title: 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.affiliation: First Affiliated Hospital, Anhui Medical University, Hefei, China; Second Affiliated Hospital, Anhui Medical University, Hefei, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Second Affiliated Hospital, Anhui Medical University, Hefei, China.
authors.forename: Qing-Qing
authors.initials: QQ
authors.lastname: Wu
authors.affiliation: Second Affiliated Hospital, Anhui Medical University, Hefei, China.
authors.forename: Lin-Feng
authors.initials: LF
authors.lastname: Cao
authors.affiliation: Second Affiliated Hospital, Anhui Medical University, Hefei, China.
authors.forename: Hou-Ying
authors.initials: HY
authors.lastname: Qing
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei, China.
authors.forename: Yuan-Hua
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: First Affiliated Hospital, Anhui Medical University, Hefei, China.
authors.forename: R Y L
authors.initials: RY
authors.lastname: Liu
authors.affiliation: First Affiliated Hospital, Anhui Medical University, Hefei, China.
authors.forename: Rong-Ru
authors.initials: RR
authors.lastname: Liu
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei, China.
authors.forename: De-Xiang
authors.initials: DX
authors.lastname: Xu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001761:Bleomycin / Q000009:adverse effects*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D008297:Male; D008550:Melatonin / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D001761:Bleomycin; D008550:Melatonin