本文選題：顱腦損傷 + 腦死亡　； 參考：《鄭州大學》2015年博士論文

【摘要】：背景與目的 顱腦損傷(head injury)是臨床上導致腦死亡(brain death,BD)的主要原因之一。腦死亡是指包括腦干在內的全腦功能喪失的不可逆轉的狀態(tài)。腦死亡概念是1959年由法國學者P.Mollaret和M.Goulon在第23屆國際神經學會上首次提出并使用,用來描述這種嚴重大腦損傷后失去反射需要機械呼吸支持的不可逆昏迷的狀態(tài)。1966年美國學者提出腦死亡是臨床死亡的標志。在1968年在第22屆世界醫(yī)學大會上,美國哈佛醫(yī)學院腦死亡定義審查特別委員會提出“腦功能不可逆性喪失”作為新的死亡標準,并制定了世界上第一個腦死亡診斷標準,法律上承認腦死亡等同于死亡。目前,世界大多數發(fā)達國家已認可腦死亡,并相繼頒布腦死亡法,從法律上保障腦死亡臨床診斷。我國2003年中華醫(yī)學雜志等主要醫(yī)學雜志刊登了衛(wèi)生部腦死亡判定標準起草小組制訂的《腦死亡判定標準(成人)(征求意見稿)》和《腦死亡判定技術規(guī)范(成人)(征求意見稿)》。2009年4月,經過修改與完善,其修訂稿發(fā)表,比較詳細,具有可操作性。由于腦死亡是一個涉及醫(yī)學、倫理學、法學、社會學等多個學科的概念,盡管呼聲很高,我國實現腦死亡立法還有許多實際問題,但將是一種必然趨勢。腦死亡供體是聯合國推薦優(yōu)先發(fā)展的器官移植供體,動物模型和臨床研究均已證明腦死亡是一個直接影響器官形態(tài)和功能的動態(tài)過程,其機制仍然不能完全明了。研究表明,腦死亡可引起心、腎細胞凋亡增加。進而引起形態(tài)改變和功能受損。2003年發(fā)表于《Transplantation》雜志上的關于腦死亡的文章,進一步揭示腦死亡誘導肝細胞凋亡增加,且以肝實質細胞為主,其機制與死亡受體途徑和線粒體途徑均有關。另有多項研究證實,凋亡是造成腦死亡供體器官移植后生存力下降的原因之一。最近的研究表明,內質網應激(endoplasmic reticulum stress,ERs)也是細胞凋亡調節(jié)中的重要環(huán)節(jié)之一。內質網(endoplasmic reticulum,ER)在細胞內分布廣泛,參與重要生理功能的維持,主要負責蛋白質的合成轉運、信號肽識別、糖基化修飾等過程和鈣離子的貯存,信號轉導及細胞內鈣的再分布。內質網巨大的膜結構在細胞內提供了一個寬廣的分子組裝、反應平臺,使之在多種信號調控中起到關鍵作用。內質網的功能對大多細胞的活動和生存是必需的。ERs途徑是獨立于細胞膜受體或線粒體途徑的第3條凋亡信號途徑。ER對諸如能干擾ATP、氧化狀態(tài)及Ca2+濃度等的內環(huán)境改變非常敏感,這些改變會降低內質網蛋白折疊能力,引起未折疊蛋白的積累和聚集,從而激活未折疊蛋白反應(unfolded protein response,UPR),以保護由ERs所引起的細胞損傷,恢復細胞功能。但當損傷超過修復能力時,ERs則引起細胞凋亡。以ERs相關生物大分子作為靶點進行藥物研究將為相關疾病的預防和治療開辟新的途徑。許多肝臟疾病的發(fā)病機制均與ERs引起的損傷有關,但ERs是否參與、介導腦死亡狀態(tài)下肝損傷、肝細胞凋亡的過程至今未見文獻報道。如能證實ERs參與了該過程的介導,并找到針對ERs途徑的干預措施來減輕肝損傷,將為腦死亡后器官功能保護提供新的思路,從而為臨床肝移植提供潛在的供體。本課題擬分三個部分從組織及細胞水平揭示內質網應激參與SD大鼠腦死亡狀態(tài)下肝損傷的分子機制。第一部分:SD大鼠腦死亡模型的建立與維持目的 本研究擬在我們前期研究的基礎上進一步探索采用緩慢間歇顱內加壓法模擬顱內出血、腦疝形成建立穩(wěn)定的Sprague Dawley(SD)大鼠腦死亡模型以及較長時間維持腦死亡狀態(tài)的方法,為研究SD大鼠腦死亡狀態(tài)下的肝臟形態(tài)和功能變化及其他相關基礎、臨床研究提供穩(wěn)定的實驗動物模型。材料與方法 實驗動物:成年,雄性,健康,SD大鼠,體重250g~350g,自由飲食。實驗方法:顱骨鉆孔,硬腦膜外腔置入Fogarty 3F氣囊導管,其尖端指向大鼠尾側,氣囊導管連接球囊壓力注射泵,通過向氣囊注入生理鹽水進行顱內加壓,直至達到腦死亡狀態(tài)。腦死亡判斷標準:(1)深昏迷;(2)角膜反射消失;(3)瞳孔固定、散大;(4)靜息腦電圖;(5)自主呼吸消失。觀察指標:全程記錄生命體征(心率HR、呼吸R、體溫T、血壓BP)、尿量、血流動力學、腦電圖、脈搏氧飽和度(SPO2)及其與顱內壓變化的相關規(guī)律。實驗分組:健康SD大鼠隨機分為:①對照組(C組):與腦死亡組對應,每個時間點n=10只,腹腔注射麻醉后隱動脈置管(24G靜脈留置針,行有創(chuàng)動脈血壓監(jiān)測)、氣管插管、顱骨鉆孔并置入Fogarty 3F導管,并實時監(jiān)測動脈壓、脈搏氧飽和度、體溫、腦電圖變化,顱內不加壓不建立腦死亡模型;②腦死亡組(BD組),按實驗設計分為腦死亡0h、1h、2h、4h、6h時間點組,每時間點組10只,除以上操作外,應用緩慢間歇顱內加壓法建立腦死亡模型,通過呼吸、循環(huán)支持維持實驗動物腦死亡狀態(tài)0h、1h、2h、4h、6h,維持腦死亡狀態(tài)要求大鼠生命體征穩(wěn)定:實時監(jiān)測平均動脈血壓(mean artery pressure,MAP)≥80mm Hg,體溫38.1±0.2℃,脈搏氧飽和度≥95%,呼吸機機械通氣支持,適當增加吸入氣中氧含量,呼吸頻率、潮氣量由HARVARD動物呼吸機自動據體重計算參數,可適當微調整,腦電圖呈靜息狀態(tài),血流動力學穩(wěn)定。結果 1.大鼠腦死亡模型的穩(wěn)定建立采用緩慢間歇顱內加壓法可模擬腦出血病理生理過程建立簡便、易重復的SD大鼠腦死亡模型,按實驗要求穩(wěn)定保持腦死亡狀態(tài)6h,為后續(xù)相關研究提供可靠的動物模型。模型建立過程詳見圖1-2,3,4,5,6,7,8。2.平均動脈壓(MAP)的變化腦死亡各組顯示相似的平均動脈壓變化過程,并與文獻報道結果一致。腦死亡判定后,在呼吸機支持的情況下,適當調整吸入氣中氧濃度,腦死亡模型血流動力學穩(wěn)定,平均動脈壓維持在80mm Hg以上,實驗全程不使用血管活性藥物。與對照組相比較,差異有統計學意義(P0.05)。(圖1-14)3.心率的變化腦死亡過程心率出現典型的變化,每個實驗組內動物模型出現相同的變化過程,與對照組相比較,差異具有統計學意義(P0.05)。詳見圖1-13。4.腦電圖的變化隨著緩慢顱內加壓誘導開始,腦電活動開始紊亂,腦電壓不穩(wěn)定,隨著顱內壓的增高,腦電活動逐漸減弱,漸成一直線。腦死亡組各時間點組均出現相似的腦電變化過程,與對照組比較,差異顯著。詳見圖1-10,11,12。第二部分:探討腦死亡狀態(tài)下SD大鼠肝臟形態(tài)與功能的變化目的觀察腦死亡狀態(tài)下SD大鼠肝臟形態(tài)與功能的變化特點,研究腦死亡對肝臟的影響。方法腦死亡組SD大鼠在腦死亡判定后0h、1h、2h、4h、6h分別停止呼吸支持,剖腹,于下腔靜脈處抽靜脈血,室溫靜止、離心后取血清分裝凍存管后-20℃或-80℃凍存待測;取相同部位肝組織分別:①迅速置入凍存管液氮保存;②切成小顆粒狀(0.5-1mm3)置入4%戊二醛液固定,4℃冷藏備電鏡切片;③肝組織切成片狀(約1-2cm2大小,厚度為0.2-0.3cm)放入中性福爾馬林溶液浸泡制成石蠟塊。