睡眠呼吸暂停模式间歇低氧对大鼠淋巴细胞凋亡及淋巴细胞与血管内皮细胞相互作用机制的研究
发布时间：2018-07-13 15:02
【摘要】：研究目的与背景：阻塞性睡眠呼吸暂停综合征(OSAS)是指在睡眠期反复发生上气道阻塞并引起呼吸暂停的一种常见病。该病睡眠时反复出现呼吸暂停,伴随不同程度的间歇低氧(IH)。OSAS是一种全身系统性疾病,炎症和氧化应激是其主要特征,对心血管系统的损害已得到国内外呼吸和心血管领域的普遍认可和关注。白细胞与内皮细胞黏附可导致内皮细胞损伤,在内皮功能障碍导致的心血管合并症中发挥重要作用。目前认为OSAS模式IH激活的中性粒细胞及中性粒细胞与血管内皮细胞的相互作用可引起一系列炎症介质的变化,但迄今IH对淋巴细胞作用研究甚少,淋巴细胞与内皮细胞的黏附及相互作用导致内皮损伤等机制尚不清楚。研究表明在OSAS中,IH能够激活单核细胞,进而促使黏附分子和ROS的产生且单核细胞对内皮细胞的黏附活性显著增强,提示在OSAS损伤内皮细胞机制中单核细胞具有重要的功能。基于以上结果我们假设IH诱导大鼠循环血中淋巴细胞的激活,激活的淋巴细胞与内皮细胞黏附增加,并进一步激活内皮细胞,释放促炎细胞因子TNF-α、IL-8、CRP和ICAM-1等,同时氧化及抗氧化状态失衡,炎性介质以接触依赖的方式诱导内皮细胞的损伤,多种转录因子参与内皮细胞损伤及凋亡。为此,本研究模拟OSAS建立IH大鼠模型,观察IH模型大鼠淋巴细胞及亚型的凋亡,检测淋巴细胞与内皮细胞共培养炎性因子及氧化应激的水平,同时检测参与内皮细胞凋亡及通路的信号蛋白,最后探讨抗氧化剂干预效果,为临床OSAS合并症的发病机制提供理论依据。内容1.IH暴露下大鼠淋巴细胞亚群凋亡状态及抗氧化剂Tempol干预研究2.IH暴露下大鼠淋巴细胞与血管内皮细胞共培养后炎症及氧化应激程度,及内皮细胞凋亡机制的研究。方法1.将56只雄性Wistar大鼠随机分为①常氧对照组(NC);②IH 4周组(IH4);③IH 6周组(IH6);④早期抗氧化干预(IH6T)组;⑤早期生理盐水干预(IH6N);⑥晚期抗氧化干预组(IH6T2);⑦晚期生理盐水干预(IH6N2)。每组8只,IH暴露环境最低氧浓度均为5%,AHI 30/h。应用Tempol从暴露开始时及暴露4周后分别进行早期(IH6T组)和晚期(IH6T2组)干预,予生理盐水干预作对照。暴露结束后,各组大鼠均麻醉后腹主动脉取血,分离纯化淋巴细胞,无血清RPMI-1640培养基中重悬,用抗体标记淋巴细胞亚群,流式检测凋亡2.使用正常大鼠主动脉内皮细胞,细胞分为常氧对照组及IH组(IH暴露5h),淋巴细胞选用大鼠IH 6周组(IH6)、早期干预(IH6T)及常氧对照组(NC),直接接种于已含内皮细胞的孔板中,共培养分为6组：①常氧大鼠淋巴细胞与常氧内皮组(NC+NE)；②常氧大鼠淋巴细胞与IH内皮组(NC+IHE)；③IH6周大鼠淋巴细胞与常氧内皮组(IH6+NE)；④IH6周大鼠淋巴细胞与IH内皮组(IH6+IHE)；⑤抗氧化干预大鼠淋巴细胞与常氧内皮(IH6T+NE)；⑥抗氧化干预大鼠淋巴细胞与IH内皮组(IH6T+IHE).将共培养板置于细胞培养箱内共培养4h,取上清液离心后分装待检测,内皮细胞提取蛋白及mRNA.3.采用ELISA法检测各上清液CRP.TNF-α、IL-8、ICAM-1、MDA、CAT及SOD的水平,用蛋白印迹法检测内皮细胞内Caspase3、NF-κB P65、Bcl-2及Bax蛋白的表达。Real-time PCR法检测内皮细胞内NADPH P22、C-FOS、HIF-1α以及MAPK P38 mRNA表达水平。结果第一部分IH6组、IH4组与NC组比较,IH6组与IH4组比较,CD4、CD8淋巴细胞凋亡减少,B、NK淋巴细胞凋亡增多。IH6T、IH6T2组与IH6比较,IH6T与IH6T2比较,CD4、CD8淋巴细胞凋亡增加,B、NK淋巴细胞凋亡减少。IH6TIH6T2组与NC比较,CD4、CD8淋巴细胞凋亡减少,B、NK淋巴细胞凋亡增多,F值分别为：15.57(CD4)；24.79(CD8)；18.158(B)；21.94(NK)。第二部分结果1.淋巴细胞与内皮共培养后,IH6+IHE.H6+NE组与NC+NE组,IH6+IHE分别与IH6+NE.NC+IHE相比,NC+IHE组与NC+NE组相比,共培养液CRP、TNF-α、IL-8、ICAM-1及MDA的水平明显升高,但SOD和CAT明显下降；IH6T+NE与IH6+NE组,IH6T+IHE与IH6+IHE比较,TNF-α、IL-8、ICAM-1、CRP及MDA的水平明显下降,但SOD和CAT明显上升；但IH6T+NE组与NC+NE组,IH6T+IH组E与NC+IHE组比较,TNF-α、IL-8、ICAM-1、CRP及MDA的水平仍明显升高,但SOD和CAT明显下降；F值分别为26.30(TNF-α)、 14.048(IL-8)、26.96(ICAM-1)、17.477(CRP)、76.75(MDA)、18.76(SOD)及 28.30(CAT).2.淋巴细胞与内皮共培养后,IH6+IHE组、H6+NE组与NC+NE组,IH6+IHE组分别与IH6+NE组、NC+IHE相比,NC+IHE组与NC+NE组相比,内皮细胞表达NF-kB P65、Caspase-3、Bax蛋白增加,BCL-2蛋白表达减少；IH6T+NE组与IH6+NE组,IH6T+IHE组与IH6+IHE比较,内皮细胞表达NF-kB P65、 Caspase-3、Bax蛋白减少,BCL-2蛋白表达增加；但IH6T+NE组与NC+NE组,IH6T+IHE组与NC+IHE比较,内皮细胞表达NF-kB P65、Caspase-3、Bax仍蛋白增加,BCL-2蛋白表达减少；F值分别为82.65(NF-kB P65).37.68(Caspase-3)、 41.009(Bax)、51.72(BCL-2)、60.681(BCL-2/Bax)。3.