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TNF-α、IL-1β和IL-6在退变性腰椎侧凸发病中的表达及意义

Expression and Significance of TNF-α、IL-1β and IL-6 in Degenerative Lumbar Scoliosis

【作者】 贺延雷

【导师】 丁文元;

【作者基本信息】 河北医科大学 , 外科学, 2010, 硕士

【摘要】 目的:探讨细胞因子TNF-α、IL - 1β和IL - 6在人类退变性腰椎侧凸椎间盘组织中的表达情况,以及这些细胞因子与退变性腰椎侧凸椎间盘退变的关系,为临床上分析退变性腰椎侧凸的病因和指导治疗提供理论依据。传统上认为退变性腰椎侧凸是指骨骼发育成熟之后,冠状面上cobb角度大于10度的腰椎畸形。但是随着生物力学,脊柱解剖,及显微成像技术的进步,人们认识到,侧凸不仅仅是冠状位的失衡,还包括矢状面平衡的丢失和椎体旋转。因此退变性腰椎侧凸是一种复杂的三维立体旋转畸形,治疗方法的选择亦应围绕着回复脊柱平衡展开。随着我国人口老龄化进程,退变性腰椎侧凸的发病率明显升高,此类患者的就医人数越来越多,严重的影响老年人的生活质量。退变性腰椎侧凸没有明确的分类标准,病因复杂,其确切发病原因至今仍不能被完全阐明。许多作者认为椎间盘和小关节的不对称改变是退变性腰椎侧凸发病的始动因素。退变性脊柱侧凸,尤其是退变性腰椎侧凸具有特征性的病理变化过程。椎间盘和/或小关节的不对称性退变首先导致脊柱节段性不对称负荷的出现,继而产生全脊柱的不对称性负荷,导致脊柱侧凸或后凸,不对称负荷进一步加重了不对称退变,周而复始形成恶性循环导致侧凸的进行性发展。椎间盘、关节面和关节囊的破坏导致脊柱冠状位和/或矢状位单节段或多节段的明显不稳定,引起椎间盘冠状面的移位和成角,矢状面的椎体滑移和/或旋转移位,以及腰椎前凸减小甚至腰椎后凸。长期的脊柱失稳使得脊柱柔韧性降低,产生了一系列的生物化学反应,导致软骨终板间骨赘形成以及小关节增生、关节囊及黄韧带肥厚、钙化,造成各种形式的椎管及椎间孔有效空间的减小即椎管狭窄(侧凸型或中央型),压迫神经出现根性疼痛或间歇性跛行。椎间盘退变后,其生物学性能降低,软骨终板、髓核、纤维环的组成成分改变。椎间盘的退行性变过程非常复杂,许多学者从分子和基因水平对其退行性变机制进行了探索,证实细胞因子与椎间盘退变的密切相关。目前,已经发现TNF-α、IL-1β和IL-6等种细胞因子参与了椎间盘退变过程。这些细胞因子通过炎症介质的激活,介导炎症反应,引起椎间盘退变。尽管一些研究发现了颈椎病、腰椎间盘突出症等椎间盘退变性疾病中存在TNF-α、IL-1β和IL-6等细胞因子的表达。但是,TNF-α、IL-1β和IL-6是否在退变性腰椎侧凸椎间盘细胞上表达尚没有得到证实。方法:收集2008年3月~2009年10月河北医科大学第三医院脊柱外科收治的34例退变性腰椎侧凸患者的病例资料,详细记录其临床症状及影像学结果。由同一术者完整摘除共36个腰椎节段的椎间盘组织(包括纤维环、髓核及软骨终板)作为实验组。选取同一时期住院手术治疗的青少年脊柱侧凸患者17例,术中完整摘取正常腰椎间盘组织(同实验组)共17个,作为对照组。4%多聚甲醛固定标本组织,制成石蜡标本后切片,按照免疫组化标准规程对标本中不同部位细胞因子的含量进行检测,高倍镜视野下至少计数20个不重复视野,计数TNF-α、IL-1β及IL -6的阳性细胞例数。使用CMIAS系列–多功能真彩色病理图像分析系统对免疫组化的结果进行分析处理,比较两组病例资料中TNF-α、IL-1β及IL -6在椎间盘组织中含量表达的差异。应用SPSS13.0统计软件包对试验数据进行统计分析。结果:1.实验组36个腰椎间盘组织中,TNF-α细胞表达阳性者共17例;对照组17例椎间盘组织中,TNF-α细胞表达阳性者共1例,统计学分析结果有显著性差异(P<0.05)。2.实验组36个腰椎间盘组织中,IL-1β细胞表达阳性者共14例;对照组17例椎间盘组织中,IL-1β细胞表达阳性者共2例,统计学分析结果有显著性差异(P<0.05)。3.实验组36个腰椎间盘组织中,IL-6细胞表达阳性者共13例;对照组17例椎间盘组织中,IL-6细胞表达阳性者共1例,统计学分析结果有显著性差异(P<0.05)。4.实验组36个腰椎间盘组织中,TNF-α、IL-1β及IL-6细胞均表达阳性者共9例;对照组17例椎间盘组织中,TNF-α、IL-1β、IL-6细胞均表达阳性者共0例,统计学分析结果有显著性差异。5.免疫组化的图像结果经过CMIAS系列–多功能真彩色病理图像分析系统处理后,统计学结果显示TNF-α、IL-1β及IL-6在退变椎间盘组织中的表达显著高于正常对照椎间盘组织,具有统计学差异(P<0.05)。结论:退变性腰椎侧凸的椎间盘组织的不同部位可产生TNF-α、IL- 1β和IL-6,阳性细胞主要存在于腰椎间盘组织周围的炎性肉芽组织内,其次为软骨终板、纤维环、髓核。阳性细胞以成纤维细胞、软骨细胞、中性粒细胞及淋巴细胞为主。这些细胞因子在退变性腰椎侧凸的发病中发挥重要作用。

