修回日期: 2005-10-01
接受日期: 2005-10-10
在线出版日期: 2005-11-15
乙醇是一种无色有特殊香味的液态有机溶剂, 是饮用酒及乙醇性饮料的主要成分. 高浓度乙醇可直接腐蚀胃黏膜组织, 引起胃黏膜急性炎症,黏膜出现充血、水肿、出血、糜烂及溃疡形成等. 慢性饮酒对胃十二指肠黏膜的影响较为复杂. 慢性酗酒可致胃肠功能紊乱、慢性萎缩性胃炎, 与胃癌发生关系密切. 此外, 慢性适量饮酒可能对胃黏膜具有适应性细胞保护作用. 乙醇在胃内经乙醇脱氢酶作用可被氧化成乙醛而损伤胃黏膜. 乙醇尚可影响胃酸分泌、引起胃组织产生损伤性介质使胃黏膜损伤性因素增强, 损伤胃黏膜屏障、减少胃黏膜保护性物质含量、影响胃黏膜微循环等使胃黏膜保护性因素削弱, 影响胃、十二指肠动力等而致胃黏膜损伤.
引文著录: 何绍珍, 任建林. 乙醇对胃黏膜作用机制的研究进展. 世界华人消化杂志 2005; 13(21): 2591-2596
Revised: October 1, 2005
Accepted: October 10, 2005
Published online: November 15, 2005
N/A
- Citation: N/A. N/A. Shijie Huaren Xiaohua Zazhi 2005; 13(21): 2591-2596
- URL: https://www.wjgnet.com/1009-3079/full/v13/i21/2591.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v13.i21.2591
世界上有饮酒习惯者众多, 可饮用的酒类或乙醇性饮料有很多种, 其主要成分为乙醇. 乙醇是无色有特殊香味的液体, 易挥发, 是一种有机溶剂, 能溶解多种有机物和无机物. 乙醇的分子式是C2H6O, 其中含有一个-OH基团称为羟基.
人们饮酒后, 乙醇首先在胃内潴留, 并与胃十二指肠黏膜接触, 其对胃十二指肠黏膜生理的影响非常显著, 与多种急慢性胃十二指肠黏膜发病和修复关系密切. 我们就其对胃黏膜的损伤作用和保护作用及其机制的研究进展做一简要综述.
乙醇对胃黏膜的损害, 可分为急性乙醇中毒所引起的胃黏膜急性损害和慢性乙醇中毒所引起的胃黏膜慢性损伤.
动物实验证实胃腔内乙醇浓度>14%时可直接损伤胃黏膜屏障, 使胃黏膜炎症加剧, 黏膜出现糜烂、出血、甚至急性溃疡. 陆震宇et al [1]发现无水乙醇1 mL灌胃后, 光镜: 无水乙醇组大鼠的胃黏膜出现广泛浅表性糜烂, 黏膜表面有较多的炎性渗出物, 黏膜浅层细胞有明显变性、坏死或脱落, 固有膜内有灶性出血及急性炎症反应, 与正常大鼠的胃黏膜比较显著不同. 扫描电镜: 无水乙醇组大鼠的胃黏膜遭到极严重的破坏, 表层上皮脱落, 表面呈蜂窝状, 与正常的胃黏膜超微结构完全不同. 透射电镜: 无水乙醇组大鼠的壁细胞、黏液细胞膜结构不清, 线粒体肿胀, 嵴断裂, 甚至溶解, 与正常胃黏膜细胞超微结构完全不同. 夏敏et al[2]也发现75%或95%乙醇灌胃后, 可引起小鼠胃黏膜上皮细胞不同程度地变性、坏死, 间质血管瘀血, 电镜下壁细胞核、线粒体等结构异常, 且胃黏膜损伤程度, 随乙醇浓度升高而加重. Sibilia et al[3]研究发现乙醇处理后胃黏膜出现的坏死性改变主要表现为腺体凝固性坏死伴黏膜弥漫性出血. Knoll et al[4]对47名健康志愿者分别予4%、10%、40%乙醇及等渗盐水作为对照喷洒胃黏膜, 0.5 h、1 h、4 h、24 h后运用内镜评分系统评估胃、十二指肠黏膜损伤情况. 发现胃黏膜损伤程度与乙醇浓度呈剂量依赖性, 1 h后内镜下黏膜损伤评分分别为: 4%乙醇 = 1.3; 10%乙醇 = 1.8; 40%乙醇 = 3.8; 等渗盐水 = 1.5, 内镜检查显示喷洒40%乙醇的志愿者胃黏膜出现充血、黏膜下出血等损伤, 组织学检查显示胃黏膜表面上皮细胞脱落和变性, 黏膜固有层出血及嗜酸粒细胞等炎性细胞浸润的炎症性病理改变. 以上研究均证实乙醇可致急性胃黏膜损伤而且损伤与乙醇浓度呈正相关.
