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Overexpression of the MSK1 Kinase in Patients With Chronic Lung Allograft Dysfunction and Its Confirmed Role in a Murine Model
- Source :
- Transplantation. 105(6)
- Publication Year :
- 2021
-
Abstract
- 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.
- Subjects :
- Male
2747 Transplantation
medicine.medical_treatment
T-Lymphocytes
030230 surgery
0302 clinical medicine
Re-Epithelialization
Bronchiolitis Obliterans
Lung
Cells, Cultured
Mice, Inbred BALB C
biology
Kinase
Fasudil
Middle Aged
10081 Institute of Veterinary Physiology
Up-Regulation
medicine.anatomical_structure
10076 Center for Integrative Human Physiology
Mitogen-activated protein kinase
030211 gastroenterology & hepatology
Female
France
Lung Transplantation
Adult
Adolescent
Ribosomal Protein S6 Kinases, 90-kDa
Proinflammatory cytokine
03 medical and health sciences
Young Adult
medicine
Animals
Humans
Protein Kinase Inhibitors
Aged
Cell Proliferation
Transplantation
business.industry
Interleukin-6
Fibroblasts
Epithelium
Mice, Inbred C57BL
Disease Models, Animal
Chronic Disease
Cancer research
biology.protein
570 Life sciences
business
Allotransplantation
Subjects
Details
- ISSN :
- 15346080
- Volume :
- 105
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Transplantation
- Accession number :
- edsair.doi.dedup.....99b2dc1e1727c2139d1b132aa044389b