替普瑞酮对门脉高压性胃病胃黏膜上皮细胞紧密连接蛋白表达的影响
发布时间：2018-09-06 15:15
【摘要】：门脉高压性胃病(portal hypertensive gastropathy, PHG)是肝硬化门静脉高压的常见并发症之一。其主要的临床表现为上消化道出血，是肝硬化门脉高压症并发上消化道出血的主要原因之一，仅次于食管胃底静脉曲张破裂引起的上消化道出血，具有重要的临床意义。PHG患者会出现胃部微循环的异常，胃黏膜血流量减少，引起胃黏膜屏障损伤，使胃黏膜对各种损伤更加敏感，且抗损伤能力减弱。胃黏膜上皮细胞间的紧密连接是胃黏膜屏障的重要组成部分，其位于相邻细胞间隙的顶端侧面，具有维持细胞极性和调节渗透性两个主要功能。对于维持胃黏膜屏障功能的稳定具有非常重要的作用。与胃黏膜上皮细胞紧密连接(tight junction, TJ)相关的蛋白，主要包括闭锁(Occludin)蛋白、Claudin蛋白、zonula occludens (ZOs)蛋白以及连接黏附分子(junction adhesion molecular, JAM)等。胃黏膜上皮细胞紧密连接蛋白表达量的降低，提示胃黏膜屏障功能受损。 盐酸普萘洛尔是一种非选择性β受体阻滞剂，是目前在治疗门脉高压中应用最为广泛的药物。它可以通过降低门静脉血压、减少胃黏膜血流量，从而起到治疗PHG的作用。替普瑞酮是一萜类化合物，现广泛应用于抗溃疡治疗。目前研究认为，它可通过诱导热休克蛋白(HSP)的表达和促进胃黏膜内源性前列腺素E(prostaglandin E, PGE)的合成与释放来保护胃黏膜。 因此，本项研究的目的在于探讨紧密连接相关蛋白在PHG患者胃黏膜屏障损伤中的作用，同时探讨盐酸普萘洛尔以及联合替普瑞酮对PHG胃黏膜紧密连接蛋白表达的影响。 目的：本研究旨在揭示PHG胃黏膜屏障损伤的分子机制，并探讨盐酸普萘洛尔和替普瑞酮对PHG的治疗效果及对胃黏膜上皮细胞紧密连接蛋白表达的影响。 方法：收集行胃镜检查的PHG患者10例。将其随机分为两组，在行胃镜检查及标本采集后，其中一组给予盐酸普萘洛尔（30mg/天）治疗，另一组给予盐酸普萘洛尔（30mg/天）联合替普瑞酮胶囊（150mg/天）治疗，两组患者均在治疗1个月后复查胃镜并再次采集标本，同时观察患者内镜下胃黏膜病变的变化情况。另外收集10例行上消化道内镜检查的健康体检者作为健康对照组。于胃底体交界处口侧3~5cm大弯侧取材，应用免疫组织化学方法检测各组胃黏膜上皮细胞间紧密连接蛋白Occludin和ZO-1的表达情况。 结果：PHG患者胃黏膜上皮细胞紧密连接蛋白Occludin和ZO-1表达减少。PHG患者治疗前与健康对照组相比：①胃镜下表现：PHG患者内镜下可见到典型的马赛克样改变、蛇皮样改变、散在的樱桃红样斑点或弥漫性出血性改变等。②组织形态学表现：PHG患者黏膜层及黏膜下层可见明显的毛细血管扩张，无明显的炎症改变。③Occludin蛋白和ZO-1蛋白的免疫组织化学结果：健康对照组Occludin蛋白及ZO-1蛋白均呈棕褐色线状连续均匀分布于胃黏膜上皮细胞的细胞膜，PHG患者药物干预前与健康对照组比较，Occludin蛋白及ZO-1蛋白染色均明显变浅，不连续，有部分缺失，且分布也不均匀，Occludin的平均光密度值(optical density,OD)分别为：(0.03±0.01),(0.14±0.02),(P0.001), ZO-1的OD值分别为：(0.03±0.01),(0.16±0.02),(P0.001)，均有统计学差异。 盐酸普萘洛尔可以增加PHG患者胃黏膜上皮细胞紧密连接蛋白Occludin和ZO-1的表达量。单用盐酸普萘洛尔干预组，PHG患者治疗后与治疗前比较：①胃镜下表现：治疗后PHG患者胃黏膜病变较前好转。②组织形态学表现：治疗后PHG患者黏膜层及黏膜下层毛细血管扩张减轻。③Occludin蛋白和ZO-1蛋白的免疫组织化学结果：治疗后的患者胃黏膜上皮细胞的Occludin蛋白和ZO-1蛋白染色均较前加深，仍可见部分缺失，但缺失较前减少，其中Occludin蛋白的OD值分别为：(0.06±0.01),(0.03±0.01),(P0.01), ZO-1蛋白的OD值分别为：(0.07±0.01),(0.03±0.01),(P0.01)，均有统计学差异。 联合应用盐酸普萘洛尔和替普瑞酮比单用盐酸普萘洛尔对PHG患者胃黏膜上皮细胞紧密连接蛋白Occludin和ZO-1表达量的增加更明显。联合应用盐酸普萘洛尔和替普瑞酮干预组治疗后与单独应用盐酸普萘洛尔干预组治疗后比较：①胃镜下表现：联合应用盐酸普萘洛尔和替普瑞酮组比单用盐酸普萘洛尔组胃黏膜病变好转更加明显。②组织形态学表现：联合应用盐酸普萘洛尔和替普瑞酮组比单用盐酸普萘洛尔组黏膜层及黏膜下层毛细血管扩张减轻更加明显。③Occludin蛋白和ZO-1蛋白的免疫组织化学结果：联合应用盐酸普萘洛尔和替普瑞酮治疗后，PHG患者胃黏膜上皮细胞的Occludin蛋白和ZO-1蛋白染色加深更明显，缺失部分减少更明显，Occludin蛋白的OD值分别为：(0.11±0.01),(0.06±0.01),(P0.01)，，ZO-1蛋白的OD值分别为：(0.12±0.02),(0.07±0.01),(P0.01)，均有统计学差异。 结论：PHG患者胃黏膜上皮细胞紧密连接蛋白Occludin和ZO-1表达减少，这可能是PHG胃黏膜屏障损伤的重要原因，替普瑞酮可能通过上调Occludin和ZO-1的表达来保护胃黏膜屏障。
