IL-37在2型糖尿病視網(wǎng)膜病變患者血清及玻璃體中的表達(dá)
發(fā)布時(shí)間：2018-08-31 19:51
【摘要】：背景:糖尿病(diabetic mellitus,DM)是一種代謝性疾病,其特點(diǎn)是血糖增高,長(zhǎng)時(shí)間的高血糖與代謝紊亂可導(dǎo)致全身多器官損害,尤以眼、腎和神經(jīng)系統(tǒng)功能障礙為主。截止到目前,世界糖尿病患者總?cè)藬?shù)近乎4億,而我國約占其中的1/3,成為DM患者最多的國家。在DM中,常見且嚴(yán)重的微血管并發(fā)癥之一是糖尿病視網(wǎng)膜病變(diabetic retinopathy,DR),它的患病率約為23%~43%[1],且隨著生活水平的提高,DR的患病率亦逐年增加,威脅視力的糖尿病視網(wǎng)膜病變約占2.8%~6.3%,它是目前促使成人視力下降甚至失明的重要因素之一[1]。但DR的確切發(fā)病機(jī)制至今仍然不完全清楚,除傳統(tǒng)的多元醇-肌醇代謝異常、氧化應(yīng)激及抗氧化防御系統(tǒng)的損傷、蛋白激酶C的激活以及線粒體損傷等觀點(diǎn)外。炎癥因素也是DR發(fā)病的一個(gè)重要因素。在炎癥反應(yīng)中,白介素1(interleukin 1,IL-1)已被證實(shí)參與了DR的發(fā)病,其中IL-1α,IL-1β以及IL-18在炎癥反應(yīng)和血管生成的過程中扮演著重要的角色。而白介素37(interleukin 37,IL-37)是近年來新發(fā)現(xiàn)的IL-1家族中的一員,于2000年由Kuma發(fā)現(xiàn)并于2010年由Nold更名為IL-37[2,3],它可以在胸腺、淋巴結(jié)、骨髓、單核細(xì)胞以及內(nèi)皮細(xì)胞等組織中檢測(cè)到[4,5]。它以強(qiáng)大的抗炎作用被人們熟知,研究表明它可能是通過下調(diào)促炎性因子表達(dá)而發(fā)揮抗炎作用[3],在類風(fēng)濕性關(guān)節(jié)炎(rheumatoid arthritis,RA)、系統(tǒng)性紅斑狼瘡(systemic lupus erythematosus,SLE)、銀屑病等與自身免疫炎癥相關(guān)的疾病患者血清中都可以發(fā)現(xiàn)IL-37表達(dá)增強(qiáng)[6-8]。但近兩年來,通過體內(nèi)、外研究還證實(shí)了IL-37具有促進(jìn)內(nèi)皮細(xì)胞增殖、遷移及血管腔形成的作用,是一種新型的促血管生成因子[9]。目前,血管內(nèi)皮生長(zhǎng)因子(vascular endothelial growth factor,VEGF)是一種被大家所熟知的促血管生成因子,它的過度表達(dá)已被證實(shí)與DR的發(fā)病密切相關(guān),所以,在臨床上,VEGF拮抗劑常常應(yīng)用于DR患者的治療,同時(shí)取得了顯著的療效。但仍有部分DR患者多次抗VEGF治療后病情仍反復(fù)復(fù)發(fā),黃斑反復(fù)水腫,視力進(jìn)行性下降。這提示我們除了VEGF外,可能還有其他促血管生成因子參與了DR的發(fā)病,所以,單純的抗VEGF治療不能獲得理想的治療效果。而IL-37作為另一種新型的促血管生成因子,可能在DR中起著至關(guān)重要的作用�；诖�,我們有必要去探討IL-37是否參與了DR的發(fā)生及發(fā)展,甚至可以更深層次探討是否可以通過使用IL-37的拮抗劑,從而減輕甚至穩(wěn)定DR病情的發(fā)展。所以,本實(shí)驗(yàn)通過檢測(cè)DR患者體內(nèi)IL-37的濃度變化,分析探討IL-37與DR的關(guān)系,以期為以后DR的治療提供新的靶點(diǎn)及方向。目的:IL-37是近年來新發(fā)現(xiàn)的促血管生成因子,本實(shí)驗(yàn)主要是檢測(cè)IL-37在糖尿病視網(wǎng)膜病變患者血清及玻璃體中的表達(dá),并分析其臨床意義,為以后DR的防治提供新的依據(jù)。