颅脑损伤后血清、脑脊液IL1β，IL6的变化及临床意义
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摘要
在颅脑损伤发生时,尤其是重型颅脑损伤,中枢神经系统可产生大量的IL-1、IL-6等炎性细胞因子,它们在脑创伤后继发性炎症反应及神经元损害方面发挥着重要作用。
本文通过联合动态检测患者血清及脑脊液IL-1β, IL-6达到初步了解炎性细胞因子在不同程度颅脑损伤、颅脑损伤不同阶段的变化规律的目的,探讨炎症细胞因子IL-1β, IL-6与颅脑损伤的关系。
根据Glasgow (GCS)昏迷计分法将病人分为轻度组,中度组,重度组,并设正常对照组。分别在伤后第1天、第2天、第3天、第5天、第7天、第14天取外周静脉血及脑脊液,采用双抗体夹心ELISA法检测血清及脑脊液IL-1β,IL-6含量变化。重度组手术治疗并于术中在硬膜下放置颅内压检测仪探头检测颅内压。
本论文发现全组患者血清及脑脊液IL-1β, IL-6在伤后均有升高；重度组脑脊液中IL-1β在伤后第一天,第五天出现两次峰值,血中IL-1β第五天达到高峰；伤后第14天仍高于正常水平；中轻度组脑脊液中IL-1β伤后第二天达到高峰,血中IL-1β第五天达到高峰；伤后第14天高于正常水平。重度组脑脊液中的IL-6于伤后第一天达到高峰,以后呈现两种表现,大部分逐渐下降表现为单峰,小部分于伤后第五天再次升高,表现为双峰,血液中的IL-6值于伤后第一天达到高峰,以后逐渐下降；但伤后第14天仍高于正常水平。中轻度组脑脊液及血清IL-6伤后第二天达到高峰；伤后第14天高于正常水平；重度组血清及脑脊液IL-1β, IL-6与颅内压变化密切相关：重度组死亡患者脑脊液和血清中的IL-1β,IL-6含量极高并且随时间变化持续不降。
本论文初步结论：
1、颅脑损伤后脑脊液、血清中IL-1β,L-6水平增高及在损伤后不同时期的变化,提示炎性因子IL-1β,IL-6参与了早期颅脑损伤的病理生理过程；不同程度颅脑损伤在不同时间点脑脊液、血中IL-1β,L-6含量,呈现出反映脑损伤后的继发脑损害的动态变化,因此检测颅脑损伤后患者脑脊液及血中IL-1β,IL-6对于临床诊断和损伤严重程度判断、尽早评估预后以及指导不同颅脑损伤治疗,提高颅脑损伤救治水平,具有一定意义。
2、本实验表明脑脊液及血清中IL-1β与IL-6含量与重度及中轻度脑损伤之间正相关。IL-1β与IL-6含量越高,脑创伤越严重,患者预后越差。重度组IL-1β与IL-6同时出现双峰者预后差,结合本组患者的随访观察,脑脊液中IL-6呈现“双峰”表现的患者与呈单峰表现患者预后比较有显著性差异；术后第14天脑脊液及血清中IL-1β与IL-6含量仍高于正常水平,考虑是由于患者血脑屏障的破坏严重,修复缓慢所致,这对指导临床用药治疗提供了一定的依据,从而可以更有效的防治继发性颅脑损伤。本组实验证实重度组死亡患者脑脊液和血清中的IL-1β和IL-6含量极高且持续不降。
3、IL-1β, IL-6在脑脊液中的表达高于外周血中的表达。IL-1β, IL-6水平增高主要体现在脑脊液中,这可能是导致创伤后局部脑组织继发炎性反应及神经损害的重要原因。因此,在反应颅脑损伤变化方面,脑脊液IL-1β,IL-6含量检测较血清更为敏感、特异。
4、重度损伤组,颅脑损伤术后脑脊液、血清中IL-1β和IL-6与颅内压正相关,表明表明IL-1β和IL-6可能参与了颅脑损伤后继发脑水肿、颅内高压的发生、发展过程。
5、与单纯检测相比,联合检测患者血清、脑脊液IL-1β和IL-6的水平反应颅脑损伤的变化会更全面、准确,联合检测可以反映伤情的严重程度及病情的演变,并可以对预后作出一定的判断,是一种新的较为可靠的手段,可以提高临床预测的精确度。
本论文的创新点是：
1、采用动态检测血浆、脑脊液中IL-1, IL-6在创伤性脑损伤不同时期中的表达,探讨IL-1, IL-6在不同程度颅脑损伤中的动态变化规律及与预后的相关性。
2、通过检测比较脑脊液和血液中炎症因子IL-1,IL-6的含量变化和差异,了解综合检测指标在颅脑损伤程度、预后评估方面的作用,摸索二者在伤后不同时期的同步表达规律,为临床诊治提供参考。
3、多时项点动态检测脑脊液中IL-1, IL-6变化规律。
4、探讨重度颅脑损伤IL-1,IL-6含量与颅内压的关系。
动态联合检测IL-1β和IL-6的含量可以作为临床判断颅脑损伤程度和预后的一个重要指标,但脑脊液中白介素含量变化与颅脑损伤之间的具体机制是什么?脑脊液和血清中细胞因子的测定是能否充分代表脑实质本身的变化,白介素与颅脑损伤两者间的许多研究仍需进一步探讨和深入研究。
It has been proved that central nervous system can generate a large amount of inflammatory cytokines such as IL-1, IL-6when traumatic brain injury (TBI) occurs, especially when severe traumatic brain injury (sTBI) occurs. These inflammatory cytokines play an important role in secondary inflammation and neuronal damage after TBI.
