IL-37在2型糖尿病视网膜病变患者血清及玻璃体中的表达
发布时间：2018-08-31 19:51
【摘要】：背景:糖尿病(diabetic mellitus,DM)是一种代谢性疾病,其特点是血糖增高,长时间的高血糖与代谢紊乱可导致全身多器官损害,尤以眼、肾和神经系统功能障碍为主。截止到目前,世界糖尿病患者总人数近乎4亿,而我国约占其中的1/3,成为DM患者最多的国家。在DM中,常见且严重的微血管并发症之一是糖尿病视网膜病变(diabetic retinopathy,DR),它的患病率约为23%~43%[1],且随着生活水平的提高,DR的患病率亦逐年增加,威胁视力的糖尿病视网膜病变约占2.8%~6.3%,它是目前促使成人视力下降甚至失明的重要因素之一[1]。但DR的确切发病机制至今仍然不完全清楚,除传统的多元醇-肌醇代谢异常、氧化应激及抗氧化防御系统的损伤、蛋白激酶C的激活以及线粒体损伤等观点外。炎症因素也是DR发病的一个重要因素。在炎症反应中,白介素1(interleukin 1,IL-1)已被证实参与了DR的发病,其中IL-1α,IL-1β以及IL-18在炎症反应和血管生成的过程中扮演着重要的角色。而白介素37(interleukin 37,IL-37)是近年来新发现的IL-1家族中的一员,于2000年由Kuma发现并于2010年由Nold更名为IL-37[2,3],它可以在胸腺、淋巴结、骨髓、单核细胞以及内皮细胞等组织中检测到[4,5]。它以强大的抗炎作用被人们熟知,研究表明它可能是通过下调促炎性因子表达而发挥抗炎作用[3],在类风湿性关节炎(rheumatoid arthritis,RA)、系统性红斑狼疮(systemic lupus erythematosus,SLE)、银屑病等与自身免疫炎症相关的疾病患者血清中都可以发现IL-37表达增强[6-8]。但近两年来,通过体内、外研究还证实了IL-37具有促进内皮细胞增殖、迁移及血管腔形成的作用,是一种新型的促血管生成因子[9]。目前,血管内皮生长因子(vascular endothelial growth factor,VEGF)是一种被大家所熟知的促血管生成因子,它的过度表达已被证实与DR的发病密切相关,所以,在临床上,VEGF拮抗剂常常应用于DR患者的治疗,同时取得了显著的疗效。但仍有部分DR患者多次抗VEGF治疗后病情仍反复复发,黄斑反复水肿,视力进行性下降。这提示我们除了VEGF外,可能还有其他促血管生成因子参与了DR的发病,所以,单纯的抗VEGF治疗不能获得理想的治疗效果。而IL-37作为另一种新型的促血管生成因子,可能在DR中起着至关重要的作用。基于此,我们有必要去探讨IL-37是否参与了DR的发生及发展,甚至可以更深层次探讨是否可以通过使用IL-37的拮抗剂,从而减轻甚至稳定DR病情的发展。所以,本实验通过检测DR患者体内IL-37的浓度变化,分析探讨IL-37与DR的关系,以期为以后DR的治疗提供新的靶点及方向。目的:IL-37是近年来新发现的促血管生成因子,本实验主要是检测IL-37在糖尿病视网膜病变患者血清及玻璃体中的表达,并分析其临床意义,为以后DR的防治提供新的依据。方法:1.选取明确诊断为2型糖尿病的患者30例,并按疾病严重程度分为:1)糖尿病不合并糖尿病视网膜病变(diabetes without retinopathy,DWR)组,共10例;2)非增殖期糖尿病视网膜病变组(non-proliferative diabetic retinopathy,NPDR)10例;3)增殖期糖尿病视网膜病变组(proliferative diabetic retinopathy,PDR)。此外,再选择于重医附一院行常规体检,且体检报告显示不伴疾患的健康体检者10例作为正常对照组。所有受试者于清晨空腹时经肘正中静脉采取5ml血液,使用ELISA方法来测定血清中IL-37的表达水平,并将所有受试者血清中IL-37的浓度做统计学分析。2.选取15例自愿于重庆医科大学附属第一医院眼科行玻璃体切割手术的PDR确诊者作为本研究的实验组,同时,选取15例因黄斑前膜、特发性黄斑裂孔于我院行玻璃体切割手术的患者作为对照组,使用玻璃体切割法收集所有受试对象的玻璃体0.1-0.3ml,并使用ELISA法测量不同组别玻璃体中IL-37的浓度,并将其结果做统计学分析。3.选取8例自愿于术前行玻璃体腔抗VEGF(康伯西普)治疗的PDR患者,并于注射康伯西普3-7天后行玻切手术治疗,收集抗VEGF治疗前后的玻璃体标本,使用ELISA法测量其中IL-37浓度,将结果进行统计学分析。结果:1.DWR组血清IL-37浓度:65.09±9.83 pg/ml,NPDR组血清IL-37浓度:109.87±13pg/ml,PDR组血清IL-37浓度:115.88±17.37pg/ml,均高于正常对照组IL-37的浓度(54.62±6.79pg/ml),其中PDR与DWR组,PDR与正常对照组之间差异均有统计学意义(P0.05);此外,尽管DWR组比正常对照组稍高,但是结果并没有统计学意义。2.PDR组患者玻璃体IL-37浓度:370.94±22.63pg/ml,明显高于对照组(175.26±15.77pg/ml),差异具有统计学意义(P0.001)。3.抗VEGF治疗前后玻璃体IL-37的浓度变化无统计学差异(P=0.11390.05)。结论:IL-37在PDR患者体内显著增高,随着DR病情严重程度增加,IL-37表达逐渐增强,表明IL-37参与了DR的发生发展过程;此外,抗VEGF治疗前后IL-37浓度的变化无统计学差异,说明了单纯拮抗VEGF,可能不会对IL-37的表达产生影响。
[Abstract]:BACKGROUND: Diabetes mellitus (DM) is a metabolic disease characterized by elevated blood glucose. Long-term hyperglycemia and metabolic disorders can lead to multiple organ damage, especially eye, kidney and nervous system dysfunction. Diabetic retinopathy (DR) is one of the most common and serious microvascular complications in DM. The prevalence of DR is about 23%~43%[1]. With the improvement of living standards, the prevalence of DR is increasing year by year. The incidence of diabetic retinopathy (DR) which threatens vision is about 2.8%~6.3%. It is now promoting adult vision. However, the exact pathogenesis of DR is still unclear. In addition to traditional polyol-inositol metabolism, oxidative stress and antioxidant defense system damage, protein kinase C activation and mitochondrial damage, inflammatory factors are also an important factor in the pathogenesis of DR. Interleukin-1 (IL-1) has been shown to be involved in the pathogenesis of DR, in which IL-1a, IL-1beta and IL-18 play an important role in inflammatory response and angiogenesis. Interleukin-37 (IL-37), a member of the newly discovered IL-1 family, was