[Abstract]:Portal hypertensive gastropathy (PHG) is one of the common complications of portal hypertension in cirrhosis. The main clinical manifestation of PHG is upper gastrointestinal bleeding, which is one of the main causes of upper gastrointestinal bleeding in cirrhotic portal hypertension, second only to upper gastrointestinal bleeding caused by rupture of esophageal and gastric varices. PHG patients may have abnormal gastric microcirculation, decreased gastric mucosal blood flow, resulting in damage to the gastric mucosal barrier, making the gastric mucosa more sensitive to various kinds of damage, and weakening the ability to resist damage. On the apical side, it has two main functions: maintaining cell polarity and regulating permeability. It plays an important role in maintaining the stability of gastric mucosal barrier function. Proteins related to tight junction (TJ) of gastric mucosal epithelial cells, mainly including Occludin, Claudin, zonula occludens (ZOs), and so on. The expression of tight junction molecule (JAM) in gastric mucosal epithelial cells decreased, suggesting impaired gastric mucosal barrier function.
Propranolol hydrochloride is a non-selective beta-blocker, which is the most widely used drug in the treatment of portal hypertension. It can reduce portal blood pressure, gastric mucosal blood flow, and thus play a role in the treatment of PHG. Teprenone is a terpenoid compound and is widely used in anti-ulcer therapy. It can protect gastric mucosa by inducing the expression of heat shock protein (HSP) and promoting the synthesis and release of endogenous prostaglandin E (PGE).
Therefore, the purpose of this study was to investigate the role of tight junction related proteins in gastric mucosal barrier injury in PHG patients, and to investigate the effects of propranolol hydrochloride and teprenone on the expression of tight junction proteins in gastric mucosa of PHG patients.
AIM: To explore the molecular mechanism of gastric mucosal barrier injury in PHG and the effects of propranolol hydrochloride and teprenone on the expression of tight junction protein in gastric epithelial cells.
Methods: 10 patients with PHG underwent gastroscopy were randomly divided into two groups. After gastroscopy and specimen collection, one group was treated with propranolol hydrochloride (30mg/day), the other group was treated with propranolol hydrochloride (30mg/day) combined with teprenone capsule (150mg/day). Both groups were re-examined by gastroscopy one month after treatment. The specimens were collected again and the changes of gastric mucosal lesions were observed under endoscopy. In addition, 10 healthy volunteers who underwent upper gastrointestinal endoscopy were selected as healthy control group. The expression of in and ZO-1.
