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The Significance and Relevance between the Expressions of Hypoxia-inducible Factor-1α (HIF-1α) and Cylooxygenase-2 (COX-2) in Lumbar Disc Herniation

Author: LiZhiHao
Tutor: ZhuLiXin
School: Southern Medical University,
Course: Orthopedics
Keywords: Lumbar disc degeneration Cyclooxygenase- 2 Hypoxia-inducible factor - 1 alpha
CLC: R681.53
Type: Master's thesis
Year: 2010
Downloads: 149
Quote: 1
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Abstract

Lumbar degenerative changes caused by local pathological anatomy, pathophysiology changes can not only lead to disc abnormalities, lumbar spinal stenosis, and also may affect the stability of the motion segment, abnormal activities, such unusual activity can be further damage the disc The structure and function, further exacerbating the degeneration and destruction. Many studies confirmed that the disc is a spinal degenerative process in the first change in the structure of lumbar disc degeneration is a series of lumbar degenerative disease prerequisite and basis for pathological processes. Often clinically manifested as lumbar spinal stenosis, lumbar instability, lumbar disc disease, thus demonstrating the nerve root, spinal cord compression, and thus produce a series of symptoms, such as low back pain, lower extremity weakness, paresthesias and so on. The exact mechanism caused by lumbar disc degeneration inconclusive, lumbar disc degeneration occurs in addition to with traditional mechanical factors, neurophysiological factors, biochemical factors, the immune response is closely related. In recent years, with the rapid development of molecular biology and molecular immunology as well as in-depth study of cytokines and inflammatory mediators, cytokines and inflammatory mediators in intervertebral disc degeneration more and more attention. Numerous studies indicate that the degenerative lumbar disc tissue can produce inflammatory mediators, inflammatory component has been considered one of the main factors that lead to disc degeneration. Apoptosis of nucleus pulposus cells mediated by cytokines and inflammatory mediators, disc proteoglycan content decreased, the formation of new blood vessels and are generally considered to play an important role in the process of disc degeneration. With further research, the role of neovascularization in degenerative disc gradually attracted researchers attention. Early foreign scholars found in degenerative lumbar disc tissue vascular structures, and found that the more common vascular structures in the intervertebral disc. They think that angiogenesis plays an important role in the intervertebral disc spontaneously absorption process in. At present, domestic and foreign scholars on blood vessel formation in disc degeneration, there are two different points of view. Some scholars believe that angiogenesis is the body trying to repair tissue damage, delaying the spontaneous change of disc degeneration, is a reaction against degeneration, because the normal intervertebral disc has no blood supply, and the supply of nutrients mainly through two ways passive diffusion from: endplate way is the fibrous ring way. The intervertebral disc degeneration early passive diffusion of nutrients weakened the disc angiogenesis helps provide nutrients to the intervertebral disc cells, thus is beneficial to the body. Some scholars think that the disc vascularization lead to disc degeneration occurs initiating factor is the pathological basis of disc degeneration. Because the substance of the disc degeneration is the degradation of the matrix components, disc under the physiological state of the blood supply organization, vascular invasion may meet the conditions required for the activation of matrix metalloproteinase and matrix degrading enzymes, resulting in the degradation of the matrix, causing disc degeneration, and therefore harmful to the body. Cyclooxygenase -2 (COX-2) factor is a multifunctional protein expressed in many malignant tumors increased with tumor cell proliferation, apoptosis, angiogenesis closely related. This correlation mainly for the role of COX-2 tumor angiogenesis process. Studies have already confirmed the degeneration of the intervertebral disc neovascularization is very common, COX-2 factor in degenerative disc in the new role in the angiogenesis process as its role in tumor neovascularization? Addition, COX-2 factor or arachidonic acid converted to the rate-limiting enzyme of the prostaglandin, the earliest researchers found that prostaglandin concentration of the substance in the herniated disc tissue was significantly higher than the normal intervertebral disc, and its concentration there is a certain regularity. Prostaglandins inhibited proteoglycan synthesis disc cells and nucleus pulposus proteoglycan content reduce the lead to disc degeneration. Many studies have shown that COX-2 cytokine expression in human intervertebral disc degeneration was significantly higher than normal levels, and clinical studies have shown that the use of selective COX-2 inhibitor treatment of lumbar disc selective COX-2 inhibitors can significantly reduce disc herniation in patients with inflammatory response. Hypoxia induced factor -1 (HIF-1alpha) in 1992 found that an oxygen-dependent transcriptional activator, triggering downstream gene transcription by binding to hypoxia response element (HRE). HIF-1alpha is a tissue cells important molecular adaptation hypoxic environment, which can increase the erythropoietin receptor, glucose, glycolytic enzymes, angiogenic factors as well as the regulation of the expression of cell differentiation and apoptosis-related molecules. Will definitely lead to local tissue due to rapid tumor growth, proliferation rate of more than the growth rate of the