discovered by Kuma in 2000 and by Nold in 2010. Renamed IL-37 [2,3], it can be detected in thymus, lymph nodes, bone marrow, monocytes and endothelial cells and other tissues [4,5].It is well known for its powerful anti-inflammatory effect, studies have shown that it may play an anti-inflammatory role by down-regulating the expression of inflammatory factors [3], in rheumatoid arthritis (RA), systemic. Increased expression of IL-37 can be found in the serum of patients with systemic lupus erythematosus (SLE), psoriasis and other autoimmune inflammation-related diseases [6-8]. However, in recent two years, in vivo and in vitro studies have also confirmed that IL-37 can promote the proliferation, migration and angiogenesis of endothelial cells, and is a new type of angiogenesis. Gene [9]. At present, vascular endothelial growth factor (VEGF) is a well-known angiogenic factor, its overexpression has been confirmed to be closely related to the pathogenesis of DR, so, in clinical, vascular endothelial growth factor antagonists are often used in the treatment of DR patients, but still achieved significant results. Some DR patients still relapse after multiple anti-VEGF treatments, macular edema and progressive visual loss. This suggests that besides VEGF, there may be other angiogenic factors involved in the pathogenesis of DR. Therefore, anti-VEGF therapy alone can not achieve the desired effect. IL-37 as another new type of angiogenic. Therefore, it is necessary to explore whether IL-37 is involved in the occurrence and development of DR, and even further explore whether the development of DR can be alleviated or even stabilized by the use of IL-37 antagonists. Objective: IL-37 is a newly discovered angiogenic factor in recent years. The purpose of this study is to detect the expression of IL-37 in serum and vitreous of patients with diabetic retinopathy, and analyze its clinical significance, so as to provide a new target and direction for the treatment of DR in the future. Methods: 1. 30 patients with type 2 diabetes mellitus were selected and divided into: 1) diabetes without retinopathy (DWR) group, 10 cases; 2) non-proliferative diabetic retinopathy (NPDR) group, 10 cases; 3) proliferative glycosuria. The proliferative diabetic retinopathy (PDR) group. In addition, 10 healthy volunteers who had received routine physical examination in the First Affiliated Hospital of Heavy Medical College and whose physical examination report showed no disease were selected as normal control group. All subjects were given 5 ml blood through the median cubital vein in the early morning fasting, and serum IL-37 was determined by ELISA method. Serum IL-37 levels of all subjects were analyzed statistically. 2. Fifteen PDR patients who had undergone vitrectomy voluntarily in the ophthalmology department of the First Affiliated Hospital of Chongqing Medical University were selected as the experimental group. Fifteen patients with idiopathic macular hole and macular epiretinal membrane underwent vitrectomy in our hospital. Vitrectomy was used to collect 0.1-0.3 ml of vitreous body of all subjects, and ELISA was used to measure the concentration of IL-37 in vitreous body of different groups. The results were analyzed statistically. 