TY - JOUR T1 - Long-Acting Human Serum Albumin-Thioredoxin Fusion Protein Suppresses Bleomycin-Induced Pulmonary Fibrosis Progression JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 271 LP - 283 DO - 10.1124/jpet.112.201814 VL - 345 IS - 2 AU - Ryota Tanaka AU - Hiroshi Watanabe AU - Azusa Kodama AU - Victor Tuan Giam Chuang AU - Yu Ishima AU - Keisuke Hamasaki AU - Ken-ichiro Tanaka AU - Tohru Mizushima AU - Masaki Otagiri AU - Toru Maruyama Y1 - 2013/05/01 UR - http://jpet.aspetjournals.org/content/345/2/271.abstract N2 - 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. ER -