Mast Cell Promotes the Development of Intracranial Aneurysm Rupture.
Aneurysm, Ruptured
/ immunology
Animals
Cathepsin G
/ genetics
Chymases
/ genetics
Cromolyn Sodium
/ pharmacology
Disease Models, Animal
Interleukin-6
/ genetics
Intracranial Aneurysm
/ immunology
Male
Mast Cell Stabilizers
/ pharmacology
Mast Cells
/ drug effects
Matrix Metalloproteinase 9
/ genetics
Mice
Mice, Transgenic
Mutation
Proto-Oncogene Proteins c-kit
/ genetics
RNA, Messenger
/ metabolism
Receptor, Angiotensin, Type 1
/ genetics
Subarachnoid Hemorrhage
/ immunology
Tryptases
/ genetics
Tumor Necrosis Factor-alpha
/ genetics
p-Methoxy-N-methylphenethylamine
/ pharmacology
intracranial aneurysm
mast cells
mice
subarachnoid hemorrhage
tryptase
Journal
Stroke
ISSN: 1524-4628
Titre abrégé: Stroke
Pays: United States
ID NLM: 0235266
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
pubmed:
7
10
2020
medline:
17
2
2021
entrez:
6
10
2020
Statut:
ppublish
Résumé
Inflammation has emerged as a key component of the pathophysiology of intracranial aneurysms. Mast cells have been detected in human intracranial aneurysm tissues, and their presence was associated with intramural microhemorrhage and wall degeneration. We hypothesized that mast cells play a critical role in the development of aneurysmal rupture, and that mast cells can be used as a therapeutic target for the prevention of aneurysm rupture. Intracranial aneurysms were induced in adult mice using a combination of induced systemic hypertension and a single injection of elastase into the cerebrospinal fluid. Aneurysm formation and rupture were assessed over 3 weeks. Roles of mast cells were assessed using a mast cell stabilizer (cromolyn), a mast cell activator (C48/80), and mice that are genetically lacking mature mast cells (Kit Pharmacological stabilization of mast cells with cromolyn markedly decreased the rupture rate of aneurysms (80% versus 19%, n=10 versus n =16) without affecting the aneurysm formation. The activation of mast cells with C48/80 significantly increased the rupture rate of aneurysms (25% versus 100%, n=4 versus n=5) without affecting the overall rate of aneurysm formation. Furthermore, the genetic deficiency of mast cells significantly prevented aneurysm rupture (80% versus 25%, n=10 versus n=8, wild-type versus Kit These results suggest that mast cells play a key role in promoting aneurysm rupture but not formation. Stabilizers of mast cells may have a potential therapeutic value in preventing intracranial aneurysm rupture in patients.
Sections du résumé
BACKGROUND AND PURPOSE
Inflammation has emerged as a key component of the pathophysiology of intracranial aneurysms. Mast cells have been detected in human intracranial aneurysm tissues, and their presence was associated with intramural microhemorrhage and wall degeneration. We hypothesized that mast cells play a critical role in the development of aneurysmal rupture, and that mast cells can be used as a therapeutic target for the prevention of aneurysm rupture.
METHODS
Intracranial aneurysms were induced in adult mice using a combination of induced systemic hypertension and a single injection of elastase into the cerebrospinal fluid. Aneurysm formation and rupture were assessed over 3 weeks. Roles of mast cells were assessed using a mast cell stabilizer (cromolyn), a mast cell activator (C48/80), and mice that are genetically lacking mature mast cells (Kit
RESULTS
Pharmacological stabilization of mast cells with cromolyn markedly decreased the rupture rate of aneurysms (80% versus 19%, n=10 versus n =16) without affecting the aneurysm formation. The activation of mast cells with C48/80 significantly increased the rupture rate of aneurysms (25% versus 100%, n=4 versus n=5) without affecting the overall rate of aneurysm formation. Furthermore, the genetic deficiency of mast cells significantly prevented aneurysm rupture (80% versus 25%, n=10 versus n=8, wild-type versus Kit
CONCLUSIONS
These results suggest that mast cells play a key role in promoting aneurysm rupture but not formation. Stabilizers of mast cells may have a potential therapeutic value in preventing intracranial aneurysm rupture in patients.
Identifiants
pubmed: 33019897
doi: 10.1161/STROKEAHA.120.030834
pmc: PMC7606717
mid: NIHMS1629220
doi:
Substances chimiques
Interleukin-6
0
Mast Cell Stabilizers
0
RNA, Messenger
0
Receptor, Angiotensin, Type 1
0
Tnf protein, mouse
0
Tumor Necrosis Factor-alpha
0
interleukin-6, mouse
0
p-Methoxy-N-methylphenethylamine
4091-50-3
Proto-Oncogene Proteins c-kit
EC 2.7.10.1
Cathepsin G
EC 3.4.21.20
Ctsg protein, mouse
EC 3.4.21.20
Chymases
EC 3.4.21.39
Tryptases
EC 3.4.21.59
Matrix Metalloproteinase 9
EC 3.4.24.35
Mmp9 protein, mouse
EC 3.4.24.35
Cromolyn Sodium
Q2WXR1I0PK
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3332-3339Subventions
Organisme : NINDS NIH HHS
ID : R01 NS082280
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS109382
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS109584
Pays : United States
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