應用全自動生化分析儀檢測血清肝臟酶學(ALT、AST)的變化;透射電鏡(TEM)觀察肝臟形態(tài)學變化;羅氏公司原位末端凋亡檢測試劑盒觀察肝組織凋亡細胞。對照組SD大鼠按上述時間點同樣方法取材。結果 1.腦死亡組大鼠0h、1h、2h、4h、6h不同時間點血清ALT、AST變化腦死亡誘導判定后SD大鼠肝功能(ALT、AST)出現不同程度的變化,隨時間的推移,ALT、AST呈逐漸升高趨勢,與對照組相比較,差異具有統計學意義(附表2-1)。2.電鏡下觀察肝細胞形態(tài)結構變化對照組SD大鼠肝組織細胞未見明顯異常,腦死亡組SD大鼠隨時間推移,肝組織結構出現損傷性變化,且逐漸加重,如輕度損傷為線粒體輕度腫脹,線粒體脊欠清晰,線粒體內外膜破損(BD-2h),中度損傷表現為部分線粒體脊損傷(BD-4h),重度為線粒體脊融合,內外膜破損,線粒體腫脹明顯,線粒體增生且膜性結構融合(附圖2-1)。3.肝組織肝細胞凋亡檢測對照組大鼠肝臟TUNEL染色少見凋亡。腦死亡組,SD大鼠肝臟細胞凋亡數量明顯增加,且隨腦死亡維持時間的延長,肝細胞凋亡細胞逐漸增加(附圖2-2,3)。第三部分:SD大鼠腦死亡過程是否啟動肝細胞內質網應激;內質網應激是否介導或參與腦死亡狀態(tài)下肝損傷、肝細胞凋亡過程目的探討SD大鼠腦死亡過程是否啟動肝細胞內質網應激,研究內質網應激是否介導或參與腦死亡狀態(tài)下肝損傷、肝細胞凋亡過程。方法 分別采用Western blot及實時熒光定量PCR(real-time quantitative polymerase chain reaction,q PCR)、免疫組化(immunohistochemistry,IHC),對各實驗組及不同時間點組肝組織標本進行GRP78;XBP-1;CHOP;JNK;Caspase-12;ATF4基因及其部分蛋白表達分析。結果與對照組相比,腦死亡狀態(tài)下SD大鼠肝組織不同時間點隨時間推移內質網應激相關大分子物質GRP78/Bi P;XBP-1;CHOP/GADD153;JNK;Caspase-12;ATF4從基因水平均表達增加,其中GRP78、CHOP、XBP-1、Caspase-12蛋白表達明顯增加,初步表明腦死亡過程誘導SD肝組織損傷,并啟動內質網應激、未折疊蛋白反應,參與肝細胞損傷過程,差異具有顯著性,具有統計學意義。(附圖2-4,5,6,7,8,9,10,11,12,13,14)結論 1.采用緩慢間歇顱內加壓法可建立穩(wěn)定的SD大鼠腦死亡模型,為進行下一步動物實驗提供可靠的基礎。2.腦死亡過程對SD大鼠肝臟有損傷作用,引起肝細胞凋亡。3.腦死亡過程啟動SD大鼠肝細胞內質網應激,參與肝細胞損傷、肝細胞凋亡過程。
[Abstract]:Background and objective craniocerebral injury (head injury) is one of the main causes of the clinical brain death (BD). Brain death is an irreversible state of the loss of whole brain function including the brain stem. The concept of brain death was first proposed and used by French scholars P.Mollaret and M.Goulon at the twenty-third International Neuroscience Society in 1959. To describe the state of irreversible coma that lost reflection and need mechanical respiratory support after the severe brain damage, American scholars have suggested that brain death is a sign of clinical death in.1966. At the twenty-second world medical conference in 1968, the brain death definition Review Committee of the Harvard Medical School proposed "the loss of brain function irreversible loss." "As the new standard of death, the first diagnostic standard of brain death in the world has been established, and it is legally recognized that brain death is equivalent to death. At present, most of the developed countries in the world have recognized brain death and promulgated the brain death method successively to ensure the clinical diagnosis of brain death. The major medical journals such as the Chinese Medical Journal of China in 2003 published the major medical journals published in China. The "brain death criteria (adult)" (Draft) and the technical specification for brain death (solicitation draft), formulated by the drafting group of the Ministry of health's brain death criteria (adult), and the technical specification for brain death (solicitation draft), in April >.2009, were revised and perfected, and their revised manuscripts are more detailed and operable. Brain death is a medical, ethical, and jurisprudential process. There are many practical problems in the realization of brain death legislation in China, although the concept of sociology and other disciplines has many