淋巴细胞与内皮细胞共培养后,IH6+IHE组、H6+NE组与NC+NE组,IH6+IHE组分别与IH6+NE组、NC+IHE组相比,NC+IHE组与NC+NE组相比较,内皮细胞表达NADP P22 mRNA、C-FOS mRNA、HIF-1α、MAPK P38 mRNA增多；IH6T+NE组与IH6+NE组,IH6T+IEH组与IH6+IHE组比较,内皮细胞表达NADPH P22、C-FOS、HIF-1α和MAPK P38 mRNA减少；但IH6T+NE组与NC+NE组,IH6T+IHE组与NC+IHE组比较,内皮细胞表达 NADP P22 mRNA、C-FOS mRNA、HIF-1α、MAPK P38 mRNA仍增多；F值分别为27.64(NADPH P22).72.772(C-FOS)、30.04(HIF-1α)、43.84(MAPK P38)。结论1.IH暴露大鼠体内的淋巴细胞凋亡状态被改变,并可导致免疫失衡,抗氧化剂干预能够改善IH的损伤作用。2.IH暴露大鼠淋巴细胞与血管内皮细胞相互作用,导致氧化/抗氧化失衡,血管内皮细胞释放炎症因子及细胞损伤与凋亡增加。Ⅲ暴露淋巴细胞诱导血管内皮细胞凋亡,进而导致内皮功能障碍,在IH导致心血管合并症的发病机制中发挥重要作用。3.多种凋亡相关信号蛋白参与相关血管内皮细胞凋亡过程,促进相关血管内皮细胞凋亡4.抗氧化干预能够改善IH损伤性炎性反应和氧化／抗氧化失衡,且早期干预效果明显。为抗氧化干预预防和治疗间歇低氧引发的心脑血管合并症提供研究理论依据。
[Abstract]:Objective and background: obstructive sleep apnea syndrome (OSAS) is a common disease caused by recurrent airway obstruction and apnea during sleep. The recurrent apnea during sleep is recurrent, with varying degrees of intermittent hypoxia (IH).OSAS, a systemic disease, and inflammation and oxidative stress. Characteristics, the damage to the cardiovascular system has been widely recognized both at home and abroad. Adhesion of leukocytes and endothelial cells can lead to endothelial cell damage and play an important role in cardiovascular complications caused by endothelial dysfunction. Currently, OSAS mode IH activated neutrophils and neutrophils and neutrophils are considered. The interaction of vascular endothelial cells can cause a series of changes in inflammatory mediators, but so far little research has been made on the action of IH on lymphocytes. The mechanisms of adhesion and interaction of lymphocytes and endothelium are not clear. The study shows that in OSAS, IH can activate monocytes and then induce adhesion molecules and ROS production. The adhesion activity of mononuclear cells to endothelial cells increased significantly, suggesting that monocytes have important functions in the mechanism of OSAS damage to endothelial cells. Based on the above results, we hypothesized that IH induced activation of lymphocytes in circulating blood in rats, activated lymphocytes and endothelial cells, and further activated endothelial cells to release the cells. Inflammatory cytokine TNF- alpha, IL-8, CRP and ICAM-1, and oxidative and antioxidant state imbalance, inflammatory mediators induce endothelial cell damage in contact dependent manner, and multiple transcription factors participate in endothelial cell injury and apoptosis. Therefore, this study simulated OSAS to establish IH rat model, observe the apoptosis of lymphocyte and subtype of IH model rats, and detect the apoptosis of lymphocyte and subtype in IH model rats. The levels of inflammatory factors and oxidative stress were co cultured with endothelial cells, and the signal proteins involved in the apoptosis and pathways involved in endothelial cells were detected. Finally, the effect of antioxidant intervention was explored to provide a theoretical basis for the pathogenesis of clinical OSAS complication. Content of apoptosis and antioxidant activity of lymphocyte subsets in rats exposed to 1.IH Tempol intervention to study the study of inflammation and oxidative stress after co culture of lymphocytes and vascular endothelial cells in 2.IH exposed rats and the mechanism of endothelial cell apoptosis. Method 1. 