Inflammation in Murine Aneurysm Healing: The Role of CXCL1

Abstract INTRODUCTION Cerebral aneurysm rupture results in subarachnoid hemorrhage which has a mortality of up to 40%. Current prophylactic treatment options include surgical clipping, flow diversion, and endovascular coiling. A significant drawback of coiling is that up to 20% of aneurysms recur and require retreatment due to insufficient fibrotic healing. Thus, it is crucial to develop more effective treatments. As inflammation appears to be critical in cerebral aneurysm pathophysiology, it is necessary to investigate aneurysm healing in the context of key inflammatory mediators. Using a novel in Vitro flow chamber model, we found increased expression of CXCL1, a neutrophil chemoattractant, at arterial bifurcations and in aneurysms. We hypothesized that CXCL1 is a key mediator in aneurysm healing. METHODS Using our murine aneurysm healing model, aneurysms were created in the right common carotid artery of female C57BL/6 mice using elastase. Three weeks later, aneurysms were implanted with either poly (lactic-co-glycolic acid) (PLGA) + CXCL1—coated coils or PLGA only—coated coils. Three weeks after coil implantation, aneurysms were harvested for data collection. In a subsequent experiment, the same aneurysm model was used but all mice were coiled with PLGA-coated coils. Animals were randomly assigned to receive intraperitoneal injections of either CXCL1 neutralizing antibody or IgG control. Three weeks after coiling, aneurysms were harvested for data collection. RESULTS Animals treated with PLGA + CXCL1—coated coils had significantly decreased aneurysm healing than those treated with PLGA only—coated coils (21.8% vs 39.8%, P = .048). Animals treated with CXCL1 neutralizing antibody had significantly increased aneurysm healing compared to IgG control (63.8% vs 42.4%, P = .00012). CXCL1 neutralizing antibody also decreased neutrophil infiltration into the aneurysm compared to IgG control (2.0 cells/hpf vs 5.4 cells/hpf, P = .03). CONCLUSION Our findings suggest CXCL1 decreases murine aneurysm healing after coil implantation. Therapeutic intervention with CXCL1 neutralizing antibody appears to increase aneurysm healing by decreasing neutrophil infiltration.

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Risk Factors for Cerebral Aneurysm Rupture in Mongolia

Clinical Neuroradiology ◽

10.1007/s00062-021-01051-z ◽

2021 ◽

Author(s):

Matthias Bechstein ◽

Amarjargal Gansukh ◽

Boldbat Regzengombo ◽

Oyun Byambajav ◽

Lukas Meyer ◽

...

Keyword(s):

Risk Factors ◽

Medical History ◽

Cerebral Aneurysm ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Imaging Modality ◽

Treatment Options ◽

Time Estimation ◽

Developed Countries ◽

Aneurysm Rupture ◽

Risk Of Rupture

Abstract Purpose Identification of country-specific demographic, medical, lifestyle, and geoenvironmental risk factors for cerebral aneurysm rupture in the developing Asian country of Mongolia. First-time estimation of the crude national incidence of aneurysmal subarachnoid hemorrhage (aSAH). Methods A retrospective analysis of all intracranial digital subtraction angiographies (DSA) acquired in Mongolia during the 2‑year period 2016–2017 (1714 examinations) was performed. During this period, DSA was used as primary diagnostic imaging modality for acute severe neurological symptoms in the sole hospital nationwide dedicated to neurological patients. The catchment area of the hospital included the whole country. Patients with incidental and ruptured aneurysms were reviewed with respect to their medical history and living conditions. The data was used to install a Mongolian aneurysm registry. Results The estimated annual crude incidence of cerebral aneurysm rupture was 6.71 for the country of Mongolia and 14.53 per 100,000 persons for the capital region of Ulaanbaatar. Risk factors common in developed countries also applied for the Mongolian population: A medical history of hypertension, smoking or the presence of multiple aneurysms led to a higher relative risk of rupture. In contrast, female gender was not associated with a higher risk in this national cohort. Males pursuing a traditional nomadic living may exhibit a specifically high risk of rupture. Conclusion Disease management of over 200 individuals/year with aSAH constitutes a socioeconomic burden in Mongolia. Efforts to raise awareness of the risk factors hypertension and smoking among the Mongolian population are desirable. Measures to improve the nationwide availability of modern neurovascular treatment options are currently under consideration.

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Abstract TP93: Early Morphological Changes in Cerebral Arteries of Cerebral Aneurysm Rupture Model Rats

Stroke ◽

10.1161/str.47.suppl_1.tp93 ◽

2016 ◽

Vol 47 (suppl_1) ◽

Author(s):

Hidetsugu Maekawa ◽

Takeshi Miyamoto ◽

Keiko T Kitazato ◽

Kenji Yagi ◽

Yoshiteru Tada ◽

...

Keyword(s):

Carotid Artery ◽

Cerebral Aneurysm ◽

Cerebral Artery ◽

Morphological Changes ◽

Cerebral Aneurysms ◽

Aneurysm Rupture ◽

Anterior Communicating Artery ◽

Artery Ligation ◽

Ruptured Aneurysms ◽

The Right

Introduction: To study the pathomechanisms of cerebral aneurysms, we developed a rat model of cerebral aneurysm rupture. In order, the ruptured aneurysms were located at the P1 segment of the left posterior cerebral artery, on the anterior cerebral artery (ACA), the right internal carotid artery (ICA), the right middle cerebral artery (MCA), and the anterior communicating artery (AcomA). We investigated the early morphological changes in these arteries that preceded aneurysm formation. Methods: We subjected 10-week-old Sprague-Dawley rats to bilateral ovariectomy and modified carotid artery ligation. They were fed a high salt diet. Two weeks later, the bilateral posterior renal arteries were ligated. Vascular corrosion casts were created 2 weeks after renal artery ligation (n=11) and the morphological features were compared on casts from these- and sham rats (n=3) using a scanning electron microscope. Results: The diameter of the left- was larger than of the right P1 in all rats with hypertension and estrogen deficiency. Endothelial changes were predominantly seen in the AcomA and the left P1. In 5 rats we observed small protrusions without loss of endothelial imprints suggesting local loss of internal elastic lamina in the left P1 where ruptured aneurysms were frequently formed. No aneurysms formed at the right ACA-olfactory artery (OA) bifurcation within 2 weeks after aneurysm induction. None of these changes were found in the controls. As ACA-OA aneurysms were frequently seen at 3 months but never ruptured, the pathophysiology of such, and of aneurysms formed at other sites may be different. Conclusion: We first demonstrate the initial morphological changes that occurred as early as two weeks after aneurysm induction in rats. Early intervention for hypertension and endothelial damage may be beneficial in the management of cerebral aneurysms.

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Influence of Cyclophosphamide on L-Asparaginase-Induced Allergy in Animal Model

Blood ◽

10.1182/blood-2019-127179 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5119-5119

Author(s):

Ai Nogami-Hara ◽

Akira Shimada ◽

Mitsunobu Mio

Keyword(s):

Conflicts Of Interest ◽

Ex Vivo ◽

Lymphoblastic Leukemia ◽

Neutralizing Antibody ◽

Treg Cells ◽

Mouse Serum ◽

Ear Edema ◽

The Right

BACKGROUND: L-Asparaginase (L-ASP) is one of the essential drugs for acute lymphoblastic leukemia and lymphoma. Since L-ASP proteins used clinically are derived from bacteria, they often cause allergies, including anaphylaxis. However, the characteristics of L-ASP-induced hypersensitivity are not well documented so far. Also, there is neither suitable treatment for hypersensitivity to L-ASP nor adequate experimental model of L-ASP allergy. In addition, some anti-cancer drugs, used concomitantly with L-ASP, are known to affect lymphocyte activities, although the role of such drugs on L-ASP hypersensitivity is not known. Previously, we have established mouse model of L-ASP allergy and found that a neutralizing antibody (Ab) of IgE is effective to inhibit L-ASP-induced allergic reaction. Aims: In order to establish in vitro model of L-ASP allergy, we used RBL-2H3 mast cells and evoked degranulation of the cells sensitized with L-ASP-allergic mouse serum using L-ASP as an antigen. Furthermore, we examined the effect of cyclophosphamide (CY), which reportedly impairs the functions of regulatory T (Treg) cells, on L-ASP allergy both in vivo and in vitro. Methods: Male BALB/c mice (7 week old) were sensitized with L-ASP (100 units) with Al(OH)3 gel (1 mg) on days 1 and 15. The right ears of the mice were locally sensitized on days 18, 21, 24 by i.d. injection of L-ASP (10 units). Antigen challenge was carried out on day 27 by i.d. injection (10 units). CY (75, 150, 300 mg/kg) was i.p. administrated at day -1 and day 13. Anti-IgE treatment (BD Bioscience, clone R35-92; 100 μg, i.p.) was carried out on the day before L-ASP challenge. The serum was collected on day 27. Total IgE level in the serum was measured by ELISA kit (Yamasa). RBL-2H3 cells were sensitized by the serum and stimulated by L-ASP to determine β-hexosaminidase (β-Hex) release in vitro. Results : L-ASP-sensitization induced allergic ear edema and an increase in serum IgE level in mice, both of which are augmented by an administration of CY at 150 mg/kg. L-ASP-induced allergic ear edema was inhibited by a pretreatment with anti-IgE Ab. L-ASP-induced CY-enhanced ear edema was also inhibited by anti-IgE Ab. On the other hand, at 300 mg/kg of CY, L-ASP-induced ear edema was much lower than 150 mg/kg group, though IgE concentration in the serum was as high as CY 150 mg/kg group. When RBL-2H3 cells were sensitized by anti-L-ASP serum, L-ASP challenge induced β-Hex release. Anti-L-ASP serum of CY 150 mg/kg-treated mice induced higher β-Hex release than normal anti-L-ASP sera in vitro, though that of CY 300 mg/kg-treated mice did not induce β-Hex release. After removing IgG from the serum of CY 300 mg/kg-treated mice using protein G Mag Sepharose (GE Healthcare), β-Hex release became higher than normally sensitized mice. Anti-IgE Ab treatment both ex vivo and in vitro inhibited L-ASP-induced β-Hex release from the RBL-2H3 cells sensitized by anti-L-ASP serum of CY-treated mice. Conclusions: In this study, we showed that L-ASP sensitization induced IgE production in vivo and this serum could bring about β-Hex release from RBL-2H3 cells in vitro; both allergic reactions were inhibited by an anti-IgE antibody which binds to Fc region of IgE molecule. From these results, we propose that non-anaphylactogenic neutralizing antibody of IgE, such as omalizumab, can be a candidate drug for the treatment of L-ASP hypersensitivity. Also in this study, CY induced biphasic effects on L-ASP allergy in mice, enhancing it at low dosage and attenuating it at high dosage. Since CY is reportedly impair the functions of Treg cells, CY-induced suppression of Treg may enhance Th2 responses so as to augment L-ASP hypersensitivity. Further investigations for the detection and avoidance of L-ASP hypersensitivity are under the way. Disclosures No relevant conflicts of interest to declare.

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Intraprocedural cerebral aneurysm rupture during endovascular coiling

Neurology India ◽

10.4103/0028-3886.82736 ◽

2011 ◽

Vol 59 (3) ◽

pp. 369 ◽

Cited By ~ 6

Author(s):

Peizhuo Zang ◽

Qiang Shi ◽

Chuansheng Liang ◽

Yunjie Wang

Keyword(s):

Cerebral Aneurysm ◽

Aneurysm Rupture ◽

Endovascular Coiling

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Generation of Realistic Physical Models of Cerebral Aneurysms for In Vitro Flow Visualisation

ASME 2009 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2009-206656 ◽

2009 ◽

Cited By ~ 1

Author(s):