【Abstract】 Objective: To explore the expression of TNF-α, IL-1βand IL-6 in degener ative human intervertebral discs, the relationship between those cytokines and disc degeneration of the degenerative lumbar scoliosis, and analyze the cause of th- e disease, supply theory base in the clinical use. Degenerative lumb sco- liosis has historically been simply defined as a spinal deformity in a skeletally mature atient with a Cobb angle of more than 10°in the coronal plain, which develops after skeletal maturity with a predominant lumbar location. However, recently, through a better understanding of biomechanics, spinal anatomy, and imaging techniques, it has been recognized that, in addition to the coronal im- balance, there is also an associated loss of sagittal balance and malrotation of the spine, which are integral components of the deformity. Degenerative lum- bar scoliosis, therefore, represents a complex three-dimensional rotational def- ormity that affects the spine in the coronal, sagittal, and axial planes and thus treatment paradigms should be devised to address all three components of this disorder. With the well documented age shift of our population, degenerative lumbar scoliosis is becoming increasingly prevalent, and seriously affects the life quality of the elderly. The degenerative lumbar scoliosis has no categorica separate criteria. The cause of degenerative lumbar scoliosis is unclear.The in- itiating agent of the degenerative lumbar scoliosis is a symmetric degeneration of the disc and/or the facet joints. Degenerative scoliosis, specifically in the l- umbar spine, is characterized by quite a uniform pathomorphology and patho- mechanism. The asymmetric degeneration of the disc and/or the facet joints l- eads to an asymmetric loading of the spinal segment and consequently of a w- hole spinal area. This again leads to an asymmetric deformity, for example, sc- oliosis and/orkyphosis. Such a deformity again triggers asymmetric degenerat- ion and induces asymmetric loading, creatin g a vicious circle and enhancing curve progression. On the one hand, the curve progression is given by the pat- homechanism of an adult degenerative curve, and on the other hand by the sp- ecific bone metabolism of the post-menopause female patients with a certain degree of osteoporosis, who are most frequently affected by the degenerative form of scoliosis. The potential of individual asymmetric deformation and col- lapse in the weak osteoporotic vertebra is clearly increased and contributes fu- rther to the curve progression. The osteophytes of the facet joints and the spo- ndylotic osteophytes, however, may not sufficiently stabilize a diseased spinal segment; such a condition leads to a dynamic, mostly foraminal stenosis with radicular pain or claudication type pain.The changing of the moity of the endplat, nucleus pulposus and anulus fibrosus is the grounding of degenerative of the ntervertebral disc, which induces the biology function down. However, the process of disc degeneration is unclear. A lot of scholars explore the degenerative mechanism at the molecule and the gene. The recent results showed close relationship between TNF-α, IL-1βand IL-6 and the intervertebral discs degeneration. These cytokines have an effect on mediating the inflammatory reactions. The expression of TNF-α, IL-1βand IL-6 in cervical spondylotic and lumbar intervertebral disc is definite, but is unclear in the degenerative lumbar scoliosis.Methods: From March 2008 to October 2009, a total of 53 cases were enrolled in the department of spine surgery of the third hospital of He Bei Medical University. In the test group, 36 specimens of lumbar intervertebral disc tissue were surgically obtained from 34 patients who suffered from degenerative lumbar scoliosis. Each included end plate, fibrosus annulus and nucleus. And in the control group, 17 specimens of intervertebral disc tissue were obtained from 17 adolescent idiopathic scoliosis patients with no disc degenerationn who were strong and healthy. All the specimens were fixed with 4% poly-paraformaldehyde, embedded in the paraffin, and made to slices for the immuno-histochemical analysis. At last, positive cells in different areas of the disc tissues, including endplatem, fibrosus annulus and nucleus, were counted and analyzed separately in twenty HP ( 400×) and then added to make statistical analysis. The expression of TNF-α, IL-1βand IL-6 were detected by immuno-Histochemistology, and the results were calculated by image procedure software. The data were dealt with SPSS 13.0.Results1. In the test group, the positive cases for TNF-α, were17; in the control gr- oup, there were only 1 positive case in all the 17 cases. There was significant difference between the two groups (P<0.05).2. In the test group, the positive cases for IL-1β, were14; in the control gro- up, there were only 2 positive cases. There was difference between the two gr- oups(P < 0.05).3. In the test group, the positive cases for IL-6, were 13; in the control gro- up, there were also 1 positive cases. There was difference between the two gr- oups by using SPSS 13. 0 statistics software (P<0.05).4. In the test group, the positive cases for TNF-α, IL-1βand IL -6 were 9; in the control group, there were no positive cells in all the 17 cases. There was difference between the two groups by using SPSS 13. 0 statistics software..5. The results of the immune-chemistry showed a very good statistic differ- ence exited among all the groups.Conclusion: The tissues of degenerative disc could produce TNF-α, IL-1β, and IL-6 cytokines, which were mainly found in the granulation tissue of circ- umambient intervertebral discs. The positive cells were mainly fibroblasts, ca- rtilage cells and lymphocytes. These cytokines may play an important role in the degeneration of degenerative lumbar scoliosis.

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