoshi Maeda, Kenshiro Hirata, Hiroshi Watanabe, Yu Ishima, Victor Tuan Giam Chuang, Kazuaki Taguchi, Akihito Inatsu, Manabu Kinoshita, Motohiko Tanaka, Yutaka Sasaki, Masaki Otagiri, Toru Maruyama

研究成果: Article査読

9 被引用数 (Scopus)

抄録

Since reactive oxygen species (ROS) derived from Kupffer cells (KC), especially CD68+ KC, play a key role in the induction of hepatic oxidative stress and injuries, we developed a polythiolatedand mannosylated human serum albumin (SH-Man-HSA), which functions as a novel nanoantioxidant for delivering thiol to CD68+ KC. In vitro electron paramagnetic resonance coupled with pharmacokinetics and immunohistochemical studies showed that SH-Man-HSA possessed powerful radical-scavenging activity and rapidly and selectively delivered thiols to the liver via mannose receptor (CD206) on CD68+ cells. SH-Man-HSA significantly improved the survival rate of concanavalin-A (Con-A)-treated mice. Moreover, SH-Man-HSA exhibited excellent hepatoprotective functions, not by decreasing tumor necrosis factor or interferon-γ production that is closely associated with Con-A-induced hepatitis, but by suppressing ROS production. Interestingly, the protective effect of SH-Man-HSA was superior to N-acetyl cysteine (NAC). This could be attributed to the difference in the inhibition of hepatic oxidative stress between the two antioxidants depending on their potential for thiol delivery to the liver. Similar results were also observed for acetaminophen (APAP)-induced hepatopathy models. Flow cytometric data further confirmed that an increase in F4/ 80+/ROS+ cells was dramatically decreased by SH-Man-HSA. The administration of SH-Man-HSA at 4 hours following a Con-A or APAP injection also exhibited a profound hepatoprotective action against these hepatitis models, whereas this was not observed for NAC. It can be concluded therefore that SH-Man-HSA has great potential for use in a rescue therapy for hepatopathy as a nanoantioxidant because of its ability to efficiently and rapidly deliver thiols to CD68+/CD206+ KC.

本文言語English
論文番号A7
ページ(範囲)244-257
ページ数14
ジャーナルJournal of Pharmacology and Experimental Therapeutics
352
2
DOI
出版ステータスPublished - 2015 1 1
外部発表はい

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

フィンガープリント 「Polythiol-containing, recombinant mannosylated-albumin is a superior CD68<sup>+</sup>/CD206<sup>+</sup> Kupffer cell-targeted nanoantioxidant for treatment of two acute hepatitis models」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

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