Paul Fahy ◽

Tim McGloughlin ◽

Patrick Delassus ◽

Liam Morris

Keyword(s):

Treatment Options ◽

Cerebral Aneurysms ◽

Physical Models ◽

Endovascular Coiling ◽

Flow Visualisation ◽

Cerebral Vasculature ◽

Surgical Clipping ◽

The Media ◽

Media Layer

An aneurysm is a localised persistent dilation of the blood vessel wall. Aneurysm formation is hypothesised to be a consequence of haemodynamically generated forces working on the arterial wall leading to degeneration of the media layer (1). This focal degeneration typically occurs at curved arterial segments and at bifurcation points around the circle of Willis. Intracranial aneurysms are traditionally classified by aetiology and morphology. The majority are idiopathic and saccular. It is estimated that 1.5–6% of the general population have or will develop an intracranial aneurysm, predominantly occurring in women, most of them being asymptomatic (1). If left undetected these aneurysms may rupture with a 30 day mortality rate of 45% (1). There are two treatment options surgical clipping or endovascular coiling. Both of these techniques exclude the aneurysm from the normal circulation. Endovascular coiling is preferred due to its minimally invasive nature. Numerous studies have been done so far based on idealized glass models and using FVM, FEA methods, but very little testing has been carried out on devices using realistic silicone models. This is mainly because of the complexity of the cerebral vasculature. Silicone replicas of both realistic and idealised models were manufactured based on CT scans and anatomical dimensions obtained from literature, respectively (2).

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Interleukin-6 Promotes Murine Estrogen Deficiency-Associated Cerebral Aneurysm Rupture

Neurosurgery ◽

10.1093/neuros/nyz220 ◽

2019 ◽

Vol 86 (4) ◽

pp. 583-592 ◽

Cited By ~ 1

Author(s):

Daisuke Wajima ◽

Siham Hourani ◽

William Dodd ◽

Devan Patel ◽

Chad Jones ◽

...

Keyword(s):

Cerebral Aneurysm ◽

Cerebral Aneurysms ◽

Neutralizing Antibody ◽

Aneurysm Rupture ◽

Estrogen Deficiency ◽

Circle Of Willis ◽

Macrophage Infiltration ◽

Wild Type ◽

Rupture Rate ◽

Deficient Mice

Abstract BACKGROUND Estrogen deficiency is associated with cerebral aneurysm rupture, but the precise mechanism is unknown. OBJECTIVE To test the hypothesis that IL-6 is required for the increase in aneurysm rupture rate observed in estrogen-deficient mice. METHODS We analyzed IL-6 expression in human cerebral aneurysms. We induced cerebral aneurysms in estrogen-deficient female C57BL/6 mice that had undergone 4-vinylcyclohexene diepoxide (VCD) treatment or bilateral ovariectomy (OVE). Mice were blindly randomized to selective IL-6 inhibition (IL-6 receptor [IL-6R] neutralizing antibody, n = 25) or control (isotype-matched IgG, n = 28). Murine cerebral arteries at the circle of Willis were assessed for aneurysm rupture and macrophage infiltration. RESULTS IL-6 is expressed in human cerebral aneurysms, but not in control arteries. Serum IL-6 is elevated in ovariectomized female mice compared to sham control (14.3 ± 1.7 pg/mL vs 7.4 ± 1.5 pg/mL, P = .008). Selective IL-6R inhibition suppressed cerebral aneurysm rupture in estrogen-deficient mice compared with control (VCD: 31.6% vs 70.0%, P = .026; OVE: 28.6% vs 65.2%, P = .019). IL-6R inhibition had no effect on formation or rupture rate in wild-type mice. IL-6R neutralizing antibody significantly reduced macrophage infiltration at the circle of Willis (1.9 ± 0.2 vs 5.7 ± 0.6 cells/2500 μm2; n = 8 vs n = 15; P < .001). CONCLUSION IL-6 is increased in the serum of estrogen-deficient mice and appears to play a role in promoting murine estrogen deficiency-associated cerebral aneurysm rupture via enhanced macrophage infiltration at the circle of Willis. Inhibition of IL-6 signaling via IL-6 receptor neutralizing antibody inhibits aneurysm rupture in estrogen-deficient mice. IL-6 receptor inhibition had no effect on aneurysm formation or rupture in wild-type animals.

