Involvement of neutrophils in machineries underlying the rupture of intracranial aneurysms

2019 ◽  
Author(s):  
Mika Kushamae ◽  
Haruka Miyata ◽  
Manabu Shirai ◽  
Kampei Shimizu ◽  
Mieko Oka ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Rat Model ◽  
Immunohistochemical Study ◽  
Therapeutic Modality ◽  
Major Type ◽  
Collagenolytic Activity ◽  
Inflammatory Stimuli ◽  
A Site ◽  
Gene Expression Profile Data

Abstract Background: Subarachnoid hemorrhage due to rupture of an intracranial aneurysm (IA) has quite a poor prognosis once after the onset despite of the modern technical advancement. The development of a novel therapeutic modality to prevent rupture or a diagnostic method to stratify dangerous lesions from many stable ones is thus mandatory for social health. To this end, mechanisms underlying rupture of lesions should be clarified. Methods: We and others have developed the rat model in which induced IAs spontaneously rupture resulting in subarachnoid hemorrhage. To clarify molecular cascades regulating rupture, we obtained gene expression profile data from rupture-prone lesions and revealed the enrichment of neutrophil-related terms in rupture-prone lesions by Gene Ontology analysis. Next, to validate a role of neutrophils in rupture of lesions, G-CSF was administered to a rat model. Results: As a result, G-CSF treatment not only increased number of neutrophils infiltrating in lesions but also significantly facilitated rupture of the lesions without increase the incidence. To clarify mechanisms how neutrophils facilitate rupture of IAs, we used HL-60 cell line and found that inflammatory stimuli enhanced the collagenolytic activity of MMP9. Immunohistochemical study using IA lesions from a rat model identified neutrophils as a major type of cells producing MMP9 around a site of rupture and consistently the collagenolytic activity of MMP9 was detected in ruptured lesions. Conclusions: These results combined together suggest the crucial role of neutrophil to rupture of IAs and also propose the potential of this type of cells as a candidate of therapeutic or diagnostic targets.

scholarly journals Involvement of neutrophils in machineries underlying the rupture of intracranial aneurysms in rats

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Mika Kushamae ◽  
Haruka Miyata ◽  
Manabu Shirai ◽  
Kampei Shimizu ◽  
Mieko Oka ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Intracranial Aneurysms ◽  
Collagenolytic Activity ◽  
Inflammatory Stimuli ◽  
Technical Advances ◽  
Gene Expression Profile Data ◽  
Metalloproteinase 9 ◽  
Immunohistochemical Analyses

AbstractSubarachnoid hemorrhage due to rupture of an intracranial aneurysm has a quite poor prognosis after the onset of symptoms, despite the modern technical advances. Thus, the mechanisms underlying the rupture of lesions should be clarified. To this end, we obtained gene expression profile data and identified the neutrophil-related enriched terms in rupture-prone lesions using Gene Ontology analysis. Next, to validate the role of neutrophils in the rupture of lesions, granulocyte-colony stimulating factor (G-CSF) was administered to a rat model, in which more than half of induced lesions spontaneously ruptured, leading to subarachnoid hemorrhage. As a result, G-CSF treatment not only increased the number of infiltrating neutrophils, but also significantly facilitated the rupture of lesions. To clarify the mechanisms of how neutrophils facilitate this rupture, we used HL-60 cell line and found an enhanced collagenolytic activity, corresponding to matrix metalloproteinase 9 (MMP9), upon inflammatory stimuli. The immunohistochemical analyses revealed the accumulation of neutrophils around the site of rupture and the production of MMP9 from these cells in situ. Consistently, the collagenolytic activity of MMP9 could be detected in the lysate of ruptured lesions. These results suggest the crucial role of neutrophils to the rupture of intracranial aneurysms; implying neutrophils as a therapeutic or diagnostic target candidate.

Abstract 314: Elevation of (pro)renin and Its Receptor in Preeclampsia: A Rat Model and Human Patients

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Mohammad N Uddin ◽  
Darijana Horvat ◽  
Russell E Fothergill ◽  
Kelsey R Kelso ◽  
Richard O Jones ◽  
...  
Keyword(s):  
Rat Model ◽  
Renin Angiotensin System ◽  
Placental Tissue ◽  
Pregnant Rats ◽  
Angiotensin System ◽  
Ras Activation ◽  
Kolmogorov Smirnov ◽  
Desoxycorticosterone Acetate ◽  
A Site

