title: 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.affiliation: Second Affiliated Hospital, Anhui Medical University, Hefei 230601, China. Electronic address: zhaohuichenxi@126.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Second Affiliated Hospital, Anhui Medical University, Hefei 230601, China.
authors.forename: Hou-Ying
authors.initials: HY
authors.lastname: Qin
authors.affiliation: Second Affiliated Hospital, Anhui Medical University, Hefei 230601, China.
authors.forename: Lin-Feng
authors.initials: LF
authors.lastname: Cao
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei 230032, China.
authors.forename: Yuan-Hua
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Second Affiliated Hospital, Anhui Medical University, Hefei 230601, China.
authors.forename: Zhu-Xia
authors.initials: ZX
authors.lastname: Tan
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei 230032, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei 230032, China. Electronic address: xudex@126.com.
authors.forename: De-Xiang
authors.initials: DX
authors.lastname: Xu
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001761:Bleomycin; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D019610:Cytoprotection; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010654:Phenylbutyrates / Q000494:pharmacology*; D020011:Protective Agents / Q000494:pharmacology*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects; D051996:Transcription Factor RelA / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D010654:Phenylbutyrates; D020011:Protective Agents; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D001761:Bleomycin
keywords: Bleomycin; Endoplasmic reticulum stress; Epithelial-mesenchymal transition; Phenylbutyric acid; Unfolded protein response