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Mechanics of the Tricuspid Valve—From Clinical Diagnosis/Treatment, In-Vivo and In-Vitro Investigations, to Patient-Specific Biomechanical Modeling

Bioengineering ◽

10.3390/bioengineering6020047 ◽

2019 ◽

Vol 6 (2) ◽

pp. 47 ◽

Cited By ~ 16

Author(s):

Chung-Hao Lee ◽

Devin W. Laurence ◽

Colton J. Ross ◽

Katherine E. Kramer ◽

Anju R. Babu ◽

...

Keyword(s):

Heart Valve ◽

Tricuspid Valve ◽

Tricuspid Regurgitation ◽

Treatment Options ◽

Biomechanical Properties ◽

Patient Specific ◽

Functional Tricuspid Regurgitation ◽

The Right

Proper tricuspid valve (TV) function is essential to unidirectional blood flow through the right side of the heart. Alterations to the tricuspid valvular components, such as the TV annulus, may lead to functional tricuspid regurgitation (FTR), where the valve is unable to prevent undesired backflow of blood from the right ventricle into the right atrium during systole. Various treatment options are currently available for FTR; however, research for the tricuspid heart valve, functional tricuspid regurgitation, and the relevant treatment methodologies are limited due to the pervasive expectation among cardiac surgeons and cardiologists that FTR will naturally regress after repair of left-sided heart valve lesions. Recent studies have focused on (i) understanding the function of the TV and the initiation or progression of FTR using both in-vivo and in-vitro methods, (ii) quantifying the biomechanical properties of the tricuspid valve apparatus as well as its surrounding heart tissue, and (iii) performing computational modeling of the TV to provide new insight into its biomechanical and physiological function. This review paper focuses on these advances and summarizes recent research relevant to the TV within the scope of FTR. Moreover, this review also provides future perspectives and extensions critical to enhancing the current understanding of the functioning and remodeling tricuspid valve in both the healthy and pathophysiological states.

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Neutrophil-Derived Interleukin 16 in Premetastatic Lungs Promotes Breast Tumor Cell Seeding

Cancer Growth and Metastasis ◽

10.1177/1179064417738513 ◽

2017 ◽

Vol 10 ◽

pp. 117906441773851 ◽

Cited By ~ 15

Author(s):

Kim Donati ◽

Christelle Sépult ◽

Natacha Rocks ◽

Silvia Blacher ◽

Catherine Gérard ◽

...

Keyword(s):

Tumor Cell ◽

Molecular Mechanisms ◽

Neutralizing Antibody ◽

Neutrophil Infiltration ◽

Lung Parenchyma ◽

Cell Seeding ◽

Premetastatic Niche ◽

Metastatic Cell ◽

And Migration

The premetastatic niche in distant organs prior to metastatic cell arrival emerged as an important step in the metastatic cascade. However, molecular mechanisms underlying this process are still poorly understood. In particular, whether neutrophil recruitment at a premetastatic stage promotes or inhibits metastatic cell seeding has to be clarified. We aimed at unraveling how neutrophil infiltration in lung parenchyma induced by the distant primary tumor influences the establishment of lung metastasis. Elevated neutrophil counts and IL-16 levels were found in premetastatic lungs in a syngenic mouse model using 4T1 tumor cells. 4T1 cell–derived soluble factors stimulated IL-16 secretion by neutrophils. The functional contribution of IL-16 is supported by metastasis burden reduction in lungs observed on instillation of an IL-16 neutralizing antibody. Moreover, IL-16 promotes in vitro 4T1 cell adhesiveness, invasiveness, and migration. In conclusion, at a premetastatic stage, neutrophil-derived IL-16 favors tumor cell engraftment in lung parenchyma.