56 male Wistar rats were randomly divided into 1 normal oxygen control group (NC); (2) IH 4 week group (IH4); IH 6 weeks group (IH6); (4) early antioxidant intervention (IH6T) group; 5 Stage physiological saline intervention (IH6N); (6) advanced antioxidation intervention group (IH6T2); terminal physiological saline intervention (IH6N2). 8 rats in each group were 5%, and AHI 30/h. applied Tempol from the beginning of exposure and 4 weeks after exposure to the early (IH6T) and late (IH6T2 group) intervention, respectively, to the physiological saline dry advance control. Exposure to the end of the exposure to the end of the exposure. After anesthesia, all rats were taken blood from the abdominal aorta, isolated and purified the lymphocytes, the serum free RPMI-1640 medium was suspended, the lymphocyte subgroup was marked with antibodies, and the flow cytometry was used to detect the apoptosis 2. of the normal rat aortic endothelial cells. The cells were divided into the normal oxygen control group and the IH group (IH exposure 5H), the lymphocyte was selected in the IH 6 week group (IH6), and the early stage (IH6). The intervention (IH6T) and the normal oxygen control group (NC) were directly inoculated to the Kong Banzhong containing endothelial cells. The co culture was divided into 6 groups: (1) the lymphocytes of the normal oxygen rats and the normoxic endothelial group (NC+NE); (2) the lymphocytes of the normal oxygen rats and the IH endothelium group (NC+IHE); (3) the lymphatic cells and the normal oxygen endothelium (IH6+NE) in the IH6 week rats; (4) the lymphocyte and IH in IH6 week rats and IH Endothelial group (IH6+IHE); (5) antioxidative intervention in rat lymphocytes and oxygen endothelium (IH6T+NE); (6) the lymphocyte and IH endothelial group (IH6T+IHE) in antioxidant intervention rats (IH6T+IHE). Co culture plate was placed in cell culture box to co culture 4h, and the supernatant was centrifuged after centrifugation to be detected. The endothelial cells extracted protein and mRNA.3. were used to detect the supernatant by ELISA method. The levels of CRP.TNF- alpha, IL-8, ICAM-1, MDA, CAT and SOD were detected by Western blot, and the expressions of NF- kappa B P65, Bcl-2 and Bax proteins were detected in endothelial cells. Lymphocyte apoptosis decreased, B, NK lymphocyte