title: Long-acting human serum albumin-thioredoxin fusion protein suppresses bleomycin-induced pulmonary fibrosis progression.
abstract: Idiopathic pulmonary fibrosis (IPF) is thought to involve inflammatory cells and reactive oxygen species (ROS), such as superoxide anion radical (O2(·-)). 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)-β 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 O2(·-) 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.
authors: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
authors: Ryota
authors: R
authors: Tanaka
authors: Hiroshi
authors: H
authors: Watanabe
authors: Azusa
authors: A
authors: Kodama
authors: Victor Tuan Giam
authors: VT
authors: Chuang
authors: Yu
authors: Y
authors: Ishima
authors: Keisuke
authors: K
authors: Hamasaki
authors: Ken-ichiro
authors: K
authors: Tanaka
authors: Tohru
authors: T
authors: Mizushima
authors: Masaki
authors: M
authors: Otagiri
authors: Toru
authors: T
authors: Maruyama
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic; D001761:Bleomycin; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D018450:Disease Progression; D006909:Hydroxyproline / Q000378:metabolism; D015850:Interleukin-6 / Q000032:analysis / Q000378:metabolism; D008168:Lung / Q000473:pathology; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D011993:Recombinant Fusion Proteins; D012709:Serum Albumin / Q000627:therapeutic use*; D013879:Thioredoxins / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D015850:Interleukin-6; D008263:Macrophage Migration-Inhibitory Factors; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D012709:Serum Albumin; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D001761:Bleomycin; D008315:Malondialdehyde; D013879:Thioredoxins; D006909:Hydroxyproline