Overexpression of the MSK1 Kinase in Patients With Chronic Lung Allograft Dysfunction and Its Confirmed Role in a Murine Model.
Adolescent
Adult
Aged
Animals
Bronchiolitis Obliterans
/ drug therapy
Cell Proliferation
Cells, Cultured
Chronic Disease
Disease Models, Animal
Female
Fibroblasts
/ drug effects
France
Humans
Interleukin-6
/ metabolism
Lung
/ drug effects
Lung Transplantation
/ adverse effects
Male
Mice, Inbred BALB C
Mice, Inbred C57BL
Middle Aged
Protein Kinase Inhibitors
/ pharmacology
Re-Epithelialization
Ribosomal Protein S6 Kinases, 90-kDa
/ antagonists & inhibitors
T-Lymphocytes
/ drug effects
Up-Regulation
Young Adult
Journal
Transplantation
ISSN: 1534-6080
Titre abrégé: Transplantation
Pays: United States
ID NLM: 0132144
Informations de publication
Date de publication:
01 06 2021
01 06 2021
Historique:
pubmed:
10
2
2021
medline:
27
7
2021
entrez:
9
2
2021
Statut:
ppublish
Résumé
Chronic lung allograft dysfunction (CLAD) and its obstructive form, the obliterative bronchiolitis (OB), are the main long-term complications related to high mortality rate postlung transplantation. CLAD treatment lacks a significant success in survival. Here, we investigated a new strategy through inhibition of the proinflammatory mitogen- and stress-activated kinase 1 (MSK1) kinase. MSK1 expression was assessed in a mouse OB model after heterotopic tracheal allotransplantation. Pharmacological inhibition of MSK1 (H89, fasudil, PHA767491) was evaluated in the murine model and in a translational model using human lung primary fibroblasts in proinflammatory conditions. MSK1 expression was graded over time in biopsies from a cohort of CLAD patients. MSK1 mRNA progressively increased during OB (6.4-fold at D21 posttransplantation). Inhibition of MSK1 allowed to counteract the damage to the epithelium (56% restoration for H89), and abolished the recruitment of MHCII+ (94%) and T cells (100%) at the early inflammatory phase of OB. In addition, it markedly decreased the late fibroproliferative obstruction in allografts (48%). MSK1 inhibitors decreased production of IL-6 (whose transcription is under the control of MSK1) released from human lung fibroblasts (96%). Finally, we confirmed occurrence of a 2.9-fold increased MSK1 mRNA expression in lung biopsies in patients at 6 months before CLAD diagnosis as compared to recipients with stable lung function. These findings suggest the overall interest of the MSK1 kinase either as a marker or as a potential therapeutic target in lung dysfunction posttransplantation.
Sections du résumé
BACKGROUND
Chronic lung allograft dysfunction (CLAD) and its obstructive form, the obliterative bronchiolitis (OB), are the main long-term complications related to high mortality rate postlung transplantation. CLAD treatment lacks a significant success in survival. Here, we investigated a new strategy through inhibition of the proinflammatory mitogen- and stress-activated kinase 1 (MSK1) kinase.
METHODS
MSK1 expression was assessed in a mouse OB model after heterotopic tracheal allotransplantation. Pharmacological inhibition of MSK1 (H89, fasudil, PHA767491) was evaluated in the murine model and in a translational model using human lung primary fibroblasts in proinflammatory conditions. MSK1 expression was graded over time in biopsies from a cohort of CLAD patients.
RESULTS
MSK1 mRNA progressively increased during OB (6.4-fold at D21 posttransplantation). Inhibition of MSK1 allowed to counteract the damage to the epithelium (56% restoration for H89), and abolished the recruitment of MHCII+ (94%) and T cells (100%) at the early inflammatory phase of OB. In addition, it markedly decreased the late fibroproliferative obstruction in allografts (48%). MSK1 inhibitors decreased production of IL-6 (whose transcription is under the control of MSK1) released from human lung fibroblasts (96%). Finally, we confirmed occurrence of a 2.9-fold increased MSK1 mRNA expression in lung biopsies in patients at 6 months before CLAD diagnosis as compared to recipients with stable lung function.
CONCLUSIONS
These findings suggest the overall interest of the MSK1 kinase either as a marker or as a potential therapeutic target in lung dysfunction posttransplantation.
Identifiants
pubmed: 33560725
doi: 10.1097/TP.0000000000003606
pii: 00007890-202106000-00015
doi:
Substances chimiques
IL6 protein, human
0
Interleukin-6
0
Protein Kinase Inhibitors
0
Ribosomal Protein S6 Kinases, 90-kDa
EC 2.7.11.1
mitogen and stress-activated protein kinase 1
EC 2.7.11.1
Types de publication
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1212-1224Informations de copyright
Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
Déclaration de conflit d'intérêts
The authors declare no conflicts of interest.
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