In this paper, joint dynamic detection of IL-1β and IL-6in serum and cerebrospinal fluid are conducted to know the variation of the inflammatory cytokines in the varying degrees and different stages of brain injury; to study the relationship between the inflammatory cytokines IL-1β IL-6and brain injury.
Based on glasgow coma scoring (GCS) method, the patients were divided into four groups:mild group, medium group, severe group, and normal control group. Take the peripheral venous blood and cerebrospinal fluid samples after the injury occurred one day,2days,3days,5days,7days and14days respectively. Double antibody sandwich ELISA method was used to detect the IL-1β and IL-6contents in serum and cerebrospinal fluid. Surgical treatment was conducted to the severe group. And during the surgery, intracranial pressure monitoring probe was placed under the subdural to monitor intracranial pressure.
The study found that for all patients the IL-1β, IL-6in both serum and cerebrospinal fluid are increased after injury; For the severe group, IL-1β in cerebrospinal fluid got its peak in the first day after injury, and in the fifth day the second peak appeared, well, IL-1β in serum peaked in the fifth day, and was still higher than normal after14days. For the medium and mild group, IL-1β in cerebrospinal fluid reached a peak in the next day after injury, in serum reached its peak in the fifth day; and decreased to normal levels in the14th day after injury. IL-6in the cerebrospinal fluid of severe group reached the peak in the first postoperative day. After that, there are two possibilities:one is that it gradually declined and only a single peak occurred for most severe patients, another one is, for a small part of severe patients, it increased again in the fifth postoperative day and double peaks appeared. IL-6in serum increased rapidly, reached the peak in first day after injury, and then it decreased gradually, but when14days had passed after injury it was still higher than the normal levels. IL-6in both cerebrospinal fluid and serum of medium and mild groups reached the peak in the next day after injury, and decreased to the normal levels in14days after the injury. The content of IL-1β, IL-6in serum and cerebrospinal fluid of severe group were closely related to brain pressure changes, and they were very high for those dead patients, and dropped little over time.
The preliminary conclusions of this paper:
1. Increased concentrations of IL-1β, IL-6in cerebrospinal fluid and serum in different periods after brain injury showed that inflammatory factors IL-1β, IL-6participated in the pathophysiological process of early brain injury. IL-1β, IL6in cerebrospinal fluid and serum in different periods after varying degrees of brain injury can indicate the dynamic change of secondary brain damage. So the measurements of IL-1β, IL-6in cerebrospinal fluid and serum after brain injury is significant to get the clinical diagnosis and judgment of injury severity, assess prognosis and guide different brain injury treatment, to improve the level of brain injury treatment.
2. The experiments show that IL-1β and IL-6levels in the cerebrospinal fluid and serum is positively related to the severity of brain injury. The higher of IL-1β with IL-6content showed more serious traumatic brain injury and the worse the prognosis of patients. Patients in severe group with "Twin Peaks" for both IL-1β and IL-6appear poor prognosis. Combined with follow-up observation of this group of patients, there is a significant difference for the prognosis of patients between the IL-6presents "Twin Peaks" and a single peak. That IL-1β and IL-6levels in the cerebrospinal fluid and serum are still above normal levels14days after surgery is considered because these patients'blood-brain barrier is severely damaged, and recovery is slow. It provides some basis for guiding clinical drug therapy, and prevents effectively secondary brain injury. This experiment confirmed the IL-1β and IL-6level in the cerebrospinal fluid and serum of patients of the death group is very high and keeping in the high level.
