Affordable Access

deepdyve-link
Publisher Website

Penehyclidine hydrochloride defends against LPS-induced ALI in rats by mitigating endoplasmic reticulum stress and promoting the Hes1/Notch1 pathway.

Authors
  • Weng, Junting1
  • Chen, Min1
  • Lin, Qunying2
  • Chen, Jianfei1
  • Wang, ShanZuan2
  • Fang, Dexiang3
  • 1 Department of Critical Care Medicine, The Affiliated Hospital of Putian University, Putian 351100, China. , (China)
  • 2 Department of Respiratory and Critical Care, The Affiliated Hospital of Putian University, Putian 351100, China. , (China)
  • 3 Department of Critical Care Medicine, The Affiliated Hospital of Putian University, Putian 351100, China. Electronic address: [email protected] , (China)
Type
Published Article
Journal
Gene
Publication Date
Dec 30, 2019
Volume
721
Pages
144095–144095
Identifiers
DOI: 10.1016/j.gene.2019.144095
PMID: 31476403
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Penehyclidine hydrochloride (PHC) is a novel anticholinergic drug applied broadly in surgeries as a preanesthetic medication. A substantial amount of research indicates that PHC has lung defensive properties. Considering that endoplasmic reticulum (ER) stress exerts a crucial function in cell apoptosis associated with the lipopolysaccharides (LPS)-induced acute lung injury (ALI) model, we aimed to determine whether regulation of ER stress in the LPS-induced ALI model was associated with the lung defensive role of PHC. Adult male SD rats were administered LPS (5 mg/kg, intratracheally) followed by PHC (1.0 mg/kg, intravenously) for 24 h. The NR8383 alveolar macrophages were randomly separated into Sham, LPS (100 ng/mL), and PHC (1, 2.5, or 5 μg/mL) + LPS groups. PHC (1, 2.5, or 5 μg/mL) + LPS groups were treated with PHC alone for 1 h after LPS exposure. Posttreatment with PHC relieved LPS-induced pulmonary impairment and blocked LPS-mediated lung apoptosis, indicated by the downregulation of the lung apoptotic indicators malondialdehyde and superoxide dismutase in serum at 24 h after LPS-induced ALI. PHC (1-5 μg/mL) did not influence the activity of cultivated NR8383 alveolar macrophages in vitro. However, postconditioning with PHC dosage-dependently reduced LPS-mediated cell apoptosis. Additionally, many studies have indicated that PHC administration inhibits ER stress and initiates hairy and enhancer of split 1 (Hes1)/(Notch1) signaling by decreasing phosphorylated α subunit of eukaryotic initiation factor 2α (p-eIF2α)/eukaryotic translation initiation factor 2α (eIF2α) and Phospho-protein kinase R-like ER kinase (p-PERK)/ protein kinase R-like ER kinase (PERK) proportions; inhibiting C/EBP-homologous protein (CHOP), activating transcription factor 4 (ATF4), caspase-3, and Bcl2-associated x (Bax) activity; and enhancing notch1 intracellular domain (NICD), Notch1, B-cell lymphoma-2 (Bcl-2), and Hes1 activity in vivo and in vitro. In addition, the defensive functions of PHC on LPS-activated NR8383 alveolar macrophages were abrogated through the Notch1 pathway antagonist [(3,5-difluorophenacetyl)-1-alanyl] -phenylglycine-butyl ester (DAPT). In conclusion, PHC alleviates LPS-induced ALI by ameliorating ER stress-mediated apoptosis and promoting Hes1/Notch1 signaling in vivo and in vitro. Copyright © 2019 Elsevier B.V. All rights reserved.

Report this publication

Statistics

Seen <100 times