practical problems, but it will be an inevitable trend. The brain death donor is the priority of the organ transplant donor recommended by the United Nations. Animal models and clinical studies have proved that brain death is a direct influence on the dynamics of organ morphology and function. The study shows that the mechanism of the brain death can not be completely clear. The study shows that brain death can cause the heart, the apoptosis of the kidney cells increase. Then the morphological changes and function damage are caused by.2003 published in the Journal of

on brain death, which further reveals that brain death induces the increase of apoptosis in the liver cells, and the mechanism of the liver parenchyma cells is the main mechanism. A number of studies have confirmed that apoptosis is one of the reasons for the decrease of viability after brain death donor organ transplantation. Recent studies have shown that endoplasmic reticulum stress (ERs) is also one of the important links in the regulation of apoptosis. The endoplasmic reticulum (endoplasmic reticul) Um (ER) is widely distributed in cells and participates in the maintenance of important physiological functions. It is responsible for the synthesis and transport of protein, signal peptide recognition, glycosylated modification, storage of calcium ions, signal transduction and the redistribution of intracellular calcium. The large membrane structure of the endoplasmic reticulum provides a broad molecular assembly, reaction platform, The function of the endoplasmic reticulum is essential to the activity and survival of most cells. The.ERs pathway is the third apoptotic signaling pathway independent of the cell membrane receptor or mitochondrial pathway,.ER, which is very sensitive to internal environmental changes such as ATP, oxidative state and Ca2+ concentration. These changes will decrease. The folding ability of the meshwork proteins causes the accumulation and aggregation of unfolded proteins to activate the unfolded protein reaction (unfolded protein response, UPR) to protect cell damage caused by ERs and restore cell function. But when the damage exceeds the repair capacity, ERs causes apoptosis. The drug is targeted by the ERs related macromolecules. The research will open a new way for the prevention and treatment of related diseases. The pathogenesis of many liver diseases is related to the damage caused by ERs, but whether ERs is involved, mediating the liver injury under brain death, and the process of hepatocyte apoptosis have not been reported. For example, it can be proved that ERs is involved in the process, and the ERs pathway is found. Intervention measures to alleviate liver injury will provide new ideas for the protection of organ function after brain death and provide a potential donor for clinical liver transplantation. This topic is to be divided into three parts to reveal the sub mechanism of endoplasmic reticulum stress participation in the brain death of SD rats from the tissue and cell levels. The first part: the brain death model of SD rats On the basis of our previous study, the purpose of this