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Abstract WP81: Prediction of Cerebral Aneurysm Growth Using Original Magnetic Resonance Imaging-based Computational Fluid Dynamics Tool

Stroke ◽

10.1161/str.48.suppl_1.wp81 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Hidehito Kimura ◽

Kohsuke Hayashi ◽

Kohkichi Hosoda ◽

Atsushi Fijita ◽

Masaaki Taniguchi ◽

...

Keyword(s):

Magnetic Resonance ◽

Cerebral Aneurysm ◽

Fluid Dynamic ◽

Aneurysm Rupture ◽

Stream Line ◽

Endovascular Coiling ◽

Imaging Data ◽

Unruptured Aneurysms ◽

Diastolic Phase ◽

Aneurysm Growth

Background: Cerebral aneurysm growth is supposed to often precede aneurysm rupture. To predict aneurysm growth for unruptured aneurysms is still difficult by means of recently well-developed commercially available computational fluid dynamic (CFD) software. Purpose: To detect the possible factor contributing to for the aneurysm growth with our originally developed CFD tool. Methods: We retrospectively reviewed the aneurysms that were treated between April 2013 and March 2016 at our institute by surgical clipping or endovascular coiling with the reason of its growth (growth group). In contrast, we extracted unruptured aneurysms that had experienced no growth for at least five years (non- growth group). Time of flight (TOF) - magnetic resonance (MR) imaging data of them were converted to the three- dimenstional (3D) vessel geometric data and three hemodynamic indices: stream line (SL), wall shear stress (WSS), oscillatory shear index (OSI), were calculated with lattice Boltzmann method and compared between the two groups. Results: Six growth aneurysms and 5 non-growth aneurysms were analyzed in this study. In the growth group, mean initial aneurysms size was 4.7mm and increased to 6.2mm after mean follow up of 33.4 months. In the non-growth group, mean aneurysm size was 5.8mm. Analyses of flow dynamics were successfully done in all cases. In all six enlarged aneurysms, WSS was increased temporally at the early diastolic phase on the focal aneurysmal sac where the aneurysms would enlarge in the future (Fig. A,B). Furthermore, in four of them, focal increase in WSS formed crescent-like shape surrounding low WSS (Inset in Fig. A). In contrast, WSS was not increased even at the early diastolic phase in three of five non-enlarged aneurysms. The SL or OSI showed no specific differences between the two groups. Conclusion: Focal increase of WSS, some of them formed crescent-like shape, at the early diastolic phase may be the possible factor for the aneurysm enlargement in future.

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Endovascular Management of Cerebral Aneurysm: The Recent Trends

Indian Journal of Neurosurgery ◽

10.1055/s-0038-1669478 ◽

2018 ◽

Vol 07 (03) ◽

pp. 209-215

Author(s):

Vipul Gupta ◽

Shrikant Londhe ◽

Rajsrinivas Parthasarathy ◽

Hilal Ganaie

Keyword(s):

Cerebral Aneurysm ◽

Flow Diverter ◽

Aneurysm Rupture ◽

Endovascular Coiling ◽

Endovascular Management ◽

Mortality And Morbidity ◽

Balloon Catheters ◽

International Subarachnoid Aneurysm Trial ◽

Recent Trends ◽

Wide Neck

AbstractCerebral aneurysm rupture is the leading cause of mortality and morbidity in patients with hemorrhagic stroke. Surgical clipping and endovascular coiling are the mainstay of management for securing the aneurysm. After International Subarachnoid Aneurysm Trial (ISAT) and Barrow Ruptured Aneurysm Trial (BRAT) results, worldwide trend has shifted gradually in favor of endovascular management. Nonetheless, endovascular management was faced with some limitations, especially while treating giant, wide neck bifurcation, blister, and small uncoilable aneurysm. The recent introduction of new devices such as flow diverter stents, microstents, bifurcation devices, double-lumen balloon catheters, and microcoils have proved to be effective in overcoming the limitations of traditional aneurysm coiling. The authors present a review of recent advances in the endovascular management of cerebral aneurysm.

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