3. IL-1β, IL-6in the cerebrospinal fluid is higher than that in the peripheral blood. That the increased levels of IL-1β, IL-6is mainly in the cerebrospinal fluid may probably be the most important reason to lead to the inflammatory reactions and nerve damage of the post-traumatic local brain tissue. Therefore, to reflect the changes in the brain injury, IL-1β, IL-6in cerebrospinal fluid is more sensitive and specific than those in serum.
4. IL-1β and IL-6in both cerebrospinal fluid and serum is positively correlated with intracranial pressure for the patients in severe injury group after surgery of TBI. It showed that IL-1β and IL-6may be involved in the secondary cerebral edema and the intracranial hypertension occurrence and development after TBI.
5. Compared with the single detection, that combined detection of IL-1β and IL-6in both serum and cerebrospinal fluid will be more comprehensive and accurate to express the brain injury. The combined detection reflect the severity of the injury and the severity of the evolution and could make some judgments on the prognosis. It is a new and more reliable approach to improve the accuracy of clinical prediction.
The innovation of this paper is as follows:
1. Found out the dynamic change of IL-1, IL-6in varying degrees of the brain injury and its relationship with prognosis using dynamic detection of the expression of IL-1, IL-6in serum and cerebrospinal fluid during different time after TBI.
2. Figured out the function of combined detection method in the evaluation of the degree of brain injury and prognostic by comparing IL-1β and IL-6levels in both serum and cerebrospinal fluid, explored their synchronization expression after surgery, and provided a reference for clinical diagnosis and treatment.
3. Multi-temporal point of dynamic detection of IL-1,IL-6content in cerebrospinal fluid.
4. Investigated the relationship between IL-1, IL-6content and intracranial pressure when sTBI occurred.
Dynamic joint detection of IL-1β and IL-6levels can be used as an important indicator of clinical judgment extent and prognosis of traumatic brain injury in the cerebrospinal fluid content with traumatic brain injury in interleukin. But what is the mechanism? Can the measurements of cerebrospinal fluid and serum cytokines adequately represent the brain parenchyma? Studies between interleukin and brain injury need to be further explored.
本文通过联合动态检测患者血清及脑脊液IL-1β, IL-6达到初步了解炎性细胞因子在不同程度颅脑损伤、颅脑损伤不同阶段的变化规律的目的,探讨炎症细胞因子IL-1β, IL-6与颅脑损伤的关系。
根据Glasgow (GCS)昏迷计分法将病人分为轻度组,中度组,重度组,并设正常对照组。分别在伤后第1天、第2天、第3天、第5天、第7天、第14天取外周静脉血及脑脊液,采用双抗体夹心ELISA法检测血清及脑脊液IL-1β,IL-6含量变化。重度组手术治疗并于术中在硬膜下放置颅内压检测仪探头检测颅内压。