3. Eight PDR patients who volunteered to undergo vitreous cavity anti-VEGF (cumbercept) treatment before operation were selected and injected with cumbercept 3-3. After 7 days of vitrectomy, the vitreous specimens were collected before and after anti-VEGF treatment, and the concentration of IL-37 was measured by ELISA. The results were statistically analyzed. The concentration of IL-37 in the PDR group was significantly higher than that in the DWR group and the normal control group (P 0.05). In addition, although the concentration of IL-37 in the DWR group was slightly higher than that in the normal control group, the results were not statistically significant. There was no significant difference in the concentration of IL-37 before and after anti-VEGF treatment (P = 0.11390.05). Conclusion: IL-37 was significantly increased in patients with PDR. With the severity of DR increased, the expression of IL-37 gradually increased, indicating that IL-37 was involved in the occurrence and development of DR. There was no statistical difference in the changes, indicating that simply antagonizing VEGF might not affect the expression of IL-37.
【学位授予单位】：重庆医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R587.2;R774.1
本文编号：2215996
[Abstract]:BACKGROUND: Diabetes mellitus (DM) is a metabolic disease characterized by elevated blood glucose. Long-term hyperglycemia and metabolic disorders can lead to multiple organ damage, especially eye, kidney and nervous system dysfunction. Diabetic retinopathy (DR) is one of the most common and serious microvascular complications in DM. The prevalence of DR is about 23%~43%[1]. With the improvement of living standards, the prevalence of DR is increasing year by year. The incidence of diabetic retinopathy (DR) which threatens vision is about 2.8%~6.3%. It is now promoting adult vision. However, the exact pathogenesis of DR is still unclear. In addition to traditional polyol-inositol metabolism, oxidative stress and antioxidant defense system damage, protein kinase C activation and mitochondrial damage, inflammatory factors are also an important factor in the pathogenesis of DR. Interleukin-1 (IL-1) has been shown to be involved in the pathogenesis of DR, in which IL-1a, IL-1beta and IL-18 play an important role in inflammatory response and angiogenesis. Interleukin-37 (IL-37), a member of the newly discovered IL-1 family, was discovered by Kuma in 2000 and by Nold in 2010. Renamed IL-37 [2,3], it can be detected in thymus, lymph nodes, bone marrow, monocytes and endothelial cells and other tissues [4,5].It is well known for its powerful anti-inflammatory effect, studies have shown that it may play an anti-inflammatory role by down-regulating the expression of inflammatory factors [3], in rheumatoid arthritis (RA), systemic. Increased expression of IL-37 can be found in the serum of patients with systemic lupus erythematosus (SLE), psoriasis and other autoimmune inflammation-related diseases [6-8]. However, in recent two years, in vivo and in vitro studies have also confirmed that IL-37 can promote the proliferation, migration and angiogenesis of endothelial cells, and is a new type of angiogenesis. Gene [9]. At present, vascular endothelial growth factor (VEGF) is a well-known angiogenic factor, its overexpression has been confirmed to be closely related to the pathogenesis of DR, so, in clinical, vascular endothelial growth factor antagonists are often used in the treatment of DR patients, but still achieved significant results. Some DR patients still relapse after multiple anti-VEGF treatments, macular edema and progressive visual loss. This suggests that besides VEGF, there may be other angiogenic factors involved in the pathogenesis of DR. Therefore, anti-VEGF therapy alone can not achieve the desired effect. IL-37 as another new type of