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 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·- 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.
- Received November 9, 2012.
- Revision received February 22, 2013.
- Accepted February 26, 2013.
- The American Society for Pharmacology and Experimental Therapeutics