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


J Pharmacol Exp Ther. 2013 Feb 26;


Authors: Tanaka R, Watanabe H, Kodama A, Chuang VT, Ishima Y, Hamasaki K, Tanaka KI, Mizushima T, Otagiri M, Maruyama T


Abstract

Idiopathic pulmonary fibrosis (IPF) is thought to involve inflammatory cells and reactive oxygen species (ROS), such as superoxide anion radical (O(2)(·-)). 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 O(2)(·-) 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.

PMID: 23442250 [PubMed - as supplied by publisher]