The Role of Inflammasome in the Pathophysiology of Delay Ischemic Neurological Deficit after Subarachnoid Hemorrhage

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Project title/計畫英文名

Project Number/計畫編號

MOST105-2314-B002-003-MY3

Translated Name/計畫中文名

Inflammasome 在蜘蛛膜下腔出血後造成缺血性病變的角色

Project Principal Investigator/計畫主持人

KUOCHUAN WANG

Funding Organization

Ministry of Science and Technology

Co-Investigator(s)/共同執行人

蔡瑞章

Start date/計畫起

01-08-2016

Expected Completion/計畫迄

12-07-2017

摘要：血管痙攣至今仍為造成腦動脈瘤破裂病人殘障最常見的原因。自2008年以來，我們已經針對蜘蛛膜下腔出血做了一連串的研究。首先，我們證明了乳酸可有效預測動脈瘤破裂造成蜘蛛膜下腔出血 (SAH)患者發生水腦症的機會。我們還發現腦脊液中的HO1濃度可以有效預測SAH患者的預後。我們假設，大量SAH引起的蜘蛛膜下腔空間分隔，因此經由腰椎引流持續引流出腦脊液可能可以改善預後。結果顯示，MDA與病人預後相關；另外腰椎引流則可明顯降低MDA的數值。我們先前的研究引入capillary videoscopy，結果顯示SAH後可造成老鼠腦不明顯微血流的病變，且其嚴重度與缺血性病變有明顯關係。近一步的針對RAGE-HMGB1與缺血性病變的關係的研究，顯示腦室内注射sRAGE 可顯著改善蜘蛛膜下腔出血後腦部微血流，也降低陽性TUNEL染色的細胞的數目。生物體透過pattern recognition receptor來認出病源體，我們以往的研究顯示，HMGB1-RAGE途徑在SAH後的病態生理有重要影響。但inflammasome在SAH的角色仍未知。在本計晝中，我們將進一步探討inflammasome在蜘蛛膜下腔出血後發生缺血性病變的病理生理機制。本研究將使用動物模型和初級神經元培養。在動物模型中，我們使用單次注射模型誘發蛛網膜下腔出血。我們將脊髓内注射sRAGE和caspase 1抑製劑和IVIG，來看其在蜘蛛膜下腔出血後的角色。
Abstract: Aneurysmal subarachnoid hemorrhage (SAH) carries significant morbidity and mortality. We have done a serial studies on SAH since 2008. First, we proved that intrathecal lactate is a useful parameter in predicting long-term hydrocephalus in aneurysmal SAH patients. We further proposed that the level of intra-thecal CSF HO1 at day 7 post-SAH can be an effective outcome indicator in patients with SAH. We hypothesized that massive SAH caused compartmentalization of subarachnoid space and then start the next study of continuous drainage of CSF from lumbar drainage tube SAH. Our data showed that Malondialdehyde(MDA) is predictive of outcome, and lumbar drain is the most significant factors correlate with level of MDA. We demonstrated microcirculation impairment after SAH of rat model. Further, we showed that DIND after SAH of patients was highly correlated with microcirculation changes on animal model. Our previous plan of National Science Council showed that a higher level of CSF high mobility group box 1 (HMGB1) was independently associated with unfavorable outcome. Recombinant soluble receptor for advanced glycation endproducts (sRAGE) significantly reduced the number of positive TUNEL staining cells in SAH rat brain and improved cell viability in CSF-treated (post-SAH) cultured neurons. Furthermore, sRAGE treatment also improved the constriction of brain surface microvessels and related cerebral perfusion after SAH injury.The host recognizes various pathogens via pattern recognition receptors including toll-like receptors (TLRs) and specific nod-like receptors (NLRs). Our previous study showed that HMGB1 -RAGE pathway played important role in SAH. But, NLRs are cytoplasmic counterparts of TLRs. NLRs are also involved in the assembly of a cytosolic multi-protein complex termed the “inflammasome”. In this study, we will further clarify the role of inflammasome in the pathophysiology of DIND after SAH. We will investigate the inflammatory process after SAH both in animal model and primary neuron culture. In animal model, we use single injection model to induce SAH. CSF will be collected both 24 and 48 hours after SAH for the EILSA of RAGE, sRAGE, HMGB1, IL1, IL-18, Malondialdehide(MDA). The brain section after perfusion will be sent for IHC and Western study of NRPL1/3, caspase I/III, IL-1, IL-18 to clarify the role of inflammosome in SAH. Further, we will intrathecal pretreat sRAGE and caspase 1 inhibitor and IVIG to see the role and protective effect by blocking of this 2 pathway after SAH.

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The Role of Inflammasome in the Pathophysiology of Delay Ischemic Neurological Deficit after Subarachnoid Hemorrhage

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