Morphologic and molecular biological study of damage and repair of esophago-gastric mucosa in portal hypertension

门静脉高压症食管胃黏膜损伤与修复的形​​态学和分子生物学研究

• 批准号: 07671401
• 负责人: HASHIZUME Makoto
• 金额: $ 1.66万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07671401/
• 关键词: Portal hypertension; Gastric blood flow; EGF; b-FGF; VEGF; NOS; RT; PCR; EGF; VEGF; 食道胃粘膜障害; 食道静脈瘤; mitric oxide

The lower esophagus is predisposed to variceal development and rupture in the portal hypertensive (PHT) state. The esophageal muscularis mucosae and epithelium overlying large submucosal veins in PHT rats, produced by staged portal vein ligation, were significantly thinner than in controls. Extracellular matrix (ECM), which is one of the key factors in cellular and tissue structural support. In immunostaining study, fibronectin (FN) and laminin (LM) in muscularis mucosae was significantly increased, and fibronectin receptor (FNR) was significantly decreased in PHT than in controls. Basic fibroblast growth factor (bFGF) enhances cell migration, proliferation, and tissue integrity. The immunostaining intensity of bFGF and FGFR-2 in muscularis mucosa of lower esophagus was significantly reduced in PHT rats. Basic FGF and FGFR-2 mRNAs expressions in PHT esophageal mucosa were significantly reduced vs controls by 30.8% and 30.3%. We postulated that overexpression of nitric oxide (NO) synthase at this site may produce a local hyperdynamic state and varices which would alter the mucosa structurally. With immunofluorescence staining, intensities of c-NOS and i-NOS in the endothelia of submucosal veins were also higher in PHT rats than in controls. c-NOS mRNAs expressions in PHT esophageal mucosa were significantly increased than controls.Since the spatial organization of fibronectin receptors affects the strength and structural integrity of the ECM, and bFGF stimulates smooth muscle cell proliferation and their growth, our findings of ECM, bFGF and NOS abnormalities in PHT esophagus, combined with its epithelial and muscularis mucosae thinness, suggest a mechanism by which varices may be predisposed to rupture in the esophagus.

在门静脉高压（PHT）状态下，食管下段易发生静脉曲张和破裂。食管粘膜肌层和上皮覆盖大粘膜下静脉PHT大鼠，产生分期门静脉结扎，显着薄于对照组。细胞外基质（ECM）是细胞和组织结构支持的关键因素之一。免疫组化显示，PHT组粘膜肌层纤维连接蛋白（FN）和层粘连蛋白（LM）表达较对照组明显增加，纤维连接蛋白受体（FNR）表达较对照组明显减少。碱性成纤维细胞生长因子（bFGF）增强细胞迁移、增殖和组织完整性。PHT大鼠食管下段粘膜肌层bFGF和FGFR-2的免疫染色强度明显降低。PHT食管粘膜中碱性FGF和FGFR-2 mRNA的表达与对照组相比显著降低30.8%和30.3%。我们推测，过度表达一氧化氮（NO）合酶在这个网站可能会产生局部高动力状态和静脉曲张，这将改变粘膜结构。免疫荧光染色显示，PHT大鼠胃粘膜下静脉内皮细胞c-NOS和i-NOS的表达也明显高于对照组。由于纤维连接蛋白受体的空间组织影响ECM的强度和结构完整性，bFGF刺激平滑肌细胞增殖和生长，我们发现PHT食管中ECM、bFGF和NOS异常，结合其上皮和粘膜肌层薄，提出了一种机制，静脉曲张可能倾向于在食管破裂。

项目成果

Tanoue,K., et al.: "Portal hypertension activates the nitric oxide synthase genes in the esophageal mucosa of rats." Gastroenterology. 110(2). 549-557 (1996)

Tanoue,K. 等人：“门脉高压激活大鼠食管粘膜中的一氧化氮合酶基因。”

M.Hashizume: "Laparoscopic splenectomy;The latest modern technique." Hepato-Gastroenterology. (印刷中). (1998)

M.Hashizume：“腹腔镜脾切除术；最新的现代技术。”（出版中）。

Ueno K.Hashizume M.Ohta M.Tomikawa M.Kitano S.Sugimachi K.: "Noninvasive variceal pressure measurement may be useful for predicting effect of sclerotherapy for esophageal varices." Digestive Diseases & Sciences.41 (1). 191-6 (1996)

Ueno K.Hashizume M.Ohta M.Tomikawa M.Kitano S.Sugimachi K.：“无创静脉曲张压力测量可能有助于预测食管静脉曲张硬化疗法的效果。”

Ohta M.Tanoue K.Tarnawski AS.Pai R.Itani RM.Sander FC.Sugimachi K.Sarfeh IJ.: "Overexpressed nitric oxide synthase in portal-hypertensive stomach of rat : a key to increased susceptibility to damage?" Gastroenterology.112 (6). 1920-30 (1997)

Ohta M.Tanoue K.Tarnawski AS.Pai R.Itani RM.Sander FC.Sugimachi K.Sarfeh IJ.：“门脉高压大鼠胃中过度表达的一氧化氮合酶：增加损伤易感性的关键？”

M.Hashizume: "Eradiation of large gastric varices by sclerotherapy combined with percutaneous." Hepato-Gastroenterol. 44. 221-226 (1997)

M.Hashizume：“通过硬化疗法结合经皮治疗来根除大胃静脉曲张。”