【作者】 吴刚；

【导师】 黄峰平； 奚国华； 华亚； 郑康；

【作者基本信息】 复旦大学 ， 外科学， 2010， 博士

【摘要】 自发性脑出血(Spontaneous intracerebral hemorrhage, ICH)是一种常见的中风亚型,发病后情况往往很严重,其死亡率高达40%以上,而且生还者往往明显的神经功能损伤。高血压被认为是ICH的主要的危险因素和诱因之一,两者密切相关。90%的自发性脑出血的病人患有高血压,而且相当一部分在发病后的一段时间内表现为血压升高。在急诊约有27%的脑出血患者表现为收缩压高于160mmHg。然而,高血压是否会增加脑出血患者发病后再出血的几率?高血压是否会加重出血后的脑损伤?以及高血压对脑出血后脑组织病理学改变有何影响?这些问题无论是临床还是基础研究,至今依然缺乏明确的答案。至于对于那些脑出血后出现血压升高的患者,如何进行血压控制治疗才适当这一问题,在临床上,仍然缺乏充分的理论和循证医学的证据。自发性高血压大鼠(SHR)是经典的慢性高血压的动物模型,最合适用于高血压引起的脑血管病的研究。本研究将利用SHR和与其同品系的正常血压对照大鼠(WKY),采用两种常用的脑出血动物模型,研究高血压对脑出血预后的影响,包括出血量的大小,脑水肿程度,神经细胞死亡,脑内铁的蓄积与代谢,以及神经功能障碍与恢复等。目的：研究高血压对大鼠脑出血后出血量的影响。方法：采用立体定向脑内注射胶原酶的方法制作高血压与正常血压大鼠的脑出血模型。于制作模型后24小时处死大鼠,测定大鼠脑内血红蛋白的含量。结果：所有的实验大鼠,在脑内注射胶原酶后4小时内出现严重的脑出血表现,24小时处死大鼠后测得两组大鼠间脑内血红蛋白含量无明显差异。目的：研究高血压对大鼠脑出血后脑水肿,血肿演变和神经功能障碍的影响。方法：分别制作自体血注射的SHR和WKY大鼠的脑出血模型,每组大鼠每个时间点各6只大鼠在出血后1天,3天处死,检测脑组织水含量；另一部分每组各6只大鼠用于出血后第1,3,14天进行头部MRI检查,并在出血后第1,7,14天进行神经功能的评估。结果：脑出血后第1,3天,SHR大鼠出血侧脑组织水含量较WKY略低,但无统计学差异；MRI检查显示,出血后第1,3,14天,SHR大鼠脑肿胀程度轻,T2*序列低信号病灶体积小；但行为学检查表明SHR大鼠神经功能障碍严重,恢复缓慢。目的：研究高血压对大鼠脑出血后,神经细胞损伤的影响以及脑内参与铁代谢的蛋白表达的影响。方法：分别制作自体血注射的SHR和WKY大鼠的脑出血模型,在出血后1天,3天,分别用Fluoro-Jade C染色法检测神经细胞变性,用Western Blot法检测脑组织内HO-1,DNP,Tf,TfR,和Cathepsin D的蛋白表达情况。结果：在出血后第3天SHR大鼠的注射侧基底节HO-1、DNP、Tf和TfR的表达,出血后的第1,3天Cathepsin D的表达较WKY大鼠降低,而出血侧脑内Fluoro-Jade C染色阳性细胞数SHR大鼠比WKY大鼠多。本实验用SHR和WKY两种大鼠,比较研究高血压对脑出血的影响,结果表明：1.中等程度的血压升高(收缩压在180mmHg左右),不增加由胶原酶破坏大鼠的小血管引起的大鼠实验性脑出血的出血量；不加重脑出血后,脑组织含水量,但能使脑出血后影像学检查大鼠脑肿胀的程度缓解,缩小脑出血后血肿病灶的体积;2.持续的高血压,会造成大鼠实验性脑出血后,神经细胞的变性坏死增加,神经功能损伤严重,恢复缓慢；3.中等程度的血压升高,会降低实验性大鼠脑出血后,脑内与铁代谢相关的酶的表达,以及细胞内的氧化应激反应；减少了大鼠脑出血后,神经细胞的自吞噬作用。所以,对于患有慢性高血压病史的患者,平时积极控制血压,有助于脑出血后的神经功能康复,但在脑出血发病后的急性期,过分积极的进行大幅度降压治疗必须慎重。更多还原

