CCL12在衰老导致脑出血后脑损伤加重中的作用及机制

Generally, older patients with intracerebral hemorrhage (ICH) have a bad prognosis, which indicative of that ageing is the major factor aggravating the brain injury. Therefore, elucidating the mechanisms underlying ageing aggravate brain injury induced by ICH has great therapeutic significances for ICH. In the preliminary experiment, using the parabiosis ICH model, we found that the mortality of young heterochronic parabisosis ICH mice was greater than young isochronic parabiosis ICH mice. Moreover, when the mortality of young mice was increased when they recieved the plasma from old mice. These results suggest that there are some damaging molecules exist in ageing plasma. In addition, we also found that the plasma chemokine (C-C motif) ligand 12 (CCL12) levels were higher in older ICH mice than young ICH mice. Given that CCL12 could recruit more periphery immune cells infiltrating into brain tissues to aggravate brian inflammatory injury. Accordingly, we speculate that ageing increases the plasma CCL12 levels, which recruits more periphery immune cells infiltrating into brain tissue to aggravate ICH-induced brain injury. Therefore, this project aims to investigate the correlation between plasma CCL12 levels and clinical outcome of patients with ICH, then exploring the functions and mechanisms of CCL12 in ageing resulting in aggravating brain injury induced by ICH using intravenous injection of CCL12 or CCL12 knockout technologies. This project can not only elucidate the mechanism underlying ageing aggravate ICH brain injury from a novel view of ageing, but also provide a new strategy for ICH treatment.

脑出血（ICH）患者年龄越大其预后显著恶化，提示衰老是导致脑损伤加重的重要原因，因此阐明衰老致ICH脑损伤加重的机制对ICH治疗具有重要意义。我们预实验利用小鼠并联共生ICH模型，发现年轻鼠与老年鼠共生后其死亡率显著增高，而且给年轻鼠输注老年血浆后ICH死亡率异常增高，提示衰老鼠血浆中可能存在异常增高的损伤分子。后续研究还发现ICH后老年鼠血浆趋化因子12（CCL12）含量显著高于年轻鼠，鉴于CCL12可通过招募炎症细胞而加重组织炎症损伤，为此我们推测衰老导致血浆CCL12升高，通过招募更多外周炎症细胞进入脑组织加重了小鼠ICH脑损伤。因此，本课题拟在明确血浆CCL12与ICH患者临床结局相关性基础上，采用静脉注射CCL12、基因敲除CCL12等方法，探讨CCL12在衰老导致ICH后脑损伤加重中的作用及机制，从衰老导致脑损伤加重的角度阐明ICH后脑损伤的机制，可望为ICH的治疗提供新策略。

脑出血（intracerebral hemorrhage, ICH）具有高发病率、高死亡率和高致残率的特点，在我国其发病率远高于欧美国家。然而，目前针对脑出血的治疗仍缺乏有效的措施与方法，进而给社会和家庭带来了沉重的负担。因此，深入阐明ICH后病理生理机制对研发有针对性的ICH治疗药物具有重要的临床意义。.既往认为衰老是一种自然的、不可逆转的生理现象。然而越来越多的研究表明，衰老是一种疾病，并且是导致机体各种机能退化，甚至是导致或加重疾病严重程度的重要原因。随着年龄的增长，脑出血患者的临床预后显著恶化，提示衰老是导致脑出血后脑损伤加重的重要原因。此外，尽管近年来对ICH的病理生理机制研究取得了显著的进展，然而多项在ICH动物模型被证实有效的治疗药物却在临床转化研究中均显示无效。究其原因，可能与基础研究中所用的研究对象多为年轻实验动物有关，而与临床中ICH患者以中老年人群为主的客观现象不符。因此，深入阐明衰老导致ICH后脑损伤加重的作用及机制对ICH治疗具有重要意义。.研究表明年轻小鼠血浆移植到老年小鼠体内可以明显改善老年小鼠身体机能，甚至可以减轻小鼠脑出血和脑梗死后脑损伤程度，提示血浆中的某些因子可以影响大脑衰老的生理及病理过程。新近研究对血浆进行蛋白组学分析后发现，趋化因子2（CCL2）、CCL11、CCL12、CCL19、触珠蛋白（haptoglobin）及β2微球蛋白（β2-microglobulin）等分子的血浆水平在老年小鼠中显著高于年轻小鼠。多项研究表明CCL2、CCL11、CCL19、haptoglobin和β2-microglobulin等分子在正常衰老和衰老相关疾病中发挥重要作用。上述结果均提示衰老小鼠血浆中升高的CCL12可能在衰老导致ICH后脑损伤加重中起着重要作用。.CCL12也称单核细胞趋化蛋白5（MCP-5），是趋化因子的一种。CCL12在趋化诱使外周免疫细胞向受损的组织迁移并参与炎症反应中具有重要作用。并且，已有研究报道卒中后进入脑组织的外周免疫细胞在脑组织损伤中发挥着重要作用。.综上所述，我们提出如下假说：衰老导致血浆CCL12升高，通过招募更多外周炎症细胞进入脑组织加重了小鼠ICH脑损伤。