apoptosis increased.IH6T, IH6T2 group compared with IH6, IH6T and IH6T2, CD4, CD8 lymphocyte apoptosis increased, B, NK lymphocyte apoptosis decreased compared to.IH6TIH6T2 group and apoptosis, lymphoid cell apoptosis increased, respectively: 15.57; 24.79; 18.158; 21.94 (NK). Second part of result 1. lymphocyte and endothelium co culture, IH6+IHE.H6+NE group and NC+NE group, IH6+IHE compared with IH6+NE.NC+IHE, NC+IHE group compared with NC+NE group, TNF- alpha, IL-8, ICAM-1 and MDA. 8, ICAM-1, CRP and MDA significantly decreased, but SOD and CAT increased obviously, but IH6T+NE and NC+NE groups, IH6T+IH group E and NC+IHE groups, TNF- alpha, IL-8, SOD, and decreased significantly decreased, respectively, 14.048, 26.96, 17.477, 76.75, 18.76, and 28.30. (CAT) after co culture of.2. lymphocyte and endothelium, group IH6+IHE, H6+NE group and NC+NE group, IH6+IHE group were compared with IH6+NE group, NC+IHE, NC+IHE group and NC+NE group, the expression of NF-kB P65 was compared with NC+NE group. 5, Caspase-3, Bax protein decreased, and the expression of BCL-2 protein increased; but in group IH6T+NE and NC+NE, IH6T+IHE group was compared with NC+IHE, and endothelial cells expressed NF-kB P65, Caspase-3, Bax protein and decreased expression of BCL-2 protein; 41.009, 51.72, 60.681, respectively. After co culture, IH6+IHE group, H6+NE group and NC+NE group, IH6+IHE group compared with group IH6+NE, NC+IHE group, NC+IHE group compared with NC+NE group, endothelial cells expressed NADP P22 mRNA. And MAPK P38 mRNA decreased, but in group IH6T+NE and NC+NE group, IH6T+IHE group and NC+IHE group, the endothelial cells expressed NADP P22 mRNA, C-FOS mRNA, which were 27.64, 30.04 (alpha), 43.84 (respectively). Conclusion the apoptosis state of lymphocytes in exposed rats was changed, Immune imbalance can lead to immune imbalance, antioxidant intervention can improve the IH damage effect,.2.IH exposure of lymphocytes and vascular endothelial cells interaction, resulting in oxidative / antioxidant imbalance, vascular endothelial cells release inflammatory factors and cell damage and apoptosis increase. Skin dysfunction plays an important role in the pathogenesis of IH associated with cardiovascular complications..3. multiple apoptosis related signaling proteins participate in the apoptosis process of vascular endothelial cells, and the 4. antioxidant intervention to promote vascular endothelial cell apoptosis can improve the IH damage inflammatory response and oxygenation / antioxidant imbalance, and the early intervention effect is clear. It provides a theoretical basis for the prevention and treatment of cardiovascular and cerebrovascular complications induced by intermittent hypoxia.
