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Molecular mechanisms of chronic pancreatitis : Ethanol-induced dysfunction of ion channels

慢性胰腺炎的分子机制：乙醇引起的离子通道功能障碍

基本信息

批准号：
11470129
负责人：
HAYAKAWA Tetsuo
金额：
$ 3.07万
依托单位：
Nagoya University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

项目摘要

1. To investigate the secretory mechanism of HCO_3^-, across the luminal membrane of pancreatic duct cell we have measured intracellular concentrations of HCO_3^- ([HCO_3^-]_i) and of Cl^- ([Cl^-]_i) in microperfused interlobular duct segments isolated from guinea-pig pancreas. When the HCO_3^- concentration in the lumen was raised to 125 mM (24 mM Cl^-) under cAMP stimulation, pH_i did not increase above 7.2 ([HCO_3^-]_i = 〜 20 mM), indicating that luminal Cl^--HCO_3^- exchange was inhibited. Under the same condition, [Cl^-]_i was kept very low at 〜7 mM, which would tend to favor HCO_3^-' secretion via a luminal anion conductance.2. 5-hydroxytryptamine (5-HT, serotonin) at 0. 1μM strongly inhibited fluid secretion in isolated ducts via 5-HT_3 receptor. The action is mediated by the inhibition of basolateral HCO_3^- accumulation via Na^+-HCO_3^- cotransport. 5-HT released from pancreatic ductal enterochromaffin cells may regulate fluid secretion in a paracrine fashion.3. RT-PCR analysis and immunohistochemistry of isolated ducts revealed the expression of AQP1 in duct cells. The osmotic water permeability of the ductal epithelium was reduced by 80-90% with either basolateral or luminal application of HgCl_2. AQP1 of the known water channels appears to be the main water pathway in pancreatic ductal epithelium.4. Although ethanol abuse is the most common cause of acute and chronic pancreatitis, the mechanism by which ethanol causes the disease is not well understood. Ethanol at 1 mM, the concentration observed after an occasional social drinking, significantly augmented the maximal rate of fluid secretion and induced a transient increase in intracellular Ca^<2+> concentration in ducts stimulated with secretin or dibutyryl cAMP. When the flow of pancreatic juice is disturbed by protein plug or stones, fluid hypersecretion induced by ethanol would elevate the intraductal pressure in the proximal part of the duct, leading to edema formation or pancreatitis.

1.为探讨HCO_3~-的分泌机制，我们测定了豚鼠胰腺微灌流小叶间管段细胞内HCO_3~-([HCO_3~(-)]_i)和Cl~(-)的浓度。在cAMP刺激下，当管腔内的HCO3-浓度增加到125 mM(24 mMCl2-)时，pH i没有增加到7.2以上([HCO3-]i=~20 mM)，表明管腔内的Cl2--HCO3-交换受到抑制。在相同条件下，[Cl~(-)]_i保持在~7 mM，有利于HCO3~-‘通过腔内阴离子电导分泌。5-羟色胺(5-羟色胺，5-羟色胺)为0。1μM通过5-HT3受体强烈抑制离体管的液体分泌。这一作用是通过抑制Na~+-HCO3~-共转运抑制基侧HCO3~-蓄积而实现的。胰腺导管嗜铬细胞释放的5-羟色胺可能以旁分泌的方式调节液体的分泌。逆转录-聚合酶链式反应和免疫组织化学分析显示AQP1在导管细胞中有表达。无论是基侧还是腔内应用HgCl2，胰管上皮细胞的渗透水通透性均降低80-90%。已知的水通道中的AQP1可能是胰管上皮细胞的主要水通道。尽管酒精滥用是急性和慢性胰腺炎最常见的原因，但酒精导致疾病的机制尚不清楚。乙醇浓度为1 mM，在偶尔的社交饮酒后观察到的浓度，显著增加液体的最大分泌速度，并诱导促胰液素或二丁酰cAMP刺激的导管内钙离子浓度一过性增加。当胰液流量受到蛋白堵塞或结石干扰时，乙醇诱导的液体高分泌会使胰管近端的压力升高，导致水肿性或胰腺炎。