方法:1.選取明確診斷為2型糖尿病的患者30例,并按疾病嚴(yán)重程度分為:1)糖尿病不合并糖尿病視網(wǎng)膜病變(diabetes without retinopathy,DWR)組,共10例;2)非增殖期糖尿病視網(wǎng)膜病變組(non-proliferative diabetic retinopathy,NPDR)10例;3)增殖期糖尿病視網(wǎng)膜病變組(proliferative diabetic retinopathy,PDR)。此外,再選擇于重醫(yī)附一院行常規(guī)體檢,且體檢報(bào)告顯示不伴疾患的健康體檢者10例作為正常對(duì)照組。所有受試者于清晨空腹時(shí)經(jīng)肘正中靜脈采取5ml血液,使用ELISA方法來測(cè)定血清中IL-37的表達(dá)水平,并將所有受試者血清中IL-37的濃度做統(tǒng)計(jì)學(xué)分析。2.選取15例自愿于重慶醫(yī)科大學(xué)附屬第一醫(yī)院眼科行玻璃體切割手術(shù)的PDR確診者作為本研究的實(shí)驗(yàn)組,同時(shí),選取15例因黃斑前膜、特發(fā)性黃斑裂孔于我院行玻璃體切割手術(shù)的患者作為對(duì)照組,使用玻璃體切割法收集所有受試對(duì)象的玻璃體0.1-0.3ml,并使用ELISA法測(cè)量不同組別玻璃體中IL-37的濃度,并將其結(jié)果做統(tǒng)計(jì)學(xué)分析。3.選取8例自愿于術(shù)前行玻璃體腔抗VEGF(康伯西普)治療的PDR患者,并于注射康伯西普3-7天后行玻切手術(shù)治療,收集抗VEGF治療前后的玻璃體標(biāo)本,使用ELISA法測(cè)量其中IL-37濃度,將結(jié)果進(jìn)行統(tǒng)計(jì)學(xué)分析。結(jié)果:1.DWR組血清IL-37濃度:65.09±9.83 pg/ml,NPDR組血清IL-37濃度:109.87±13pg/ml,PDR組血清IL-37濃度:115.88±17.37pg/ml,均高于正常對(duì)照組IL-37的濃度(54.62±6.79pg/ml),其中PDR與DWR組,PDR與正常對(duì)照組之間差異均有統(tǒng)計(jì)學(xué)意義(P0.05);此外,盡管DWR組比正常對(duì)照組稍高,但是結(jié)果并沒有統(tǒng)計(jì)學(xué)意義。2.PDR組患者玻璃體IL-37濃度:370.94±22.63pg/ml,明顯高于對(duì)照組(175.26±15.77pg/ml),差異具有統(tǒng)計(jì)學(xué)意義(P0.001)。3.抗VEGF治療前后玻璃體IL-37的濃度變化無統(tǒng)計(jì)學(xué)差異(P=0.11390.05)。結(jié)論:IL-37在PDR患者體內(nèi)顯著增高,隨著DR病情嚴(yán)重程度增加,IL-37表達(dá)逐漸增強(qiáng),表明IL-37參與了DR的發(fā)生發(fā)展過程;此外,抗VEGF治療前后IL-37濃度的變化無統(tǒng)計(jì)學(xué)差異,說明了單純拮抗VEGF,可能不會(huì)對(duì)IL-37的表達(dá)產(chǎn)生影響。
[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.
【學(xué)位授予單位】：重慶醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R587.2;R774.1
本文編號(hào)：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.
【學(xué)位授予單位】：重慶醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R587.2;R774.1
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