【学位授予单位】：天津医科大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R766
本文编号：2119799
[Abstract]:Objective and background: obstructive sleep apnea syndrome (OSAS) is a common disease caused by recurrent airway obstruction and apnea during sleep. The recurrent apnea during sleep is recurrent, with varying degrees of intermittent hypoxia (IH).OSAS, a systemic disease, and inflammation and oxidative stress. Characteristics, the damage to the cardiovascular system has been widely recognized both at home and abroad. Adhesion of leukocytes and endothelial cells can lead to endothelial cell damage and play an important role in cardiovascular complications caused by endothelial dysfunction. Currently, OSAS mode IH activated neutrophils and neutrophils and neutrophils are considered. The interaction of vascular endothelial cells can cause a series of changes in inflammatory mediators, but so far little research has been made on the action of IH on lymphocytes. The mechanisms of adhesion and interaction of lymphocytes and endothelium are not clear. The study shows that in OSAS, IH can activate monocytes and then induce adhesion molecules and ROS production. The adhesion activity of mononuclear cells to endothelial cells increased significantly, suggesting that monocytes have important functions in the mechanism of OSAS damage to endothelial cells. Based on the above results, we hypothesized that IH induced activation of lymphocytes in circulating blood in rats, activated lymphocytes and endothelial cells, and further activated endothelial cells to release the cells. Inflammatory cytokine TNF- alpha, IL-8, CRP and ICAM-1, and oxidative and antioxidant state imbalance, inflammatory mediators induce endothelial cell damage in contact dependent manner, and multiple transcription factors participate in endothelial cell injury and apoptosis. Therefore, this study simulated OSAS to establish IH rat model, observe the apoptosis of lymphocyte and subtype of IH model rats, and detect the apoptosis of lymphocyte and subtype in IH model rats. The levels of inflammatory factors and oxidative stress were co cultured with endothelial cells, and the signal proteins involved in the apoptosis and pathways involved in endothelial cells were detected. Finally, the effect of antioxidant intervention was explored to provide a theoretical basis for the pathogenesis of clinical OSAS complication. Content of apoptosis and antioxidant activity of lymphocyte subsets in rats exposed to 1.IH Tempol intervention to study the study of inflammation and oxidative stress after co culture of lymphocytes and vascular endothelial cells in 2.IH exposed rats and the mechanism of endothelial cell apoptosis. Method 1. 56 male Wistar rats were randomly divided into 1 normal oxygen control group (NC); (2) IH 4 week group (IH4); IH 6 weeks group (IH6); (4) early antioxidant intervention (IH6T) group; 5 Stage physiological saline intervention (IH6N); (6) advanced antioxidation intervention group (IH6T2); terminal physiological saline intervention (IH6N2). 8 rats in each group were 5%, and AHI 30/h. applied Tempol from the beginning of exposure and 4 weeks after exposure to the early (IH6T) and late (IH6T2 group) intervention, respectively, to the physiological saline dry advance control. Exposure to the end of the exposure to the end of the exposure. After anesthesia, all rats were taken blood from the abdominal aorta, isolated and purified the lymphocytes, the serum free RPMI-1640 medium was suspended, the lymphocyte subgroup was marked with antibodies, and the flow cytometry was used to detect the apoptosis 2. of the normal rat aortic endothelial cells. The cells were divided into the normal oxygen control group and the IH group (IH exposure 5H), the lymphocyte was selected in the IH 6 week group (IH6), and the early stage (IH6). The intervention (IH6T) and the normal oxygen control group (NC) were directly inoculated to the