脑出血后继发性脑损伤：15-脂氧酶/15-羟基廿碳四烯酸的作用和分子机制

Intracerebral hemorrhage (ICH) represents 10-15% of all cerebrovascular events, and is associated with substantial morbidity and mortality. No medical or surgical therapy to date has been approved to significantly reduce morbidity or mortality after ICH. Secondary brain injury is, for the most part, attributable to the presence of intraparenchymal blood and hematoma triggered edema. Timely clearance of the extravasated red blood cells and irreversibly injured cells prevents them from undergoing lyses and subsequent spillage of toxic contents into the brain parenchyma. It is reported that peroxisome proliferator-activated receptors gamma (PPARγ) activators reduce the damage produced by focal ischemia and ICH. 15-hydroxyeicosatetraenoic acid (15-HETE) is a natural PPARγ ligand. However, the role of 15-HETE in the development of ICH is not studied. We propose that ICH increased the level of 15-HETE, which activated PPARγ, PPARγ repressed inflammatory mediators, inhibited nuclear factor-κB (NF-κB), upregulated catalase and CD36, promoted phagocytosis, and reduced neurological deficit. This may be a new mechanism for ICH. Based on clinical needs, we are trying to clarify the distribution of 15-lipoxygenase and the level of 15-HETE in hematoma and perihematoma area by using ICH rat and cell models, neurological deficit analysis and molecular biology techniques, and further verify in human brain samples; to clerify the role of exogenous 15-HETE on neurological deficit in rats and its molecular mechanism, and provide potential new targets for prevention and treatment of secondary brain injury after ICH.

脑出血是全球死亡率致残率极高的常见多发病。发病机制未完全阐明，尚无显著降低病死率的措施。脑出血后原发性脑损伤的治疗窗短，难把握。因此研究其继发性脑损伤更具现实意义。这种损伤，主要是脑实质内的血肿和血肿触发的水肿所致。PPARγ对清除血肿至关重要。它能够抑制炎症介质、上调过氧化氢酶和CD36。15-羟基廿碳四烯酸(15-HETE)是PPARγ的天然配体。但15-HETE与脑出血的关系，未见报道。我们推测脑出血上调15-HETE，激活PPARγ抑制炎症、抗氧化、促进吞噬清除血肿、减轻神经功能缺损，这可能是脑出血的一个新机制。本项目立足临床需求，通过复制脑出血大鼠和细胞模型，采用神经功能缺损分析和分子生物学技术，阐明血肿区15-脂氧酶的分布、表达和15-HETE水平与脑出血的相关性。明确外源性15-HETE对脑出血大鼠神经功能缺损和血肿的作用和分子机制，为继发性脑损伤的防治提供新思路和新靶点。

脑出血是全球死亡率致残率极高的常见多发病。发病机制未完全阐明，尚无显著降低病死率的措施。本项目立足临床需求，通过复制脑出血大鼠和细胞模型，采用神经功能缺损分析和分子生物学技术，阐明血肿区15-脂氧酶的分布、表达和15S-HETE水平与脑出血的相关性。明确外源性15S-HETE对脑出血大鼠神经功能缺损和血肿的作用和分子机制。项目的主要科学发现如下：（1）成功建立了一种血肿稳定，重复性好，神经行为缺损明显的大鼠脑出血模型，即半凝固自体血注入法大鼠脑出血模型；（2） 脑出血后患侧脑半球15- LOX和15S-HETE含量升高，并呈现出一定的时间相关性；（3）患侧神经元、小胶质细胞、星形胶质细胞和少突胶质细胞的15- LOX表达升高；（4）15- LOX和它的代谢产物，15S-HETE是脑出血后脑内炎症损伤的重要中间体，参与了脑出血的转归过程；（5）15S-HETE通过激活PPARγ的方式抑制脑出血后的炎症反应并减缓氧化应激状态；（6）15S-HETE能有效改善脑出血大鼠的神经功能缺损状态；（7） 15S-HETE 能显著降低血肿周围细胞的凋亡数量。本项目的研究结果表明15S-HETE可能对脑出血具有潜在的治疗作用。