study is to further explore the use of slow intermittent intracranial pressure to simulate intracranial hemorrhage, brain hernia formation to establish a stable Sprague Dawley (SD) rat brain death model and a longer time to maintain the brain death state, in order to study the liver shape in the brain death of SD rats. State and function changes and other related bases, clinical studies provide a stable experimental animal model. Materials and methods experimental animals: adult, male, healthy, SD rats, body weight 250g~350g, free diet. Experimental methods: cranial drilling, Fogarty 3F balloon catheter in the extradural cavity, its tip pointing to the tail of rat, balloon catheter connected balloon pressure Force injection pump, intracranial pressure was injected into the air bag until cerebral death was achieved. Brain death criteria: (1) deep coma; (2) disappearance of corneal reflex; (3) pupil fixed, loose; (4) resting electroencephalogram; (5) spontaneous breathing disappearance. The whole record of life signs (heart rate HR, respiratory R, temperature T, blood pressure BP), urine volume, blood Flow mechanics, electroencephalogram, pulse oxygen saturation (SPO2) and the changes in intracranial pressure. Experimental groups: healthy SD rats were randomly divided into: 1. Control group (group C): corresponding to brain death group, n=10 only at each time point, intraperitoneal injection of saphenous artery after anesthesia (24G venous indwelling needle, invasive arterial blood pressure monitoring), tracheal intubation, cranium drill The Fogarty 3F catheter was inserted into the hole, and the arterial pressure, pulse oxygen saturation, temperature, electroencephalogram and brain death model were not established, and the brain death group (group BD) was divided into group of brain death 0h, 1H, 2h, 4h, 6h time point group with 10 rats at each time point, in addition to the above operation, the brain was established by the slow intermittent intracranial pressure method. Death model, through breathing, and circulation support to maintain the brain death state of experimental animals 0h, 1H, 2h, 4h, 6h, to maintain the brain death state of the rat's vital signs is stable: real-time monitoring of the average arterial blood pressure (mean artery pressure, MAP) > 80mm Hg, temperature 38.1 + 0.2 C, pulse oxygen saturation more than 95%, ventilator mechanical ventilation support, appropriate increase of inhalation gas The content of oxygen, the frequency of respiration, and the volume of tidal gas were adjusted by the HARVARD animal ventilator automatically according to the weight calculation parameters. The electroencephalogram was resting state and the hemodynamics was stable. Results the stability of the brain death model in the 1. rats was established by using the slow intermittent intracranial pressure method to simulate the pathophysiological process of cerebral hemorrhage, which was easy to repeat and the SD was easy to repeat. The rat brain death model was maintained to keep the brain death state 6h steadily and provide a reliable animal model for subsequent related studies. The process