【Abstract】 Spontaneous intracerebral hemorrhage (ICH) is a common and often fatal stroke subtype. Community based studies have indicated a mortality of more than 40%, and many survivors are left with significant neurological deficits. Hypertension and ICH are frequently associated. High blood pressure (BP) is found in 90% of patients with ICH and persists for a few days. About 27% of ICH patients have a systolic blood pressure (SBP) of 160 mmHg or greater were found in emergency department. Transient or sustained high BP was thought to increase the risk of continuous bleeding, subsequent rebleeding, or both within the first 24 h after the initial bleeding. The mechanisms that lead to ICH in hypertension people, the consequence of hypertension to hematomal enlargement (HE), and the pathological change after ICH due to hypertension, however, are still not well understood. The optimal management of acute hypertension in the patients with ICH is still to be discussed. Many clinical trails of aggressive blood pressure lowering in acute ICH are still under investigating.Spontaneously hypertensive rats (SHR), derived from Wistar Kyoto rats (WKY), are the typical models of chronic hypertension, that have been used to learn the effects of chronic arterial hypertension on ischemic stroke. In the present study, we investigated the different outcomes, such as hematoma volume, brain edema formation, neuronal death, iron accumulation and neurological deficits after ICH in SHR and WKY rats using both collagenase and blood injection models.Objective:To investigate the effect of hypertension on hematoma volume after ICH in rats. Method:SHR and WKY rats received collagenase infusion into the right basal ganglia to induce ICH. One day after infusion, the rats were killed to determine the hemoglobin content in the brain. Results:All the rats showed severe symptom of ICH 4 hours after collagenase infusion. And 24 hours after infusion, there were no difference of hemoglobin content in brain between the two strains of rats.Objective:To investigate the effect of hypertension on brain edema and hemotoma developing after ICH, as well as the neurological deficits between the SHR and WKY rats. Method:SHR and WKY rats received 100μL autologous whole blood infusion into the right basal ganglia. On day 1 and 3, each group,6 rats were killed to determine the brain water content. Other 6 rats in each group underwent brain MRI 1,3,14 days after ICH. And also, the neurological deficits were tested 1,7,14 days after ICH. Results:1 and 3 days after ICH, the brain water content was slighter in SHR rats, but showed no difference between SHR and WKY rats. The MRI examination showed slighter brain swelling and smaller T2* lesion in SHR rats compared with those in WKY rats 1,3, and 14 days after ICH, while the SHR rats showed more severe neurological deficits and delay neurological recovering 1,7, and 14 days after ICH.Objective:To investigate the brain injury and the protein expression related with the iron metabolism after ICH influenced by hypertension. Method:SHR and WKY rats received 100μL autologous whole blood infusion into the right basal ganglia. On day 1 and 3, Fluoro-Jade C staining was used to detect degenerating neuronal cells, and Western Blot analysis was used to detect HO-1, DNP, Tf, TfR, and Cathepsin D.Results:It showed higher HO-1, Tf, TfR, DNP expression 3 days and higher Cathepsin D levels in the ipsilateral basal ganglia of WKY rats 1 and 3 days after blood injection. But there were more Fluoro-Jade C positive cells detected in the ipsilateral basal ganglia of SHR rats 1 and 3 days after ICH. Two rat ICH models were used in the present study to compare SHR with WKY rats. It indicated:1. Moderate hypertension (systolic BP≤180mmHg) did not enlarge hemotomal volume induced by collagenase infusion in experimental ICH in rats, neither did the brain water content. But it did attenuate the brain swelling and hemotomal lesion detected by imagining.2. Chronic hypertension led more neuronal degenerating and neurological deficits after ICH in rats, and delay neurological recovery.3. Moderate hypertension decreased protein expression related to iron metabolism and intracellular oxidative stress in rat brain after ICH. Also it lessened the neuronal autophagic reaction.In summary, for the patients with a long history of hypertension, it is useful for the neurological rehabilitation to get proper antihypertensive medication. But it also called us to pay more attention to aggressive antihypertensive treatment in acute phase after ICH.更多还原