Phenylbutyric acid inhibits epithelial-mesenchymal transition during bleomycin-induced lung fibrosis.

Abstract

A recent report showed that unfolded protein response (UPR) signaling was activated during bleomycin (BLM)-induced pulmonary fibrosis. Phenylbutyric acid (PBA) is an endoplasmic reticulum (ER) chemical chaperone that inhibits the UPR signaling. The present study investigated the effects of PBA on BLM-induced epithelial-mesenchymal transition (EMT) and pulmonary fibrosis. For induction of pulmonary fibrosis, all mice except controls were intratracheally injected with a single dose of BLM (3.0mg/kg). In PBA+BLM group, mice were intraperitoneally injected with PBA (150mg/kg) daily. Three weeks after BLM injection, EMT was measured and pulmonary fibrosis was evaluated. BLM-induced pulmonary UPR activation was inhibited by PBA. Moreover, BLM-induced pulmonary nuclear factor kappa B (NF-κB) p65 activation was blocked by PBA. In addition, BLM-induced up-regulation of pulmonary inflammatory cytokines was repressed by PBA. Further analysis showed that BLM-induced α-smooth muscle actin (α-SMA), a marker for EMT, was significantly attenuated by PBA. Moreover, BLM-induced pulmonary collagen (Col1α1 and Col1α2) was obviously inhibited by PBA. Importantly, BLM-induced pulmonary fibrosis, as determined using Sirius red staining, was obviously alleviated by PBA. Taken together, these results suggest that PBA alleviates ER stress-mediated EMT in the pathogenesis of BLM-induced pulmonary fibrosis.

• Authors: Hui Zhao, Hou-Ying Qin, Lin-Feng Cao, Yuan-Hua Chen, Zhu-Xia Tan, Cheng Zhang, De-Xiang Xu
• Journal: Toxicology letters (Toxicol Lett) Vol. 232 Issue 1 Pg. 213-20 (Jan 05 2015) ISSN: 1879-3169 [Electronic] Netherlands
• PMID: 25455454 (Publication Type: Journal Article)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Acta2 protein, mouse
• Actins
• Collagen Type I
• Collagen Type I, alpha 1 Chain
• Phenylbutyrates
• Protective Agents
• Rela protein, mouse
• Transcription Factor RelA
• Bleomycin

Topics

• Actins (metabolism)
• Animals
• Bleomycin
• Collagen Type I (metabolism)
• Collagen Type I, alpha 1 Chain
• Cytoprotection
• Disease Models, Animal
• Endoplasmic Reticulum (drug effects, metabolism)
• Endoplasmic Reticulum Stress (drug effects)
• Epithelial-Mesenchymal Transition (drug effects)
• Female
• Lung (drug effects, metabolism, pathology)
• Mice
• Phenylbutyrates (pharmacology)
• Protective Agents (pharmacology)
• Pulmonary Fibrosis (chemically induced, metabolism, pathology, prevention & control)
• Signal Transduction (drug effects)
• Transcription Factor RelA (metabolism)
• Unfolded Protein Response (drug effects)