angiogenic. Therefore, it is necessary to explore whether IL-37 is involved in the occurrence and development of DR, and even further explore whether the development of DR can be alleviated or even stabilized by the use of IL-37 antagonists. Objective: IL-37 is a newly discovered angiogenic factor in recent years. The purpose of this study is to detect the expression of IL-37 in serum and vitreous of patients with diabetic retinopathy, and analyze its clinical significance, so as to provide a new target and direction for the treatment of DR in the future. Methods: 1. 30 patients with type 2 diabetes mellitus were selected and divided into: 1) diabetes without retinopathy (DWR) group, 10 cases; 2) non-proliferative diabetic retinopathy (NPDR) group, 10 cases; 3) proliferative glycosuria. The proliferative diabetic retinopathy (PDR) group. In addition, 10 healthy volunteers who had received routine physical examination in the First Affiliated Hospital of Heavy Medical College and whose physical examination report showed no disease were selected as normal control group. All subjects were given 5 ml blood through the median cubital vein in the early morning fasting, and serum IL-37 was determined by ELISA method. Serum IL-37 levels of all subjects were analyzed statistically. 2. Fifteen PDR patients who had undergone vitrectomy voluntarily in the ophthalmology department of the First Affiliated Hospital of Chongqing Medical University were selected as the experimental group. Fifteen patients with idiopathic macular hole and macular epiretinal membrane underwent vitrectomy in our hospital. Vitrectomy was used to collect 0.1-0.3 ml of vitreous body of all subjects, and ELISA was used to measure the concentration of IL-37 in vitreous body of different groups. The results were analyzed statistically. 3. Eight PDR patients who volunteered to undergo vitreous cavity anti-VEGF (cumbercept) treatment before operation were selected and injected with cumbercept 3-3. After 7 days of vitrectomy, the vitreous specimens were collected before and after anti-VEGF treatment, and the concentration of IL-37 was measured by ELISA. The results were statistically analyzed. The concentration of IL-37 in the PDR group was significantly higher than that in the DWR group and the normal control group (P 0.05). In addition, although the concentration of IL-37 in the DWR group was slightly higher than that in the normal control group, the results were not statistically significant. There was no significant difference in the concentration of IL-37 before and after anti-VEGF treatment (P = 0.11390.05). Conclusion: IL-37 was significantly increased in patients with PDR. With the severity of DR increased, the expression of IL-37 gradually increased, indicating that IL-37 was involved in the occurrence and development of DR. There was no statistical difference in the changes, indicating that simply antagonizing VEGF might not affect the expression of IL-37.
【学位授予单位】：重庆医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R587.2;R774.1
【参考文献】
相关期刊论文 前7条
1 汪东生;杨金奎;;糖尿病视网膜病变发病情况调查与发病机制研究的新进展[J];中华眼科医学杂志(电子版);2016年06期
2 袁立燕;谢杰;薛汝增;谷梅;杨斌;;白细胞介素37的免疫学研究进展[J];皮肤性病诊疗学杂志;2016年04期
3 安位芳;陈荏槐;姚运红;王森;;新型抗炎因子IL-37的研究进展[J];实用临床医学;2015年12期
4 张燕;熊霞;;IL-37及其与疾病相关性的研究进展[J];基础医学与临床;2015年04期
5 杨超;刘荣臻;张晓延;李鹏花;;类风湿性关节炎患者血清中IL-37水平变化的探索研究[J];中华全科医学;2014年07期
6 贺五一;方红城;苏又苏;;抑炎因子白介素-37与动脉粥样硬化的关系[J];心血管康复医学杂志;2014年01期
7 任翠平;高闻达;沈际佳;;IL-37免疫学作用研究进展[J];国际医学寄生虫病杂志;2014年01期
，本文编号：2215996
本文链接：https://www.wllwen.com/yixuelunwen/wuguanyixuelunwen/2215996.html
最近更新
教材专著
