scholarly journals Mast Cell Promotes the Development of Intracranial Aneurysm Rupture

Stroke ◽  
2020 ◽  
Vol 51 (11) ◽  
pp. 3332-3339
Author(s):  
Hajime Furukawa ◽  
Kosuke Wada ◽  
Yoshiteru Tada ◽  
Atsushi Kuwabara ◽  
Hiroki Sato ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Intracranial Aneurysm ◽  
Intracranial Aneurysms ◽  
Critical Role ◽  
Aneurysm Rupture ◽  
Systemic Hypertension ◽  
Rupture Rate ◽  
Aneurysm Formation ◽  
Adult Mice

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 W-sh/W-sh mice). 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 W-sh/W-sh mice). 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.

scholarly journals Roles of Phytoestrogen in the Pathophysiology of Intracranial Aneurysm

Stroke ◽  
2021 ◽  
Author(s):  
Kimihiko Yokosuka ◽  
Caleb Rutledge ◽  
Yoshinobu Kamio ◽  
Atsushi Kuwabara ◽  
Hiroki Sato ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Subarachnoid Hemorrhage ◽  
Intracranial Aneurysm ◽  
Protective Effect ◽  
Postmenopausal Women ◽  
Intracranial Aneurysms ◽  
Estrogen Receptor Β ◽  
Systemic Hypertension ◽  
Female Mice ◽  
Aneurysm Formation

Background and Purpose: The incidences of intracranial aneurysm and aneurysmal subarachnoid hemorrhage are high in postmenopausal women. Although population-based studies suggest that hormone replacement therapy is beneficial for postmenopausal women with intracranial aneurysms, estrogen replacement may no longer be recommended for the prevention of chronic diseases given its association with adverse outcomes, such as cancer and ischemic stroke. The isoflavone daidzein and its intestinal metabolite equol are bioactive phytoestrogens and potent agonists of estrogen receptors. Given their estrogenic properties, we investigated whether the isoflavones daidzein and equol are protective against the formation and rupture of intracranial aneurysms in a mouse model of the postmenopausal state. Methods: We induced intracranial aneurysms in ovariectomized adult female mice using a combination of induced systemic hypertension and a single injection of elastase into the cerebrospinal fluid. We fed the mice with an isoflavone-free diet with/without daidzein supplementation, or in a combination of intraperitoneal equol, or oral vancomycin treatment. We also used estrogen receptor beta knockout mice. Results: Both dietary daidzein and supplementation with its metabolite, equol, were protective against aneurysm formation in ovariectomized mice. The protective effects of daidzein and equol required estrogen receptor-β. The disruption of the intestinal microbial conversion of daidzein to equol abolished daidzein’s protective effect against aneurysm formation. Mice treated with equol had lower inflammatory cytokines in the cerebral arteries, suggesting that phytoestrogens modulate inflammatory processes important to intracranial aneurysm pathogenesis. Conclusions: Our study establishes that both dietary daidzein and its metabolite, equol, protect against aneurysm formation in ovariectomized female mice through the activation of estrogen receptor-β and subsequent suppression of inflammation. Dietary daidzein’s protective effect required the intestinal conversion to equol. Our results indicate the potential therapeutic value of dietary daidzein and its metabolite, equol, for the prevention of the formation of intracranial aneurysms and related subarachnoid hemorrhage.

scholarly journals Sex and Genetic Background Effects on the Outcome of Experimental Intracranial Aneurysms

Stroke ◽  
2020 ◽  
Vol 51 (10) ◽  
pp. 3083-3094
Author(s):  
Takeshi Yanagisawa ◽  
Hua Zhang ◽  
Tomoaki Suzuki ◽  
Yoshinobu Kamio ◽  
Tsubasa Takizawa ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Intracranial Aneurysm ◽  
Genetic Background ◽  
Intracranial Aneurysms ◽  
Aneurysm Rupture ◽  
Circle Of Willis ◽  
Male And Female ◽  
Aneurysm Formation ◽  
Proinflammatory Mediators ◽  
Arterial Blood