Results: The expression of tight junction protein Occludin and ZO-1 in gastric mucosa epithelial cells of PHG patients decreased. Before treatment, PHG patients were compared with healthy control group: 1. Gastroscopic manifestations: typical mosaic-like changes, snakeskin-like changes, scattered cherry red spots or diffuse hemorrhagic changes were observed in PHG patients. Appearance: There was obvious telangiectasia in the mucosa and submucosa of patients with PHG, but no obvious inflammation. 3. Immunohistochemical results of Occludin and ZO-1 protein: Occludin and ZO-1 protein in healthy control group were continuously distributed in the membrane of gastric mucosal epithelial cells in brown line, and drug trunk in patients with PHG. Compared with the healthy control group, Occludin protein and ZO-1 protein staining were significantly lighter, discontinuous, partially missing, and unevenly distributed. The mean optical density (OD) of Occludin was (0.03 (+) 0.01), (0.14 (+) 0.02), (P 0.001), and the OD value of ZO-1 were (0.03 (+) 0.01, (0.16 (+) 0.02), (P 0.001), respectively. Difference.
Propranolol hydrochloride can increase the expression of tight junction protein Occludin and ZO-1 in gastric mucosa epithelial cells of PHG patients. In the intervention group of propanolol hydrochloride alone, the gastroscopic manifestations of PHG patients after treatment were compared with those before treatment: (1) After treatment, the gastric mucosal lesions of PHG patients were improved. Immunohistochemical results of Occludin and ZO-1 proteins: After treatment, the expression of Occludin and ZO-1 proteins in gastric mucosal epithelial cells of the patients were deeper than before, and some of them were still missing, but the OD value of Occludin protein was lower than before, and the OD value of Occludin protein was (0.06 + 0.01), (0.03 + 0.01) respectively. .01), (P0.01), the OD values of ZO-1 protein were: (0.07 + 0.01), (0.03 + 0.01), (P0.01), there was statistical difference.
The expression of tight junction protein Occludin and ZO-1 in gastric mucosal epithelial cells of PHG patients was increased more significantly by the combination of propranolol hydrochloride and teprenolone than by propranolol hydrochloride alone. The following manifestations: The gastric mucosal lesions in the propranolol hydrochloride and teprenone group were significantly better than those in the propranolol hydrochloride alone. 2. Histomorphological findings: The telangiectasia in the propranolol hydrochloride and teprenone hydrochloride group was more obvious than that in the propranolol hydrochloride alone group. Immunohistochemical results of in protein and ZO-1 protein: After the combination of propranolol hydrochloride and teprenone treatment, the staining of Occludin protein and ZO-1 protein in gastric epithelial cells of PHG patients was deepened more significantly, and the deletion part was decreased more significantly. The OD value of Occludin protein was (0.11 (+) 0.01, (0.06 +) 0.01, (P 0.01), and the OD value of ZO-1 protein was (P 0.01). The values were: (0.12 + 0.02), (0.07 + 0.01), (P0.01), all of which were statistically different.
CONCLUSION: Decreased expression of tight junction proteins Occludin and ZO-1 in gastric epithelial cells of PHG patients may be an important cause of gastric mucosal barrier injury. Teprenone may protect gastric mucosal barrier by up-regulating the expression of Occludin and ZO-1.
【学位授予单位】：河北医科大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R573
本文编号：2226750
[Abstract]:Portal hypertensive gastropathy (PHG) is one of the common complications of portal hypertension in cirrhosis. The main clinical manifestation of PHG is upper gastrointestinal bleeding, which is one of the main causes of upper gastrointestinal bleeding in cirrhotic portal hypertension, second only to upper gastrointestinal bleeding caused by rupture of esophageal and gastric varices. PHG patients may have abnormal gastric microcirculation, decreased gastric mucosal blood flow, resulting in damage to the gastric mucosal barrier, making the gastric mucosa more sensitive to various kinds of damage, and weakening the ability to resist damage. On the apical side, it has two main functions: maintaining cell polarity and regulating permeability. It plays an important role in maintaining the stability of gastric mucosal barrier function. Proteins related to tight junction (TJ) of gastric mucosal epithelial cells, mainly including Occludin, Claudin, zonula occludens (ZOs), and so on. The expression of tight junction molecule (JAM) in gastric mucosal epithelial cells decreased, suggesting impaired gastric mucosal barrier function.
Propranolol hydrochloride is a non-selective beta-blocker, which is the most widely used drug in the treatment of portal hypertension. It can reduce portal blood pressure, gastric mucosal blood flow, and thus play a role in the treatment of PHG. Teprenone is a terpenoid compound and is widely used in anti-ulcer therapy. It can protect gastric mucosa by inducing the expression of heat shock protein (HSP) and promoting the synthesis and release of endogenous prostaglandin E (PGE).