Preeclampsia (PreE), a syndrome manifesting with hypertension, proteinuria, and edema, is a leading cause of maternal and fetal morbidity and mortality. While preE triggers are likely many and elusive, the renin-angiotensin system (RAS) has been implicated in preE pathogenesis. However, there is no data showing involvement of (pro)renin and its receptor. We recruited 32 preE and 57 normal pregnant consenting patients. (Pro)renin levels were assayed in plasma samples using an ELISA kit. An established rat model of preE was used to evaluate the role of (pro)renin and its receptor in pathogenesis. We used normal pregnant rats (NP, n=10) and pregnant rats receiving weekly injections of desoxycorticosterone acetate and whose drinking water was replaced with 0.9% saline (PreE, n=10). The plasma and placental levels of (pro)renin were assayed by ELISA. The placental levels of (pro)renin receptor was measured by gel electrophoresis of the placental homogenate followed by detection with immunoblotting using anti-ATP6IP2 antibody. The ERK1/2 phosphorylation was analyzed by immunoblotting using antibodies to total and active ERK1/ERK2 in the placenta. The mean plasma (pro)renin of 0.27 ± 0.04 μg/mL in preE patients differ (p < 0.001 using Student’s t test) from 0.15 ± 0.05 μg/mL in those without preE. Both plasma and placental levels of (pro)renin were higher (p < 0.001 using Kolmogorov-Smirnov test) in PreE rats compared to NP (Plasma (pro)renin for NP:0.21 ± 0.04 and PreE:0.49 ± 0.09 pg/mL; placental (pro)renin for NP:152 ± 79 and PreE:302 ± 42 ng/g tissue). In addition to serving as a source of (pro)renin, the placenta is also a site for signaling as ERK1/2 phosphorylation is greater (p<0.05) in placental tissue of preE rats. These data show that circulatory and uteroplacental (pro)renin and its receptor are upregulated. Together with the upregulation of ERK1/2 phosphorylation in placenta of the rat model, there is now evidence of (pro)renin and its receptor associated novel RAS activation to play a role in preE pathogenesis through (pro)renin receptor-mediated detrimental cellular signaling at the placental boundary. This offers an opportunity for interventional treatments with signal inhibitors and interference with nonclassical (pro)renin activation of RAS.

scholarly journals Role of SCH79797 in Maintaining Vascular Integrity in Rat Model of Subarachnoid Hemorrhage

Stroke ◽  
2013 ◽  
Vol 44 (5) ◽  
pp. 1410-1417 ◽  
Author(s):  
Junhao Yan ◽  
Anatol Manaenko ◽  
Sheng Chen ◽  
Damon Klebe ◽  
Qingyi Ma ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Rat Model ◽  
Vascular Integrity

The role of p53 in brain edema after 24 h of experimental subarachnoid hemorrhage in a rat model

2008 ◽  
Vol 214 (1) ◽  
pp. 37-46 ◽  
Author(s):  
Junhao Yan ◽  
Chunhua Chen ◽  
Qing Hu ◽  
Xiaomei Yang ◽  
Jiliang Lei ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Brain Edema ◽  
Rat Model ◽  
Experimental Subarachnoid Hemorrhage

scholarly journals APC Overexpression Suppresses the Pyroptosis of Subarachnoid Hemorrhage Model Cells through Regulating NLRP3 Inflammasome Pathway

2021 ◽  
Author(s):  
Ai Yan ◽  
Xuyan Pan ◽  
Xianqiang Wen ◽  
Xiaohu Nie ◽  
Yuntao Li
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Rat Model ◽  
Nlrp3 Inflammasome ◽  
Cell Model ◽  
Activated Protein C ◽  
Dependent Manner ◽  
Balance Beam ◽  
Novel Strategy ◽  
Dose Dependent

Abstract Subarachnoid hemorrhage (SAH) is a kind of hemorrhagic stroke with high mortality. Activated protein C (APC) was implicated to play a neuroprotective role in central nervous system diseases. However, its role in SAH remains unclear. Our study aims to investigate the role of APC and its regulatory mechanism in SAH. The SAH rat model was constructed by internal carotid artery puncture. The SAH cell model was established by the application of oxygen hemoglobin. ELISA was performed to detect the level of cytokines. Flow cytometry was used to detect the population of pyroptosis cells. Neurological functions of rats were estimated using modified Garcia scoring and balance beam test. SAH hemorrhage was estimated using modified Sugawara's scoring. APC was significantly increased and NLRP3 was decreased in SAH rat model in a time-dependent manner. The application of APC recombinant protein 3K3A-APC could notably ameliorate SAH hemorrhage and improve neurological functions. Besides, 3K3A-APC could inhibit pyroptosis in a dose-dependent manner in SAH cell model. Moreover, the inhibition of NLRP3 could reverse the effects induced by the knockdown of APC. Our study revealed that APC could ameliorate SAH-induced EBI by suppressing pyroptosis via inhibiting NLRP3 inflammasome, which would provide a novel strategy for the treatment of SAH.

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