surrounding blood vessels, severe hypoxia, and induce the expression of HIF-1alpha. Early studies suggest that disc degeneration due to insufficient supply of nutrients, resulting in relatively hypoxic environment of the intervertebral disc local scholars HIF-1alpha expression in human lumbar intervertebral disc degeneration. They then confirmed by immunohistochemical methods, herniated HIF-1alpha expression is significantly higher than the normal disc, and also confirmed that HIF-1 alpha expression and apoptosis of disc cells there is a correlation. In recent years, researchers have confirmed that HIF-1alpha expression in the rat nucleus pulposus cells, and induced HIF-1alpha expression in different induction environment different degrees. A high correlation between the expression of HIF-1alpha the extent and degree of apoptosis, within the nucleus of HIF-1alpha expression corresponding increase with the increase in the degree of disc apoptosis. Research purposes earlier studies have shown that cyclooxygenase -2 (COX-2) and hypoxia inducible factor -1 (HIF-la) is an important factor within the tumor angiogenesis, and COX-2, HIF-1α have been confirmed expression in human intervertebral disc. However, previous research at home and abroad confined to these two factors are in the process of disc degeneration and mechanisms, not combined detection of these two factors in the process of disc degeneration, the relevant literature have never reported that COX-2 HIF-1alpha in the Correlation of the disc degeneration process. Therefore, the discussion between the degeneration of intervertebral disc tissue expression, and degeneration of intervertebral disc neovascularization, further reveal and perfect the mechanism of disc degeneration, and for early prevention and treatment of intervertebral disc degeneration have a is of great significance. In the degeneration of the intervertebral disc tissue expression of both whether it is related to the two disc angiogenesis, and expression of how the differences between them are of this study need to be explored. Methods surgical removal of the degeneration of intervertebral disc tissue and a small amount of normal disc tissue, the intervertebral disc tissue fixation, made biopsy. Using immunohistochemical techniques, showing that the COX-2 factor, HIF-1 alpha factor, and new blood vessels marked by CD34 expression in intervertebral disc degeneration and normal disc position and count degenerative disc microvascular density. The statistical description of intervertebral disc degeneration of COX-2 factor HIF-1alpha factor expression and microvessel density (MVD) and COX-2 factor, the expression of HIF-1alpha factor. Results light microscopy test results: normal nucleus pulposus tissue sections under the light microscope after HE staining visible nucleus pulposus collagen fibers parallel to each other are arranged fibers more uniform thickness, we can see a small amount of cartilage cells, no vesicle-like cavities and fissures; retreat becomes the nucleus pulposus fibroblast proliferation, collagen fibers uneven thickness, disorganized, or even broken, and seen a lot of fibrous cartilage-like tissue. Nucleus pulposus matrix of hyaline degeneration, scattered or focal necrosis area, some necrosis liquefaction, absorption, left behind for varying sizes honeycomb, vesicle-like cavities and fissures. Immunohistochemical staining Results: Immunohistochemical staining revealed that HIF-1α, COX-2 as a control group of normal nucleus is only weakly expressed or almost no expression. But expression was significantly increased in the degeneration of the nucleus pulposus, which COX-2 expression in the degeneration of the intervertebral disc in the positive rate was 42.5%. The slices stained positive part of the majority of the cytoplasmic membrane of the nucleus pulposus cells, microscopy showed the nucleus pulposus cytoplasmic or membrane appeared brown staining particles, and most of the nearby angiogenesis. HIF-1 alpha factor in the degeneration of the intervertebral disc in the positive expression rate of 45%. Positive staining parts of sections majority of the cytoplasm and the nucleus of the nucleus pulposus cells, microscopy showed yellow-brown stain particles in the nucleus pulposus cells cytoplasm or nucleus, and positive cells in the site of the expression of COX- 2 positive cells in position there is a significant overlap. Marked by CD34 neovascularization by immunohistochemical staining, microscopy showed brown single endothelial cells or endothelial cell clusters. Does not appear in the normal nucleus pulposus positive results, but its positive results in the degeneration of the nucleus pulposus increased significantly. (3) the results of statistical analysis: Spearman rank correlation analysis, degenerative nucleus pulposus of HIF-1alpha, COX-2 was a significant positive correlation (P lt; 0.01, r = 0.406). Independent sample t test, degeneration of nucleus pulposus MVD value in the expression of HIF-1alpha positive group than negative group, there was a statistical difference (t = -4.052, P = 0.000), degeneration of the nucleus pulposus MVD in value in the expression of COX-2 positive group than negative group, there was a statistical difference (t = -5.103, P = 0.000). The conclusion 1.HIF-1alpha, COX-2 in the degeneration of the nucleus pulposus and its expression increased significantly; 2. Degeneration of the nucleus pulposus of HIF-1alpha, was a significant positive correlation between the expression of COX-2's; 3. Degeneration MVD in the nucleus pulposus in the expression of HIF-1alpha-positive group than negative group; 4. degeneration of the nucleus pulposus MVD value in the expression of COX-2 positive group than negative group.

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