Therefore, the purpose of this study was to investigate the role of tight junction related proteins in gastric mucosal barrier injury in PHG patients, and to investigate the effects of propranolol hydrochloride and teprenone on the expression of tight junction proteins in gastric mucosa of PHG patients.
AIM: To explore the molecular mechanism of gastric mucosal barrier injury in PHG and the effects of propranolol hydrochloride and teprenone on the expression of tight junction protein in gastric epithelial cells.
Methods: 10 patients with PHG underwent gastroscopy were randomly divided into two groups. After gastroscopy and specimen collection, one group was treated with propranolol hydrochloride (30mg/day), the other group was treated with propranolol hydrochloride (30mg/day) combined with teprenone capsule (150mg/day). Both groups were re-examined by gastroscopy one month after treatment. The specimens were collected again and the changes of gastric mucosal lesions were observed under endoscopy. In addition, 10 healthy volunteers who underwent upper gastrointestinal endoscopy were selected as healthy control group. The expression of in and ZO-1.
Results: The expression of tight junction protein Occludin and ZO-1 in gastric mucosa epithelial cells of PHG patients decreased. Before treatment, PHG patients were compared with healthy control group: 1. Gastroscopic manifestations: typical mosaic-like changes, snakeskin-like changes, scattered cherry red spots or diffuse hemorrhagic changes were observed in PHG patients. Appearance: There was obvious telangiectasia in the mucosa and submucosa of patients with PHG, but no obvious inflammation. 3. Immunohistochemical results of Occludin and ZO-1 protein: Occludin and ZO-1 protein in healthy control group were continuously distributed in the membrane of gastric mucosal epithelial cells in brown line, and drug trunk in patients with PHG. Compared with the healthy control group, Occludin protein and ZO-1 protein staining were significantly lighter, discontinuous, partially missing, and unevenly distributed. The mean optical density (OD) of Occludin was (0.03 (+) 0.01), (0.14 (+) 0.02), (P 0.001), and the OD value of ZO-1 were (0.03 (+) 0.01, (0.16 (+) 0.02), (P 0.001), respectively. Difference.
Propranolol hydrochloride can increase the expression of tight junction protein Occludin and ZO-1 in gastric mucosa epithelial cells of PHG patients. In the intervention group of propanolol hydrochloride alone, the gastroscopic manifestations of PHG patients after treatment were compared with those before treatment: (1) After treatment, the gastric mucosal lesions of PHG patients were improved. Immunohistochemical results of Occludin and ZO-1 proteins: After treatment, the expression of Occludin and ZO-1 proteins in gastric mucosal epithelial cells of the patients were deeper than before, and some of them were still missing, but the OD value of Occludin protein was lower than before, and the OD value of Occludin protein was (0.06 + 0.01), (0.03 + 0.01) respectively. .01), (P0.01), the OD values of ZO-1 protein were: (0.07 + 0.01), (0.03 + 0.01), (P0.01), there was statistical difference.
The expression of tight junction protein Occludin and ZO-1 in gastric mucosal epithelial cells of PHG patients was increased more significantly by the combination of propranolol hydrochloride and teprenolone than by propranolol hydrochloride alone. The following manifestations: The gastric mucosal lesions in the propranolol hydrochloride and teprenone group were significantly better than those in the propranolol hydrochloride alone. 2. Histomorphological findings: The telangiectasia in the propranolol hydrochloride and teprenone hydrochloride group was more obvious than that in the propranolol hydrochloride alone group. Immunohistochemical results of in protein and ZO-1 protein: After the combination of propranolol hydrochloride and teprenone treatment, the staining of Occludin protein and ZO-1 protein in gastric epithelial cells of PHG patients was deepened more significantly, and the deletion part was decreased more significantly. The OD value of Occludin protein was (0.11 (+) 0.01, (0.06 +) 0.01, (P 0.01), and the OD value of ZO-1 protein was (P 0.01). The values were: (0.12 + 0.02), (0.07 + 0.01), (P0.01), all of which were statistically different.
CONCLUSION: Decreased expression of tight junction proteins Occludin and ZO-1 in gastric epithelial cells of PHG patients may be an important cause of gastric mucosal barrier injury. Teprenone may protect gastric mucosal barrier by up-regulating the expression of Occludin and ZO-1.
【学位授予单位】：河北医科大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R573
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