of model establishment was detailed to see the change of mean arterial pressure in each group of brain deaths of figure 1-2,3,4,5,6,7,8.2. (MAP). Under the condition of ventilator support, the oxygen concentration in the inhaled gas was properly adjusted, the hemodynamics of the brain death model was stable, the mean arterial pressure was maintained above 80mm Hg, and the vasoactive drugs were not used in the whole course of the experiment. The difference was statistically significant (P0.05). (Figure 1-14) 3. heart rate changes were typical changes in the heart rate of the brain death process. The animal models in each experimental group had the same change process, and compared with the control group, the difference was statistically significant (P0.05). The change of electroencephalogram (EEG) in figure 1-13.4. began with the slow induction of intracranial pressure, and the EEG activity began to be disturbed and the brain voltage was unstable. With the increase of intracranial pressure, the EEG activity gradually weakened and gradually became a straight line. The brain death group had similar electroencephalogram changes in each time point group. Compared with the control group, the difference was significant. See figure 1-10,11,12. second part: To explore the changes of liver morphology and function in SD rats under brain death. Objective To observe the changes of liver morphology and power in SD rats under brain death and the effect of brain death on the liver Methods SD rats in the brain death group were treated with 0h, 1H, 2h, 4h, and 6h respectively after the death of the brain, caesarean section, venous blood from the inferior vena cava, at room temperature at room temperature. After centrifugation, the serum was collected at -20 C or -80 C after the cryopreservation, and the same part of the liver tissue was immediately placed in the cryopreservation tube and stored in the liquid nitrogen; and second cut into small granular (0.5-1mm) 3) implantation of 4% glutaraldehyde solution and frozen section at 4 C; 3. Liver tissue cut into flakes (about 1-2cm2 size, thickness 0.2-0.3cm) and immersed in neutral formalin solution to make paraffin blocks. The changes of serum liver enzyme (ALT, AST) were detected by automatic biochemical analyzer; transmission electron microscopy (TEM) was used to observe the changes of liver morphology; Roche company The apoptotic cells in liver tissue were observed by the in situ terminal apoptosis detection kit. The same method was used in the control group of SD rats at the same time point. Results the serum ALT of 0h, 1H, 2h, 4h, 6h at different time points in the 1. brain dead rats was observed at different time points, and the liver function (ALT, AST) of SD rats was changed in varying degrees after the AST changes were induced by the brain death induction. Gradually increasing trend, compared with the control group, the difference was statistically significant (Appendix 2-1). The morphological changes of hepatocytes in the control group were observed under.2. electron microscope. The liver tissue cells in the control group of SD rats were not obviously