Kong Banzhong containing endothelial cells. The co culture was divided into 6 groups: (1) the lymphocytes of the normal oxygen rats and the normoxic endothelial group (NC+NE); (2) the lymphocytes of the normal oxygen rats and the IH endothelium group (NC+IHE); (3) the lymphatic cells and the normal oxygen endothelium (IH6+NE) in the IH6 week rats; (4) the lymphocyte and IH in IH6 week rats and IH Endothelial group (IH6+IHE); (5) antioxidative intervention in rat lymphocytes and oxygen endothelium (IH6T+NE); (6) the lymphocyte and IH endothelial group (IH6T+IHE) in antioxidant intervention rats (IH6T+IHE). Co culture plate was placed in cell culture box to co culture 4h, and the supernatant was centrifuged after centrifugation to be detected. The endothelial cells extracted protein and mRNA.3. were used to detect the supernatant by ELISA method. The levels of CRP.TNF- alpha, IL-8, ICAM-1, MDA, CAT and SOD were detected by Western blot, and the expressions of NF- kappa B P65, Bcl-2 and Bax proteins were detected in endothelial cells. Lymphocyte apoptosis decreased, B, NK lymphocyte apoptosis increased.IH6T, IH6T2 group compared with IH6, IH6T and IH6T2, CD4, CD8 lymphocyte apoptosis increased, B, NK lymphocyte apoptosis decreased compared to.IH6TIH6T2 group and apoptosis, lymphoid cell apoptosis increased, respectively: 15.57; 24.79; 18.158; 21.94 (NK). Second part of result 1. lymphocyte and endothelium co culture, IH6+IHE.H6+NE group and NC+NE group, IH6+IHE compared with IH6+NE.NC+IHE, NC+IHE group compared with NC+NE group, TNF- alpha, IL-8, ICAM-1 and MDA. 8, ICAM-1, CRP and MDA significantly decreased, but SOD and CAT increased obviously, but IH6T+NE and NC+NE groups, IH6T+IH group E and NC+IHE groups, TNF- alpha, IL-8, SOD, and decreased significantly decreased, respectively, 14.048, 26.96, 17.477, 76.75, 18.76, and 28.30. (CAT) after co culture of.2. lymphocyte and endothelium, group IH6+IHE, H6+NE group and NC+NE group, IH6+IHE group were compared with IH6+NE group, NC+IHE, NC+IHE group and NC+NE group, the expression of NF-kB P65 was compared with NC+NE group. 5, Caspase-3, Bax protein decreased, and the expression of BCL-2 protein increased; but in group IH6T+NE and NC+NE, IH6T+IHE group was compared with NC+IHE, and endothelial cells expressed NF-kB P65, Caspase-3, Bax protein and decreased expression of BCL-2 protein; 41.009, 51.72, 60.681, respectively. After co culture, IH6+IHE group, H6+NE group and NC+NE group, IH6+IHE group compared with group IH6+NE, NC+IHE group, NC+IHE group compared with NC+NE group, endothelial cells expressed NADP P22 mRNA. And MAPK P38 mRNA decreased, but in group IH6T+NE and NC+NE group, IH6T+IHE group and NC+IHE group, the endothelial cells expressed NADP P22 mRNA, C-FOS mRNA, which were 27.64, 30.04 (alpha), 43.84 (respectively). Conclusion the apoptosis state of lymphocytes in exposed rats was changed, Immune imbalance can lead to immune imbalance, antioxidant intervention can improve the IH damage effect,.2.IH exposure of lymphocytes and vascular endothelial cells interaction, resulting in oxidative / antioxidant imbalance, vascular endothelial cells release inflammatory factors and cell damage and apoptosis increase. Skin dysfunction plays an important role in the pathogenesis of IH associated with cardiovascular complications..3. multiple apoptosis related signaling proteins participate in the apoptosis process of vascular endothelial cells, and the 4. antioxidant intervention to promote vascular endothelial cell apoptosis can improve the IH damage inflammatory response and oxygenation / antioxidant imbalance, and the early intervention effect is clear. It provides a theoretical basis for the prevention and treatment of cardiovascular and cerebrovascular complications induced by intermittent hypoxia.
【学位授予单位】：天津医科大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R766
【共引文献】
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