本论文发现全组患者血清及脑脊液IL-1β, IL-6在伤后均有升高；重度组脑脊液中IL-1β在伤后第一天,第五天出现两次峰值,血中IL-1β第五天达到高峰；伤后第14天仍高于正常水平；中轻度组脑脊液中IL-1β伤后第二天达到高峰,血中IL-1β第五天达到高峰；伤后第14天高于正常水平。重度组脑脊液中的IL-6于伤后第一天达到高峰,以后呈现两种表现,大部分逐渐下降表现为单峰,小部分于伤后第五天再次升高,表现为双峰,血液中的IL-6值于伤后第一天达到高峰,以后逐渐下降；但伤后第14天仍高于正常水平。中轻度组脑脊液及血清IL-6伤后第二天达到高峰；伤后第14天高于正常水平；重度组血清及脑脊液IL-1β, IL-6与颅内压变化密切相关：重度组死亡患者脑脊液和血清中的IL-1β,IL-6含量极高并且随时间变化持续不降。
本论文初步结论：
1、颅脑损伤后脑脊液、血清中IL-1β,L-6水平增高及在损伤后不同时期的变化,提示炎性因子IL-1β,IL-6参与了早期颅脑损伤的病理生理过程；不同程度颅脑损伤在不同时间点脑脊液、血中IL-1β,L-6含量,呈现出反映脑损伤后的继发脑损害的动态变化,因此检测颅脑损伤后患者脑脊液及血中IL-1β,IL-6对于临床诊断和损伤严重程度判断、尽早评估预后以及指导不同颅脑损伤治疗,提高颅脑损伤救治水平,具有一定意义。
2、本实验表明脑脊液及血清中IL-1β与IL-6含量与重度及中轻度脑损伤之间正相关。IL-1β与IL-6含量越高,脑创伤越严重,患者预后越差。重度组IL-1β与IL-6同时出现双峰者预后差,结合本组患者的随访观察,脑脊液中IL-6呈现“双峰”表现的患者与呈单峰表现患者预后比较有显著性差异；术后第14天脑脊液及血清中IL-1β与IL-6含量仍高于正常水平,考虑是由于患者血脑屏障的破坏严重,修复缓慢所致,这对指导临床用药治疗提供了一定的依据,从而可以更有效的防治继发性颅脑损伤。本组实验证实重度组死亡患者脑脊液和血清中的IL-1β和IL-6含量极高且持续不降。
3、IL-1β, IL-6在脑脊液中的表达高于外周血中的表达。IL-1β, IL-6水平增高主要体现在脑脊液中,这可能是导致创伤后局部脑组织继发炎性反应及神经损害的重要原因。因此,在反应颅脑损伤变化方面,脑脊液IL-1β,IL-6含量检测较血清更为敏感、特异。
4、重度损伤组,颅脑损伤术后脑脊液、血清中IL-1β和IL-6与颅内压正相关,表明表明IL-1β和IL-6可能参与了颅脑损伤后继发脑水肿、颅内高压的发生、发展过程。
5、与单纯检测相比,联合检测患者血清、脑脊液IL-1β和IL-6的水平反应颅脑损伤的变化会更全面、准确,联合检测可以反映伤情的严重程度及病情的演变,并可以对预后作出一定的判断,是一种新的较为可靠的手段,可以提高临床预测的精确度。
本论文的创新点是：
1、采用动态检测血浆、脑脊液中IL-1, IL-6在创伤性脑损伤不同时期中的表达,探讨IL-1, IL-6在不同程度颅脑损伤中的动态变化规律及与预后的相关性。
2、通过检测比较脑脊液和血液中炎症因子IL-1,IL-6的含量变化和差异,了解综合检测指标在颅脑损伤程度、预后评估方面的作用,摸索二者在伤后不同时期的同步表达规律,为临床诊治提供参考。
3、多时项点动态检测脑脊液中IL-1, IL-6变化规律。
4、探讨重度颅脑损伤IL-1,IL-6含量与颅内压的关系。
动态联合检测IL-1β和IL-6的含量可以作为临床判断颅脑损伤程度和预后的一个重要指标,但脑脊液中白介素含量变化与颅脑损伤之间的具体机制是什么?脑脊液和血清中细胞因子的测定是能否充分代表脑实质本身的变化,白介素与颅脑损伤两者间的许多研究仍需进一步探讨和深入研究。
It has been proved that central nervous system can generate a large amount of inflammatory cytokines such as IL-1, IL-6when traumatic brain injury (TBI) occurs, especially when severe traumatic brain injury (sTBI) occurs. These inflammatory cytokines play an important role in secondary inflammation and neuronal damage after TBI.
In this paper, joint dynamic detection of IL-1β and IL-6in serum and cerebrospinal fluid are conducted to know the variation of the inflammatory cytokines in the varying degrees and different stages of brain injury; to study the relationship between the inflammatory cytokines IL-1β IL-6and brain injury.
Based on glasgow coma scoring (GCS) method, the patients were divided into four groups:mild group, medium group, severe group, and normal control group. Take the peripheral venous blood and cerebrospinal fluid samples after the injury occurred one day,2days,3days,5days,7days and14days respectively. Double antibody sandwich ELISA method was used to detect the IL-1β and IL-6contents in serum and cerebrospinal fluid. Surgical treatment was conducted to the severe group. And during the surgery, intracranial pressure monitoring probe was placed under the subdural to monitor intracranial pressure.