Background and Purpose: Intracranial aneurysm formation and rupture risk are, in part, determined by genetic factors and sex. To examine their role, we compared 3 mouse strains commonly used in cerebrovascular studies in a model of intracranial aneurysm formation and rupture. Methods: Intracranial aneurysms were induced in male CD1 (Crl:CD1[ICR]), male and female C57 (C57BL/6NCrl), and male 129Sv (129S2/SvPasCrl or 129S1/SvImJ) mice by stereotaxic injection of elastase at the skull base, combined with systemic deoxycorticosterone acetate–salt hypertension. Neurological deficits and mortality were recorded. Aneurysms and subarachnoid hemorrhage grades were quantified postmortem, either after spontaneous mortality or at 7 to 21 days if the animals survived. In separate cohorts, we examined proinflammatory mediators by quantitative reverse transcriptase–polymerase chain reaction, arterial blood pressure via the femoral artery, and the circle of Willis by intravascular latex casting. Results: We found striking differences in aneurysm formation, rupture, and postrupture survival rates among the groups. 129Sv mice showed the highest rates of aneurysm rupture (80%), followed by C57 female (36%), C57 male (27%), and CD1 (21%). The risk of aneurysm rupture and the presence of unruptured aneurysms significantly differed among all 3 strains, as well as between male and female C57. The same hierarchy was observed upon Kaplan-Meier analysis of both overall survival and deficit-free survival. Subarachnoid hemorrhage grades were also more severe in 129Sv. CD1 mice showed the highest resistance to aneurysm rupture and the mildest outcomes. Higher mean blood pressures and the major phenotypic difference in the circle of Willis anatomy in 129Sv provided an explanation for the higher incidence of and more severe aneurysm ruptures. TNFα (tumor necrosis factor-alpha), IL-1β (interleukin-1-beta), and CCL2 (chemokine C-C motif ligand 2) expressions did not differ among the groups. Conclusions: The outcome of elastase-induced intracranial aneurysm formation and rupture in mice depends on genetic background and shows sexual dimorphism.

Abstract P118: Inhibition of Endoplasmic Reticulum Stress Prevents Intracranial Aneurysmal Rupture in a Mouse Model

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Daisuke Kudo ◽  
Hajime Furukawa ◽  
Satoru Eguchi ◽  
Tomoki Hashimoto
Keyword(s):  
Endoplasmic Reticulum ◽  
Angiotensin Ii ◽  
Mouse Model ◽  
Er Stress ◽  
Intracranial Aneurysms ◽  
Vehicle Group ◽  
Systemic Hypertension ◽  
Aneurysmal Rupture ◽  
Rupture Rate ◽  
Salt Hypertension

Background: Aneurysmal subarachnoid hemorrhage (SAH) can cause significant mortality and morbidity. To develop a therapy for prevention of intracranial aneurysmal rupture and subsequent SAH, it is important to clarify the mechanism of intracranial aneurysmal rupture. Stimulation of the renin-angiotensin system (RAS) causes hypertension and cardiovascular remodeling. Recent evidence shows that angiotensin II enhances endoplasmic reticulum (ER) stress and inhibition of ER stress prevents angiotensin II-induced vascular remodeling but not hypertension in mice. RAS has also been implicated in intracranial aneurysms. We have previously shown that angiotensin II receptor blocker (losartan) prevented intracranial aneurysmal rupture in a mouse model without affecting systemic hypertension. To clarify the mechanism of intracranial aneurysmal rupture via RAS, we have tested our hypothesis that inhibition of ER stress prevents intracranial aneurysmal rupture in a mouse model. Method: We used a mouse model of intracranial aneurysms in which spontaneous aneurysmal rupture causes neurologic symptoms. Intracranial aneurysms were induced in wild type mice by a single stereotactic injection of elastase (35mU) into the cerebrospinal fluid at right basal cistern and deoxycorticosterone (DOCA)-salt hypertension. Vehicle or 4-phenylbutyric acid (PBA, ER stress inhibitor , 100mg/kg/day) was subcutaneously injected into all mice once a day. To detect aneurysmal rupture, we performed daily neurological examinations. Symptomatic mice were euthanized immediately when they developed neurological symptoms, and all asymptomatic mice were euthanized 21 days after aneurysm induction. The incidence of aneurysms and rupture rate were compared between vehicle group and PBA group. Results: The incidence of aneurysms was not significantly different between two groups (100% in vehicle, 20 of 20 vs. 87% in PBA, 20 of 23, p=0.09). However, rupture rate was significantly lower in the PBA group (60%, 12 of 20) than the vehicle group (95%, 19 of 20). (p=0.008). Conclusion: Inhibition of ER stress reduced aneurysmal rupture in a mouse model of intracranial aneurysm induced by combination of elastase injection and DOCA-salt hypertension.

