高迁移率族蛋白-1在急性脊髓损伤后肺损伤中作用及其分子机制的实验研究

Acute spinal cord injury（ASCI）may cause severe lung injury, which is an important pathological basis of respiratory failure and early death. However, most previous studies on ASCI-induced lung injury mainly focused on pathomorphologic description and rarely discussed the molecular mechanism of its occurrence. Our earlier study observed that High-Mobility Group Box-1(HMGB-1) was elevated in cerebrospinal fluid and serum in both ASCI patients and a rat model, and that toll like receptors (TLRs) was activated in lung tissue. We therefore hypothesized that necrotic neurons may release HMGB-1 after ASCI, which goes into the blood through the damaged blood-brain barrier and acts as an endogenous "danger signal" to mediate the occurrence of lung injury via TLRs signal pathways. This study was intended to observe the change of HMGB-1 level in the ASCI process and analyze its correlation with TLRs signal pathway activation, inflammation factor expression and histopathological change of the lung in a rat model of lung injury after ASCI. In addition, using anti-HMGB1 monoclonal antibody and gene silencing technology, the interaction between HMGB1 and TLRs will be intervened to further clarify the role of HMGB-1 and TLRs signal pathway in ASCI-induced lung injury, hoping to provide experimental evidence for the understanding and targeted therapy of ASCI-induced lung injury.

急性脊髓损伤（ASCI）有着较高的致残率和死亡率，其继发的肺损伤是引起患者呼吸衰竭和早期死亡的重要病理基础。既往对继发肺损伤的研究大多局限于病理学描述，并未深入探讨其分子机制。我们前期研究发现ASCI后脑脊液和血清中高迁移率族蛋白-1（HMGB-1）相继升高，肺组织中其相应受体Toll样受体（TLRs）活化增强。我们推测ASCI后坏死神经细胞可能释放HMGB-1，并经过损伤的血脑屏障进入血液，作为内源性"危险信号"分子介导肺损伤发生；并可能与TLRs信号通路有关。本课题拟通过ASCI后肺损伤动物模型，观察ASCI过程中HMGB1水平变化，分析其与TLRs、其下游信号分子表达及肺病理学改变等的相关性。并通过应用单克隆抗体和基因沉默技术干预HMGB-1/TLRs通路各关键靶点，进一步明确HMGB-1在ASCI继发肺损伤中的作用及其信号通路，为阐明ASCI后肺损伤发生机制及临床靶向治疗提供依据。

急性脊髓损伤是脊柱外科的常见伤病，有着较高的致残率和死亡率。脊髓损伤后呼吸系统并发症是急性脊髓损伤患者最常见的并发症和造成早期死亡最主要的原因。目前治疗措施多局限于并发症发生后对症治疗，对如何从源头阻断并发症发生研究较少。本研究拟揭示早期肺损伤介导机制，寻找干预靶点，从而从源头减轻或阻断肺损伤。本研究中，我们证实急性脊髓损伤后早期即可出现肺损伤，其损伤程度与HMGB-1表达水平呈正相关，且与HMGB-1/TLRs、HMGB-1/RAGE信号通路密切相关。通过抗RAGE、HMGB-1抗体干预后，肺损伤减轻、肺功能改善，进一步证实HMGB-1/TLRs、HMGB-1/RAGE参与其中。该研究可将早期肺损伤的认识引向深入，为充分阐述呼吸系统并发症产生机制及寻找早期安全、有效干预靶点提供理论依据，从而确实较少并发症，提高诊治水平。