abnormal. The SD rats in the brain death group changed with time, and the liver tissue structure appeared to be damaged and gradually aggravated, such as mild injury to mitochondria. Swelling, unclear mitochondrial spinal cord, mitochondrial internal and external membrane damage (BD-2h), moderate damage to mitochondrial spinal cord injury (BD-4h), severe mitochondrial spinal fusion, internal and external membrane breakage, mitochondria swelling, mitochondrial proliferation and membrane structure fusion (appended 2-1).3. liver cell apoptosis detection in the control group of rat liver TUNEL staining is rare. Apoptosis in the brain death group, the number of apoptosis in the liver cells of SD rats increased significantly, and with the prolongation of the time of the death of the brain, the number of apoptotic cells in the liver gradually increased (appended 2-2,3). The third part: whether the brain death process of SD rats started the endoplasmic reticulum stress in the liver cells; whether endoplasmic reticulum stress mediates or participates in the liver injury in the state of brain death, and the liver cell withered. The purpose of the death process is to investigate whether the brain death process of SD rats initiate the endoplasmic reticulum stress and whether endoplasmic reticulum stress mediates or participates in the liver injury and the process of hepatocyte apoptosis in the state of brain death. Methods of Western blot and real-time quantitative PCR (real-time quantitative polymerase chain reaction, Q PCR), immunohistochemistry (I) Mmunohistochemistry, IHC), GRP78, XBP-1; CHOP; JNK; Caspase-12; ATF4 gene and some protein expression analysis were carried out in the experimental group and the different time point group. The results were compared with the control group. The results were compared with the control group, and the liver tissue of SD rats at different time points was at any time in the stage of the endoplasmic reticulum stress related macromolecules GRP78/Bi P; XBP-1; XBP-1; The expression of HOP/GADD153, JNK, Caspase-12 and ATF4 increased from the gene level, in which the expression of GRP78, CHOP, XBP-1, Caspase-12 protein increased obviously. It showed that the brain death process induced the injury of the SD liver tissue, and started the endoplasmic reticulum stress, unfolded protein reaction, and participated in the liver cell damage process. The difference was significant and was statistically significant. (Figure 2-). 4,5,6,7,8,9,10,11,12,13,14) conclusion 1. a stable SD rat model of brain death can be established by the slow intermittent intracranial pressure method, which provides a reliable basis for the next animal experiment to provide a reliable basis for the damage of the.2. brain death process to the liver of SD rats, and cause the apoptosis of the hepatocyte apoptosis.3. brain to initiate the endoplasmic reticulum stress of the SD rat liver cells and participate in the liver cell apoptosis. Hepatocyte injury and the process of hepatocyte apoptosis.
【學位授予單位】：鄭州大學
【學位級別】：博士
【學位授予年份】：2015
【分類號】：R651.15

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