Abstract 147: Role of Nicotine in the Development of Intracranial Aneurysm Rupture

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Yoshinobu Kamio ◽  
Hajime Furukawa ◽  
Kimihiko Yokosuka ◽  
Masaaki Korai ◽  
Kazuha Mitsui ◽  
...  
Keyword(s):  
Intracranial Aneurysm ◽  
Tobacco Smoke ◽  
Intracranial Aneurysms ◽  
Aneurysm Rupture ◽  
Alpha7 Nicotinic Acetylcholine Receptor ◽  
Acetate Salt ◽  
Nicotine Receptors ◽  
Aneurysm Wall ◽  
Salt Hypertension

Background: Nicotine is one of main chemicals of tobacco smoke and promotes atherosclerosis and stroke. Tobacco smoke is considered an independent risk factor for intracranial aneurysm formation, growth, and rupture. There are mainly 5 subtypes of nicotine receptors. Roles of alpha7 nicotinic acetylcholine receptor (α7nAChR) in inflammation and vascular remodeling are diverse and context-dependent. Notably, endothelial α7nAChR is considered to mediate nicotine-induced inflammation. Activation of endothelial α7nAChR by nicotine may promote aneurysm rupture by increasing the aneurysm wall inflammation. Using a mouse model of intracranial aneurysm, we examined effects of nicotine in aneurysm rupture. Moreover we investigated potential roles of α7nAChR stimulation by nicotine in the pathophysiology of intracranial aneurysms. Methods: Intracranial aneurysms were induced by a combination of elastase injection into the cerebrospinal fluid and deoxycorticosteron acetate-salt (DOCA-salt) hypertension in male mice. Mice were treated with (1) nicotine (5 mg/kg/day, n=25); (2) saline sc (n=22) for three weeks after aneurysm induction. To investigate the effect of α7nAChR, mice were treated with (1) saline sc + saline ip (n=11); (2) saline sc + α7nAChR antagonist (Methyllycaconitine, MLA 5mg/kg/day) ip (n=13); (3) nicotine (5 mg/kg/day, sc, 28 days) + saline ip (n=18); (4) nicotine sc + MLA ip (n=18). Results: Nicotine alone significantly increased aneurysmal rupture compared with saline treatment (89% vs 46%, p=0.009). While α7nAChR antagonist did not affect the incidence of aneurysm or rupture rates, the α7nAChR antagonist significantly reduced the deleterious effect of nicotine as indicated by the reduction of the rupture rates (41% vs 100%: nicotine sc + MLA ip group vs nicotine sc + saline ip group, p=0.027). Conclusion: Our data indicate the promotion of aneurysm rupture by nicotine may be mediated by its stimulation of alpha7nAChR.

scholarly journals Mast cell function in prostate inflammation, fibrosis, and smooth muscle cell dysfunction

2021 ◽  
Author(s):  
Goutham Pattabiraman ◽  
Ashlee J Bell-Cohn ◽  
Stephen F. Murphy ◽  
Daniel J Mazur ◽  
Anthony J Schaeffer ◽  
...  
Keyword(s):  
Mast Cell ◽  
Smooth Muscle ◽  
Mast Cells ◽  
Cell Activation ◽  
Cell Function ◽  
Critical Role ◽  
Smooth Muscle Contraction ◽  
Urinary Dysfunction ◽  
Mast Cell Activation ◽  
Prostate Inflammation

Intraurethral inoculation of mice with uropathogenic E. coli (CP1) results in prostate inflammation, fibrosis, and urinary dysfunction, recapitulating some but not all of the pathognomonic clinical features associated with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). In both patients with LUTS and in CP1-infected mice, we observed increased numbers and activation of mast cells and elevated levels of prostate fibrosis. Therapeutic inhibition of mast cells using a combination of mast cell stabilizer (MCS), cromolyn sodium, and the histamine 1 receptor antagonist (H1RA), cetirizine di-hydrochloride, in the mouse model resulted in reduced mast cell activation in the prostate and significant alleviation of urinary dysfunction. Treated mice showed reduced prostate fibrosis, less infiltration of immune cells, and decreased inflammation. In addition, as opposed to symptomatic CP1-infected mice, treated mice showed reduced myosin light chain (MLC)-2 phosphorylation, a marker of prostate smooth muscle contraction. These results show that mast cells play a critical role in the pathophysiology of urinary dysfunction and may be an important therapeutic target for men with BPH/LUTS.

