Inhibition of mast cells: a novel mechanism by which nintedanib may elicit anti-fibrotic effects.
Aged
Animals
Anti-Inflammatory Agents, Non-Steroidal
/ pharmacology
Bleomycin
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
Chemokine CCL2
/ metabolism
Coculture Techniques
Disease Models, Animal
Female
Fibroblasts
/ pathology
Fibrosis
Humans
Idiopathic Pulmonary Fibrosis
/ drug therapy
Indoles
/ pharmacology
Lung
/ pathology
Male
Mast Cells
/ pathology
Middle Aged
Phosphorylation
/ drug effects
Protein Kinase Inhibitors
/ pharmacology
Proto-Oncogene Proteins c-kit
/ metabolism
Pyridones
/ pharmacology
Rats
Recombinant Proteins
/ pharmacology
Signal Transduction
/ drug effects
Stem Cell Factor
/ pharmacology
Vital Capacity
hypersensitivity pneumonitis
idiopathic pulmonary fibrosis
innate immunity
Journal
Thorax
ISSN: 1468-3296
Titre abrégé: Thorax
Pays: England
ID NLM: 0417353
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
21
08
2019
revised:
17
04
2020
accepted:
01
05
2020
pubmed:
28
7
2020
medline:
23
12
2020
entrez:
26
7
2020
Statut:
ppublish
Résumé
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease which presents a grave prognosis for diagnosed patients. Nintedanib (a triple tyrosine kinase inhibitor) and pirfenidone (unclear mechanism of action) are the only approved therapies for IPF, but have limited efficacy. The pathogenic mechanisms of this disease are not fully elucidated; however, a role for mast cells (MCs) has been postulated. The aim of this work was to investigate a role for MCs in IPF and to understand whether nintedanib or pirfenidone could impact MC function. MCs were significantly elevated in human IPF lung and negatively correlated with baseline lung function (FVC). Importantly, MCs were positively associated with the number of fibroblast foci, which has been linked to increased mortality. Furthermore, MCs were increased in the region immediately surrounding the fibroblast foci, and co-culture studies confirmed a role for MC-fibroblast crosstalk in fibrosis. Nintedanib but not pirfenidone inhibited recombinant stem cell factor (SCF)-induced MC survival. Further evaluation of nintedanib determined that it also inhibited human fibroblast-mediated MC survival. This was likely via a direct effect on ckit (SCF receptor) since nintedanib blocked SCF-stimulated ckit phosphorylation, as well as downstream effects on MC proliferation and cytokine release. In addition, nintedanib ablated the increase in lung MCs and impacted high tissue density frequency (HDFm) in a rat bleomycin model of lung fibrosis. Nintedanib inhibits MC survival and activation and thus provides a novel additional mechanism by which this drug may exert anti-fibrotic effects in patients with IPF.
Sections du résumé
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease which presents a grave prognosis for diagnosed patients. Nintedanib (a triple tyrosine kinase inhibitor) and pirfenidone (unclear mechanism of action) are the only approved therapies for IPF, but have limited efficacy. The pathogenic mechanisms of this disease are not fully elucidated; however, a role for mast cells (MCs) has been postulated.
OBJECTIVES
The aim of this work was to investigate a role for MCs in IPF and to understand whether nintedanib or pirfenidone could impact MC function.
METHODS AND RESULTS
MCs were significantly elevated in human IPF lung and negatively correlated with baseline lung function (FVC). Importantly, MCs were positively associated with the number of fibroblast foci, which has been linked to increased mortality. Furthermore, MCs were increased in the region immediately surrounding the fibroblast foci, and co-culture studies confirmed a role for MC-fibroblast crosstalk in fibrosis. Nintedanib but not pirfenidone inhibited recombinant stem cell factor (SCF)-induced MC survival. Further evaluation of nintedanib determined that it also inhibited human fibroblast-mediated MC survival. This was likely via a direct effect on ckit (SCF receptor) since nintedanib blocked SCF-stimulated ckit phosphorylation, as well as downstream effects on MC proliferation and cytokine release. In addition, nintedanib ablated the increase in lung MCs and impacted high tissue density frequency (HDFm) in a rat bleomycin model of lung fibrosis.
CONCLUSION
Nintedanib inhibits MC survival and activation and thus provides a novel additional mechanism by which this drug may exert anti-fibrotic effects in patients with IPF.
Identifiants
pubmed: 32709610
pii: thoraxjnl-2019-214000
doi: 10.1136/thoraxjnl-2019-214000
pmc: PMC7476277
doi:
Substances chimiques
Anti-Inflammatory Agents, Non-Steroidal
0
CCL2 protein, human
0
Chemokine CCL2
0
Indoles
0
Protein Kinase Inhibitors
0
Pyridones
0
Recombinant Proteins
0
Stem Cell Factor
0
Bleomycin
11056-06-7
pirfenidone
D7NLD2JX7U
Proto-Oncogene Proteins c-kit
EC 2.7.10.1
nintedanib
G6HRD2P839
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
754-763Informations de copyright
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: At the time of this study, all authors apart from DR, HP and SK were employees of MedImmune (part of the AstraZeneca group). DC is now an employee of Galapagos. CO-S, LM, AL, SK, GG-G and ELM are current AstraZeneca employees and have stock/stock options in AstraZeneca, and CO-S and LM are developing drugs for IPF.
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