@article {Tanakajpet.112.201814, author = {Ryota Tanaka and Hiroshi Watanabe and Azusa Kodama and Victor Tuan Giam Chuang and Yu Ishima and Keisuke Hamasaki and Ken-ichiro Tanaka and Tohru Mizushima and Masaki Otagiri and Toru Maruyama}, title = {Long-acting human serum albumin-thioredoxin fusion protein suppresses bleomycin-induced pulmonary fibrosis progression}, elocation-id = {jpet.112.201814}, year = {2013}, doi = {10.1124/jpet.112.201814}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Idiopathic pulmonary fibrosis (IPF) is thought to involve inflammatory cells and reactive oxygen species (ROS), such as superoxide anion radical (O2{\textperiodcentered}-). There is currently no effective treatment for 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 anti-oxidative 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 Trx 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-TGF-β levels in the lung and inhibited the increase of inflammatory cells in BALF, pulmonary inflammatory cytokines and oxidative stress markers. An in vitro EPR experiment using PMA-stimulated neutrophils confirmed the O2{\textperiodcentered}- 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, due to its long-acting anti-oxidative and anti-inflammatory modulation effects.}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/early/2013/02/26/jpet.112.201814}, eprint = {https://jpet.aspetjournals.org/content/early/2013/02/26/jpet.112.201814.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }