Bilirubin oxidation and intracerebral hemorrhage

胆红素氧化与脑出血

• 批准号: 7163681
• 负责人: JOSEPH Floyd CLARK
• 金额: $ 7.68万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-15 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7163681
• 关键词: Bilirubin; oxidation; intracerebral; hemorrhage

Intracerebral hemorrhage (ICH) is a type of stroke caused by bleeding into the brain, which leads to significant death and disability. Secondary and delayed pathophysiologic events can contribute to the death and disability of the ICH patient. These events are characterized by a breakdown of the blood brain barrier, edema development and cell death in white and gray matter. We have recently discovered that following hemorrhage in the brain, a new molecular species, bilirubin oxidation species (BOXes), are produced within the hematoma during the first 24 hours following ICH. Importantly, the concentration of BOXes in the hematoma is the highest (approximately 20 \iM) that we have observed in any of our experimental and clinical evaluations thus far. This finding is especially significant since we have previously demonstrated that BOXes are cytotoxic and our preliminary data indicate that they can contribute to the pathophysiological events leading to brain injury following ICH. Our overall goal in this research project is to test the Hypothesis that BOXes are acutely generated within the hematoma and contribute to edema formation and perihematomal brain injury following ICH. To address this hypothesis we will use our porcine ICH model. In Aim #1 we will measure the concentration of BOXes in the hematoma and perihematomal brain tissue to define the time course of production. In Aim #2 we will add BOXes to the infused blood to produce the hematoma and assess the damage and examine the underlying pathogenesis observed following experimental ICH. In Aim #3 we will investigate the mechanism(s) for BOXes production by examining two biochemical pathways required to generate BOXes: bilirubin generation and oxidative stress. It is anticipated the inhibition of bilirubin production and/or antioxidants will decrease BOXes production in the hematoma. These studies are important because we believe that strategies designed to prevent BOXes production in the hematoma should provide a novel and beneficial therapeutic option for patients who have suffered an ICH.

脑内出血（ICH）是由大脑出血引起的一种中风，这导致 重大死亡和残疾。次要和延迟的病理生理事件可能导致死亡 和ICH患者的残疾。这些事件的特征是血脑屏障的崩溃， 白色和灰质中的水肿发育​​和细胞死亡。我们最近发现以下 大脑中的出血，一种新的分子物种，胆红素氧化物种（盒），在内部产生 ICH后的最初24小时内血肿。重要的是，盒子中的集中度 血肿是我们在任何实验中观察到的最高（约20 \ im） 到目前为止，临床评估。这一发现尤其重要，因为我们以前已经证明 盒子是细胞毒性的，我们的初步数据表明它们可以有助于病理生理学 ICH后导致脑损伤的事件。 我们在研究项目中的总体目标是检验盒子急性生成的假设 在血肿内，有助于ICH后的水肿形成和近日围血脑损伤。到 解决这个假设，我们将使用猪ICH模型。在AIM＃1中，我们将测量 血肿和近日血肿的脑组织中的盒子来定义生产的时间过程。在AIM＃2中 我们将在注入的血液中添加盒子，以产生血肿并评估损害并检查 在实验ICH之后观察到的潜在发病机理。在AIM＃3中，我们将调查 通过检查生成盒子所需的两种生化途径来生产盒子的机制： 胆红素的产生和氧化应激。可以预期抑制胆红素的产生和/或 抗氧化剂将减少血肿中的盒子产量。 这些研究很重要，因为我们认为旨在防止盒子生产的策略 在血肿中，应为患有遭受的患者提供新颖而有益的治疗选择 ich。