Melatonin inhibits endoplasmic reticulum stress and epithelial-mesenchymal transition during bleomycin-induced pulmonary fibrosis in mice.

Abstract

Several reports indicate that melatonin alleviates bleomycin (BLM)-induced pulmonary fibrosis in rodent animals. Nevertheless, the exact mechanism remains obscure. The present study investigated the effects of melatonin on endoplasmic reticulum (ER) stress and epithelial-mesenchymal transition (EMT) during BLM-induced lung fibrosis. For the induction of pulmonary fibrosis, mice were intratracheally injected with a single dose of BLM (5.0 mg/kg). Some mice were intraperitoneally injected with melatonin (5 mg/kg) daily for a period of 3 wk. Twenty-one days after BLM injection, lung fibrosis was evaluated. As expected, melatonin significantly alleviated BLM-induced pulmonary fibrosis, as evidenced by Sirius red staining. Moreover, melatonin significantly attenuated BLM-induced EMT to myofibroblasts, as determined by its repression of α-SMA expression. Further analysis showed that melatonin markedly attenuated BLM-induced GRP78 up-regulation and elevation of the cleaved ATF6 in the lungs. Moreover, melatonin obviously attenuated BLM-induced activation of pulmonary eIF2α, a downstream target of the PERK pathway. Finally, melatonin repressed BLM-induced pulmonary IRE1α phosphorylation. Correspondingly, melatonin inhibited BLM-induced activation of XBP-1 and JNK, two downstream targets of the IRE1 pathway. Taken together, these results suggest that melatonin alleviates ER stress and ER stress-mediated EMT in the process of BLM-induced pulmonary fibrosis.

• Authors: Hui Zhao, Qing-Qing Wu, Lin-Feng Cao, Hou-Ying Qing, Cheng Zhang, Yuan-Hua Chen, Hua Wang, R Y L Liu, Rong-Ru Liu, De-Xiang Xu
• Journal: PloS one (PLoS One) Vol. 9 Issue 5 Pg. e97266 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24818755 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Endoplasmic Reticulum Chaperone BiP
• Hspa5 protein, mouse
• Bleomycin
• Melatonin

Topics

• Animals
• Antineoplastic Agents (adverse effects)
• Bleomycin (adverse effects)
• Endoplasmic Reticulum Chaperone BiP
• Endoplasmic Reticulum Stress (drug effects)
• Epithelial-Mesenchymal Transition (drug effects)
• Male
• Melatonin (pharmacology, therapeutic use)
• Mice
• Pulmonary Fibrosis (chemically induced, drug therapy, pathology)