Endoplasmic reticulum stress in human chronic wound healing: Rescue by 4-phenylbutyrate.
ER stress
chronic leg ulcers
drug repurposing
skin
wound healing
Journal
International wound journal
ISSN: 1742-481X
Titre abrégé: Int Wound J
Pays: England
ID NLM: 101230907
Informations de publication
Date de publication:
Feb 2021
Feb 2021
Historique:
received:
28
08
2020
revised:
09
11
2020
accepted:
10
11
2020
pubmed:
24
11
2020
medline:
7
8
2021
entrez:
23
11
2020
Statut:
ppublish
Résumé
During wound healing, cells have a high rate of protein synthesis and many proteins need to be folded post-translationally to function, which occurs in the endoplasmic reticulum (ER). In addition to proliferation, several cellular stress conditions, such as hypoxia, in the wound micro-environment lead to the accumulation of unfolded or misfolded proteins in the ER, causing ER stress. Eukaryotic cells have a signalling system to manage ER stress called the unfolded protein response (UPR). Mild UPR activation has a beneficial homeostatic effect; however, excessive UPR induces cell death. Herein, we examined venous leg ulcer biopsies versus normal acute incisional wounds in age-matched elderly subjects and found a large increase in ER stress markers. To study the underlying mechanism, we established several cell cultures from amputated legs from the elderly that showed inherent ER stress. While both keratinocytes and fibroblasts migration was impaired by ER stress, migration of elderly leg skin keratinocytes was markedly improved after treatment with the chemical chaperone and clinically established drug 4-phenylbutyrate (4-PBA) and demonstrated a reduction in ER stress markers. In a full-thickness human skin wound healing model, 4-PBA improved the reepithelialisation rate, which suggests it as a promising drug repurposing candidate for wound healing.
Identifiants
pubmed: 33225583
doi: 10.1111/iwj.13525
pmc: PMC7949014
doi:
Substances chimiques
Phenylbutyrates
0
4-phenylbutyric acid
7WY7YBI87E
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
49-61Subventions
Organisme : Tore Nilssons Stiftelse
Organisme : Harald och Greta Jeanssons stiftelse
Organisme : ALF medicin Stockholm
Organisme : Svenska Sällskapet för medicinsk forskning
Organisme : Hudfonden
Organisme : Vetenskapsrådet
Informations de copyright
© 2020 The Authors. International Wound Journal published by Medicalhelplines.com Inc (3M) and John Wiley & Sons Ltd.
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