急性脑出血瘀热病机单元的动态测量及其生物标志物的研究

Intracranial hemorrhage(ICH) severely influence Chinese people health. Intervention of TCM in acute phrase applying pathogenic theory of stasis-heat indicates significant effect and improves prognosis. However this good treatment can not be popularly translated to clinical use because stasis-heat can not be dynamically measured, identified and its pathogenesis of biological disorder has not been systematically clarified. The stasis-heat is a pivotal pathogenic unit which often emerges in acute phase of ICH,and it is pathogenic target of Liangxue Tongyu Fang. It can be measured using latent variable and scale. The methods of latent variable and latent growth model can disclose evolutive rule and changing process of stasis-heat. Also pathogenic network with stasis-heat pathogenic unit about how to form, change and influence on prognosis can be disclosed with these methods. Whereas measurement of soft variable of pathogenic unit has some unavoidable shortages, integrated study of correlated analysis between scores of latent variable and biomarkers based on differential display proteomics can better disclose systematic mechanism which may be systematic disorder between inflammatory factors associated brain hurt and index with cruor. This study has great significance for early warning of stasis-heat and explaining multiple targets mechanism of Chinese herbal compound. Furthermore, this study will explore a new feasible method for standardization of syndrome.

脑出血严重威胁我国人民的身体健康。急性期中医从瘀热病机论治能取得满意疗效和改善预后。但目前尚未建立瘀热病机的客观动态测量识别模式，缺乏系统阐明其发生发展的生物学紊乱机制，限制了其临床转化应用。瘀热是脑出血急性阶段关键的病机单元，也是凉血通瘀方治疗取效的中医病机靶点，可以采用潜变量和量表的方法进行动态的测量，潜变量结合潜发展模型可以揭示瘀热消长演变规律，并可分析瘀热病机发生发展的上下游病机网络机制，探讨其对预后的影响。鉴于软指标测量有其局限性，整合瘀热测量的潜变量得分和基于差异蛋白组学的生物标志物群的关联分析揭示其形成的系统机制，脑损伤相关的炎症因子及凝血相关的指标群的系统紊乱可能是其生物学基础。以上研究对于瘀热的早期预警、阻断疾病进展和中药复方的多靶点作用机制揭示具有重要意义，为证的规范和标准化探索新的路径。

急性脑出血属于急难重症，中医理论认为瘀热升腾、直冲犯脑、络伤血溢、清窍闭阻是其基本病机，临床循证也显示从“瘀热”病机立法治疗能减少死亡率和改善预后。因此，加强“瘀热”病机的测量评价和分子机制的研究将会促进其临床转化应用。本研究应用量表和潜变量方法，以相关宏观表征为条目，建立了具有一定效度和信度的“瘀热”病机单元的客观量化的测量方程，基于量表工具，揭示了脑出血急性期瘀热病机的动态发展规律及其上游影响因素，为急性脑出血的更好地防治提供了决策工具和理论依据。运用定量、动态差异蛋白质组学的方法(iTRAQ和SWATH)发现了瘀热病机的潜在标志物，小样本研究发现标志物有7个蛋白质，上游调控蛋白质有5个；大样本研究发现标志物有49个蛋白质。这些蛋白质包括急性反应相关蛋白、脂肪代谢相关蛋白、血液系统与凝血系统激活相关蛋白、细胞运动相关蛋白；AICH瘀热证患者较非瘀热证患者存在更严重的炎性反应、组织损伤、凝血功能紊乱。这在一定程度上，揭示了瘀热病机微观表征和病理本质，同时构建了蛋白质-信号通路-疾病与功能-病机的生物信息系统紊乱的网络图，从分子层面阐述了AICH瘀热病机要素可能的分子机制。以上研究极大地拓展了中医对“瘀热”病机的认识水平和临床转化应用能力。