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Ethanol/lipid metabolism, dysfunction of ion transport, and pathogenesis of alcoholic pancreatitis

乙醇/脂质代谢、离子转运功能障碍与酒精性胰腺炎的发病机制

基本信息

批准号：
15590638
负责人：
KONDO Takaharu
金额：
$ 1.86万
依托单位：
Nagoya University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

项目摘要

1. Mutations and polymorphisms (TG repeats, poly T, M470V, Q1352H, R1453W) of CFTR (cystic fibrosis transmembrane conductance regulator) were examined in Japanese patients with chronic pancreatitis. None of the cystic fibrosis-causing mutations were detected. Frequency of the genotype TG(12/12) was higher in alcoholic pancreatitis. Frequency of the genotype V470/V470 was higher in idiopathic pancreatitis.2. To estimate CFTR Cl^- channel function, we established "finger sweat chloride test" to measure Cl^- concentration in insensible sweat, which sweat is collected by holding a small tube containing 100 μl water with the thumb and the sweat rate is measured by a perspiration meter. The Cl^- content in the sample is measured by capillary electrophoresis or more easily by a highly sensitive electrode.3. The activity of Na^+-H^+ exchange (NHE) in the apical membrane was examined in luminally-microperfused interlobular pancreatic duct segments isolated from ΔF mice, a cystic fibrosis model. The apical NHE activity significantly increased in ΔF/ΔF ducts, which may cause pH decrease of pancreatic juice.4. Effects of a series of short-chain alcohols (methanol, ethanol, propanol, and butanol) on cAMP-stimulated fluid secretion and intracellular Ca^<2+> concentration were examined in interlobular pancreatic duct segments isolated from guinea-pig. Methanol and ethanol enhanced fluid secretion and caused a transient increase of intracellular Ca^<2+>. On the contrary, propanol and butanol inhibited fluid secretion and lowered intracellular Ca^<2+>. This "cut-off effect" suggests alcohols act directly on some ion channels of pancreatic duct cells.

1.在日本慢性胰腺炎患者中检查了CFTR（囊性纤维化跨膜电导调节因子）的突变和多态性（TG重复、poly T、M470V、Q1352H、R1453W）。没有检测到任何导致囊性纤维化的突变。酒精性胰腺炎中TG(12/12)基因型频率较高。 V470/V470基因型在特发性胰腺炎中出现频率较高。2．为了估计CFTR Cl^-通道功能，我们建立了“指汗氯化物测试”来测量无感汗液中的Cl^-浓度，用拇指握住装有100μl水的小管收集汗液，并通过排汗计测量出汗率。样品中的Cl^-含量通过毛细管电泳或更容易地通过高灵敏电极来测量。3．在从囊性纤维化模型 ΔF 小鼠中分离的管腔微灌注小叶间胰管段中检查了顶膜中 Na^+-H^+ 交换 (NHE) 的活性。 ΔF/ΔF管顶端NHE活性显着升高，可能导致胰液pH值降低。4．在从豚鼠分离的小叶间胰管段中检查了一系列短链醇(甲醇、乙醇、丙醇和丁醇)对cAMP刺激的液体分泌和细胞内Ca 2+ 浓度的影响。甲醇和乙醇增强液体分泌并导致细胞内Ca 2+ 短暂增加。相反，丙醇和丁醇抑制液体分泌并降低细胞内Ca 2+ 。这种“截止效应”表明酒精直接作用于胰管细胞的某些离子通道。