The study found that for all patients the IL-1β, IL-6in both serum and cerebrospinal fluid are increased after injury; For the severe group, IL-1β in cerebrospinal fluid got its peak in the first day after injury, and in the fifth day the second peak appeared, well, IL-1β in serum peaked in the fifth day, and was still higher than normal after14days. For the medium and mild group, IL-1β in cerebrospinal fluid reached a peak in the next day after injury, in serum reached its peak in the fifth day; and decreased to normal levels in the14th day after injury. IL-6in the cerebrospinal fluid of severe group reached the peak in the first postoperative day. After that, there are two possibilities:one is that it gradually declined and only a single peak occurred for most severe patients, another one is, for a small part of severe patients, it increased again in the fifth postoperative day and double peaks appeared. IL-6in serum increased rapidly, reached the peak in first day after injury, and then it decreased gradually, but when14days had passed after injury it was still higher than the normal levels. IL-6in both cerebrospinal fluid and serum of medium and mild groups reached the peak in the next day after injury, and decreased to the normal levels in14days after the injury. The content of IL-1β, IL-6in serum and cerebrospinal fluid of severe group were closely related to brain pressure changes, and they were very high for those dead patients, and dropped little over time.
The preliminary conclusions of this paper:
1. Increased concentrations of IL-1β, IL-6in cerebrospinal fluid and serum in different periods after brain injury showed that inflammatory factors IL-1β, IL-6participated in the pathophysiological process of early brain injury. IL-1β, IL6in cerebrospinal fluid and serum in different periods after varying degrees of brain injury can indicate the dynamic change of secondary brain damage. So the measurements of IL-1β, IL-6in cerebrospinal fluid and serum after brain injury is significant to get the clinical diagnosis and judgment of injury severity, assess prognosis and guide different brain injury treatment, to improve the level of brain injury treatment.
2. The experiments show that IL-1β and IL-6levels in the cerebrospinal fluid and serum is positively related to the severity of brain injury. The higher of IL-1β with IL-6content showed more serious traumatic brain injury and the worse the prognosis of patients. Patients in severe group with "Twin Peaks" for both IL-1β and IL-6appear poor prognosis. Combined with follow-up observation of this group of patients, there is a significant difference for the prognosis of patients between the IL-6presents "Twin Peaks" and a single peak. That IL-1β and IL-6levels in the cerebrospinal fluid and serum are still above normal levels14days after surgery is considered because these patients'blood-brain barrier is severely damaged, and recovery is slow. It provides some basis for guiding clinical drug therapy, and prevents effectively secondary brain injury. This experiment confirmed the IL-1β and IL-6level in the cerebrospinal fluid and serum of patients of the death group is very high and keeping in the high level.
3. IL-1β, IL-6in the cerebrospinal fluid is higher than that in the peripheral blood. That the increased levels of IL-1β, IL-6is mainly in the cerebrospinal fluid may probably be the most important reason to lead to the inflammatory reactions and nerve damage of the post-traumatic local brain tissue. Therefore, to reflect the changes in the brain injury, IL-1β, IL-6in cerebrospinal fluid is more sensitive and specific than those in serum.
4. IL-1β and IL-6in both cerebrospinal fluid and serum is positively correlated with intracranial pressure for the patients in severe injury group after surgery of TBI. It showed that IL-1β and IL-6may be involved in the secondary cerebral edema and the intracranial hypertension occurrence and development after TBI.
5. Compared with the single detection, that combined detection of IL-1β and IL-6in both serum and cerebrospinal fluid will be more comprehensive and accurate to express the brain injury. The combined detection reflect the severity of the injury and the severity of the evolution and could make some judgments on the prognosis. It is a new and more reliable approach to improve the accuracy of clinical prediction.
The innovation of this paper is as follows:
1. Found out the dynamic change of IL-1, IL-6in varying degrees of the brain injury and its relationship with prognosis using dynamic detection of the expression of IL-1, IL-6in serum and cerebrospinal fluid during different time after TBI.
2. Figured out the function of combined detection method in the evaluation of the degree of brain injury and prognostic by comparing IL-1β and IL-6levels in both serum and cerebrospinal fluid, explored their synchronization expression after surgery, and provided a reference for clinical diagnosis and treatment.
3. Multi-temporal point of dynamic detection of IL-1,IL-6content in cerebrospinal fluid.
4. Investigated the relationship between IL-1, IL-6content and intracranial pressure when sTBI occurred.
Dynamic joint detection of IL-1β and IL-6levels can be used as an important indicator of clinical judgment extent and prognosis of traumatic brain injury in the cerebrospinal fluid content with traumatic brain injury in interleukin. But what is the mechanism? Can the measurements of cerebrospinal fluid and serum cytokines adequately represent the brain parenchyma? Studies between interleukin and brain injury need to be further explored.
引文
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