Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/22863
標題: 肥大細胞釋出液對缺血腦組織保護機轉之探討
The mechanism(s) underlying mast cell-derived conditioned medium(MaCM)-mediated brain protection against cerebral ischemia
作者: 吳姿璉
Wu, Tze-Line
關鍵字: cerebral ischemia;腦缺血;GOSD;mast cell;MaCM;histamine;BBB;neutrophil;GOSD;肥大細胞;肥大細胞釋出液(MaCM);組織胺;血腦障壁;嗜中性白血球
出版社: 生命科學系所
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摘要: 
肥大細胞(mast cell)一般都被認為是-促發炎細胞,可釋放組織胺
(histamine)造成不同組織包括缺血腦組織的發炎反應。但近年來透過對不同組織胺受體的研究,發現組織胺可經由活化H2 受體保護缺血腦組織,使肥大細胞的角色另起爭議。本論文主要在評估肥大細胞釋出液(mast cell-derived condition medium or MaCM),對缺血腦組織是否具保護性及其作用機轉,以進一步釐清肥大細胞在缺血腦組織中所扮演的角色及調控機轉。實驗中,利用結紮大白鼠腦部血管的體內缺血/再灌流模式,及細胞缺糖、缺氧、缺血清(glucose-oxygen- and serum-deprivation or GOSD)的體外缺血模式,做為研究平台,針對肥大細胞在缺血腦組織中及體外GOSD環境壓力下,其存活力、數量及釋放組織胺的能力等變化做分析。接著更將經GOSD處理後所產生之MaCM 或組織胺,送入缺血腦組織皮質區,評估兩者對缺血鼠之腦組織及運動功能的受損,血腦障壁(blood brain barrier or BBB)的被破壞,及腦缺血區occludin 及血管生長因子(VEGF)的蛋白表現等,是否有保護功能。而MaCM 或組織胺,對經GOSD 處理後之腦細胞(神經細胞、星芒狀細胞、微膠細胞)及內皮細胞的存活力或移動力之影響;或對缺血鼠脾臟中嗜中性白血球的移動力及氧化活性的影響,亦在評估之列。研究結果顯示,在GOSD 的壓力下,肥大細胞的存活明顯降低,但其釋放組織胺的能力顯著提高。大鼠右大腦半球缺血皮質區,肥大細胞的數目及去顆粒化現象和左大腦半球之皮質區相比並無明顯差異,但在右大腦半球的視丘區,肥大細胞去顆粒化及釋放組織胺的現象明顯提升。MaCM 對缺血腦組織明顯具保護性,此保護作用除和H3 受體之活化有關外,亦可能經由抑制VEGF 和提升occludin 的蛋白表現,來降低缺血區BBB 的通透性,及抑制嗜中性白血球的移動力或氧化活性所致。MaCM 對於GOSD 所導致的腦細胞受損,及缺血所導致的運動功能受損情形,則不具保護性。整體而言,肥大細胞在面對缺血壓力時,可經由穩固BBB 結構、抑制促發炎細胞(嗜中性白血球)的氧化活性及移動力等特質,來降低缺血腦組織的受損程度。肥大細胞的活化(去顆粒化)明顯對缺血組織具保護功能,部分是經由釋放組織胺活化H3 受體所致。此外,MaCM 在缺血性腦中風的治療上亦具療效,其保護功能除部分仰賴組織胺外,明顯亦依賴其他分子的參與,如能進一步釐清MaCM 中具保護功能的其他成份,對未來抗中風藥物的篩選或創新研發上,均具參考及應用價值。

Mast cell has been considered as a pro-inflammatory cell and through the release of histamine it actively involved in inflammation of many tissues including ischemic brain. Nevertheless, an anti-inflammatory activity of histamine receptor (H2 subtype)has recently been suggested to protect brain from ischemic insult may also reflect an anti-inflammatory role for mast cells in cerebral ischemia. The primary goal of the thesis was to assess the mechanism(s) underlying mast cell-derived conditioned medium (MaCM)-mediated brain protection against cerebral ischemic. Through the study, the regulatory role (pro- or anti-inflammatory) of mast cell in cerebral ischemia can be further delineated. In the study, a reversible focal ischemia was first developed in Spraque‐Dawley (S.D.) rats by subjecting animals to 90 min of bilateral common carotid artery occlusion (CCAO) plus unilateral middle cerebral artery occlusion (MCAO) followed by reperfusion for 24h. In the meantime, primary neurons, astrocytes and microglia were isolated and exposed to glucose‐ oxygen‐ and serum‐deprivation (GOSD)condition to mimic cerebral ischemia in vitro. Both experimental platforms were applied to analyze the viability, number and histamine releasing capability of mast cells under either ischemic or GOSD condition. The protective effect of MaCM or histamine on ischemic brain, motor activity, blood brain barrier (BBB) or the expression of occludin and vascular endothelial growth factor (VEGF) were further examine by injecting MaCM or histamine directly into the core area (cortex) of ischemic brain.
The effects of MaCM or histamine on: survival of GOSD brain cells (neuron, astrocyte and microglia) and endothelial cells, motility of GOSD endothelial cells and neutrophils, and the release of superoxide from neutrophils were also investigated in vitro under GOSD condition. Our results showed that GOSD inhibited viability of but increased histamine release from mast cells. The number and degranulation of mast cells at cortical region of ipsilateral hemisphere remained similar to that at same region of contralateral hemisphere. Degranulation and the release of histamine from mast cells however, were significantly increased at thalamus of ipsilateral hemisphere. MaCM collected at 6 h after GOSD, significantly reduced brain infarct volume caused by ischemia/reperfusion, in a histamine receptor (H3-subtype)-dependent manner. MaCM-mediated brain protection may act through the inhibition of VEGF and stimulation of occludin expression, reduction of BBB permeability, and inhibition of neutrophil motility and release of superoxide. MaCM however, did not protect brain cells from GOSD insult in vitro, nor restored motor activity of ischemic rats in vivo.In summary, in response to ischemic stress, the activation of mast cells appeared to be brain protective by releasing substances such as histamine and/or other unidentified factors to stabilize BBB and inhibit brain entrance and oxidative activity of neutrophils that eventually led to significant reduction of brain infarction. MaCM appeared to have therapeutic value in the control of cerebral ischemia. Identification of other protective substances within MaCM may provide additional choices for future design of new anti-ischemic drugs.
URI: http://hdl.handle.net/11455/22863
其他識別: U0005-0802201011323300
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