Long-acting human serum albumin-thioredoxin fusion protein suppresses bleomycin-induced pulmonary fibrosis progression

Ryota Tanaka, Hiroshi Watanabe, Azusa Kodama, Victor Tuan Giam Chuang, Yu Ishima, Keisuke Hamasaki, Ken Ichiro Tanaka, Tohru Mizushima, Masaki Otagiri, Toru Maruyama

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Idiopathic pulmonary fibrosis (IPF) is thought to involve inflammatory cells and reactive oxygen species (ROS), such as superoxide anion radical (O22). There is currently no effective treatment of IPF. We previously developed a human serum albumin (HSA)- thioredoxin 1 (Trx) fusion protein (HSA-Trx) designed to overcome the unfavorable pharmacokinetic and short pharmacological properties of Trx, an antioxidative and anti-inflammatory protein. In this study, we examined the therapeutic effect of HSA-Trx on an IPF animal model of bleomycin (BLM)-induced pulmonary fibrosis. A pharmacokinetic study of HSA-Trx or Trx in BLM mice showed that the plasma retention and lung distribution of Trxc was markedly improved by fusion with HSA. A weekly intravenous administration of HSA-Trx, but not Trx, ameliorated BLM-induced fibrosis, as evidenced by a histopathological analysis and pulmonary hydroxyproline levels. HSA-Trx suppressed active-transforming growth factor (TGF)-b levels in the lung and inhibited the increase of inflammatory cells in bronchoalveolar lavage fluid, pulmonary inflammatory cytokines, and oxidative stress markers. An in vitro EPR experiment using phosphate-buffered saline-stimulated neutrophils confirmed the O22 scavenging ability of HSA-Trx. Furthermore, post-treatment of HSA-Trx had a suppressive effect against BLM-induced fibrosis. These results suggest that HSA-Trx has potential as a novel therapeutic agent for IPF, because of its long-acting antioxidative and anti-inflammatory modulation effects.

Original languageEnglish
Pages (from-to)271-283
Number of pages13
JournalJournal of Pharmacology and Experimental Therapeutics
Volume345
Issue number2
DOIs
Publication statusPublished - 2013 May

Fingerprint

Thioredoxins
Pulmonary Fibrosis
Bleomycin
Serum Albumin
Idiopathic Pulmonary Fibrosis
Proteins
Lung
Superoxides
Fibrosis
Anti-Inflammatory Agents
Pharmacokinetics
Hydroxyproline
Bronchoalveolar Lavage Fluid
Transforming Growth Factors
Therapeutic Uses
Intravenous Administration
Reactive Oxygen Species
Oxidative Stress
Neutrophils
Therapeutics

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Long-acting human serum albumin-thioredoxin fusion protein suppresses bleomycin-induced pulmonary fibrosis progression. / Tanaka, Ryota; Watanabe, Hiroshi; Kodama, Azusa; Chuang, Victor Tuan Giam; Ishima, Yu; Hamasaki, Keisuke; Tanaka, Ken Ichiro; Mizushima, Tohru; Otagiri, Masaki; Maruyama, Toru.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 345, No. 2, 05.2013, p. 271-283.

Research output: Contribution to journalArticle

Tanaka, R, Watanabe, H, Kodama, A, Chuang, VTG, Ishima, Y, Hamasaki, K, Tanaka, KI, Mizushima, T, Otagiri, M & Maruyama, T 2013, 'Long-acting human serum albumin-thioredoxin fusion protein suppresses bleomycin-induced pulmonary fibrosis progression', Journal of Pharmacology and Experimental Therapeutics, vol. 345, no. 2, pp. 271-283. https://doi.org/10.1124/jpet.112.201814
Tanaka, Ryota ; Watanabe, Hiroshi ; Kodama, Azusa ; Chuang, Victor Tuan Giam ; Ishima, Yu ; Hamasaki, Keisuke ; Tanaka, Ken Ichiro ; Mizushima, Tohru ; Otagiri, Masaki ; Maruyama, Toru. / Long-acting human serum albumin-thioredoxin fusion protein suppresses bleomycin-induced pulmonary fibrosis progression. In: Journal of Pharmacology and Experimental Therapeutics. 2013 ; Vol. 345, No. 2. pp. 271-283.
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