Current implications for the efficacy of noninvasive screening for occult intracranial aneurysms in patients with a family history of aneurysms

1995 ◽  
Vol 83 (1) ◽  
pp. 42-49 ◽  
Author(s):  
Nancy A. Obuchowski ◽  
Michael T. Modic ◽  
Michele Magdinec
Keyword(s):  
Family History ◽  
Natural History ◽  
Life Expectancy ◽  
Intracranial Aneurysms ◽  
Positive Family History ◽  
Aneurysm Rupture ◽  
Average Life Expectancy ◽  
Content Type ◽  
Rupture Rate ◽  
History Of

✓ Although the technology exists for accurate noninvasive screening for intracranial aneurysms, the efficacy of screening depends on several key parameters of the natural history of aneurysms. Recent studies suggest that the prevalence of intracranial aneurysms may reach 20% in the subpopulation of patients with a family history of these lesions; other key parameters are less certain. The authors investigated factors that impact the efficacy of screening to establish interim guidelines. Three plausible models for the natural history of aneurysms were constructed. For each model the monetary cost of screening and the average gain in life expectancy were computed for a range of screening ages and prevalence rates. It is shown that the efficacy of screening depends on the pattern of aneurysm rupture. If aneurysms develop and rupture rapidly, then screening has no benefit. On the other hand, if aneurysms remain at risk for some time after formation, then screening may improve average life expectancy depending on when it occurs. The authors recommend that patients with a positive family history of aneurysms who are 30 years of age or younger be screened. This recommendation is based on the belief that the gains attributable to screening, assuming a constant rupture rate, outweigh the losses attributable to screening using a decreasing rupture rate model.

scholarly journals A Review of the Evidence for and against a Role for Mast Cells in Cutaneous Scarring and Fibrosis

2020 ◽  
Vol 21 (24) ◽  
pp. 9673
Author(s):  
Traci A. Wilgus ◽  
Sara Ud-Din ◽  
Ardeshir Bayat
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
Social Issues ◽  
Critical Role ◽  
Large Body ◽  
Repair Process ◽  
Scar Tissue ◽  
Mast Cell Activation

Scars are generated in mature skin as a result of the normal repair process, but the replacement of normal tissue with scar tissue can lead to biomechanical and functional deficiencies in the skin as well as psychological and social issues for patients that negatively affect quality of life. Abnormal scars, such as hypertrophic scars and keloids, and cutaneous fibrosis that develops in diseases such as systemic sclerosis and graft-versus-host disease can be even more challenging for patients. There is a large body of literature suggesting that inflammation promotes the deposition of scar tissue by fibroblasts. Mast cells represent one inflammatory cell type in particular that has been implicated in skin scarring and fibrosis. Most published studies in this area support a pro-fibrotic role for mast cells in the skin, as many mast cell-derived mediators stimulate fibroblast activity and studies generally indicate higher numbers of mast cells and/or mast cell activation in scars and fibrotic skin. However, some studies in mast cell-deficient mice have suggested that these cells may not play a critical role in cutaneous scarring/fibrosis. Here, we will review the data for and against mast cells as key regulators of skin fibrosis and discuss scientific gaps in the field.

scholarly journals Critical role of TNF-alpha-TNFR1 signaling in intracranial aneurysm formation

2014 ◽  
Vol 2 (1) ◽  
Author(s):  
Tomohiro Aoki ◽  
Miyuki Fukuda ◽  
Masaki Nishimura ◽  
Kazuhiko Nozaki ◽  
Shuh Narumiya
Keyword(s):  
Intracranial Aneurysm ◽  
Critical Role ◽  
Tnf Alpha ◽  
Aneurysm Formation

Cerebral vasospasm: presence of mast cells in human cerebral arteries after aneurysm rupture

1981 ◽  
Vol 54 (6) ◽  
pp. 733-735 ◽  
Author(s):  
Luiz C. M. Faleiro ◽  
Conceição R. S. Machado ◽  
Amado Gripp ◽  
Rubens A. Resende ◽  
Pedro A. Rodrigues
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Population ◽  
Hydrolytic Enzymes ◽  
Aneurysm Rupture ◽  
Blue Staining ◽  
Control Group ◽  
Preliminary Note ◽  
Muscular Layer ◽  
Mast Cell Population

✓ Mast cells contain heparin, histamine, hydrolytic enzymes, and possibly serotonin in metachromatic cytoplasmic granules, and are not visualized in routine histological preparations. Special fixation, frozen sections, and toluidine blue staining are essential for counting the number of mast cells in tissue sections. Histological preparations for counting mast cells were made from arteries of the circle of Willis in persons who died after chest or abdominal trauma (control group) and in patients who had subarachnoid hemorrhage (SAH) after aneurysm rupture. The arteries were removed within 6 hours of death, taking care to avoid damage to their structure, and were immersed in the fixative solution. This preliminary note, reporting findings in only a few cases, is justified by the interesting discovery of a marked increase in mast cell population in the muscular layer of arteries after SAH. The series is small because of the difficulty in obtaining suitable material, since mast cells virtually disappear when autopsy is performed later than 6 hours after death. It is concluded from this study that there is an increase of mast cell population in cerebral arterial walls after SAH, mainly in the muscular layer, and that the number of mast cells is higher in arteries closer to the aneurysm.

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