慢性饮酒对胃的影响观点不一致. 饮酒者常出现胃肠功能紊乱[5]. 酗酒者胃食管反流病、Barrett's综合征、食管癌、Mallory-Weiss综合征及出血糜烂性胃炎患病率比正常人高. 许多研究者认为慢性饮酒可导致胃炎(包括慢性浅表性胃炎和萎缩性胃炎)或消化性溃疡(peptic ulcer, PU). 胃黏膜的损伤程度与酒精浓度和接触时间有关, 如果有胃酸存在且随着酸浓度的增加可加重损伤. Bienia et al[6]研究证实持续酗酒易致胃黏膜萎缩性炎症, 并且这型炎症变化的出现与嗜酒时间长短有关. 酗酒时间越长, 盐酸分泌越少. 研究并未显示萎缩性胃炎的患病率与酒的种类或酒中乙醇含量有关. 在与饮酒相关的胃十二指肠黏膜病变中PU也是人们争议和关注的焦点. 一些报道显示慢性饮酒并不增加PU的发病率, 而另一些调查却显示饮酒是十二指肠溃疡发病的危险因子. 还有人认为长期大量饮酒可能导致肝硬化, 而肝硬化患者胃黏膜屏障功能常常削弱, 从而增加了PU的发病危险性. 所以, 慢性饮酒在PU的发病中所起的作用有待进一步研究. 另有研究发现[7-10], 长期饮酒是胃癌发生的危险因子, 饮酒可致胃黏膜上皮化生, 胃癌的上升与饮用啤酒、葡萄酒和伏特加等有关. 由上可见慢性饮酒对胃十二指肠黏膜的影响较为复杂.
乙醇是一种有机溶剂, 对胃黏膜组织具有很强的腐蚀性, 破坏表面黏液层和颈黏液细胞, 并破坏胃黏膜的正常代谢所需的生理环境. 乙醇在胃黏膜代谢分解为乙醛后, 乙醛与胃黏膜蛋白结合, 参与了对胃黏膜的损伤. 无水乙醇或高浓度乙醇具有很强的脱水作用, 能凝固组织蛋白. 除上述直接损伤作用外, 乙醇还可通过增强胃黏膜损伤因素、削弱胃黏膜保护因素和使细胞内钙超载等机制引起胃黏膜损伤.
2.1.1 损伤性介质产生增多:
2.1.1.1 自由基产生增多: 醇从口摄取后, 80%以上由消化道迅速吸收, 其中胃占吸收量的30%, 其余70%被小肠上段吸收. 乙醇经胃吸收后, 由于胃内存在有乙醇脱氢酶和黄嘌呤氧化酶, 前者催化乙醇生成乙醛, 后者可催化乙醛代谢产生自由基. 自由基在酒精性胃黏膜损伤过程中具有重要作用[11,12]. 因为胃内给予超氧化物歧化酶(superoxide dismutase, SOD)可保护胃黏膜免受乙醇的损伤. Huh et al[13]研究发现用插管法予无水乙醇(4 g/kg)明显引起大鼠胃的出血损伤和脂质过氧化反应, 而口服予DA-9601(40 mg/kg)明显减轻乙醇引起的胃出血损伤和脂质过氧化反应, 这与DA-9601对乙醇引起的黄嘌呤类别转换和酶活性的抑制效应成比例. Chow et al[14]也发现乙醇可增强黄嘌呤氧化酶活性. 这些结果显示乙醇引起的胃黏膜损伤可能在一定程度上归因于乙醇引起黄嘌呤氧化酶活性增加和该酶发生类别转换, 而该酶类别转换对自由基产生深远影响. 动物实验还发现别嘌呤醇具有预防乙醇对胃黏膜损伤作用. 已知正常胃黏膜表层内富含还原型黄嘌呤氧化酶, 经乙醇作用转化为氧化型黄嘌呤氧化酶并增强其活性, 促进组织内黄嘌呤在代谢过程中产生超氧离子自由基, 并可转复H2O2为羟自由基(•OH), 其结果均使自由基增多.
氧自由基特别是羟自由基极易与膜脂肪酸中的不饱和键反应, 从而启动脂质过氧化链式反应, 使得不饱和脂肪酸含量下降, 引起细胞膜流动性降低. 自由基引起黏膜细胞脂质过氧化反应明显增强, 毛细血管内皮细胞也受损致使通透性升高. 胃黏膜含有高浓度的非蛋白质巯基, 氧自由基作用于巯基使蛋白质变性、酶失活, 从而导致黏膜损伤.
2.1.1.2 胃黏膜脂质过氧化物产生增多: 乙醇引起胃损伤的直接作用可能是引起胃上皮的脂质过氧化[15-19]. 乙醇使胃黏膜中的超氧化阴离子、羟基产物增多及增强脂质过氧化反应. 脂质过氧化过程由细胞膜和羟基的相互作用介导, 结果产生脂源性自由基和脂质氢过氧化物. 已知这些基团是活性极强的引起氧化损伤的产物. 乙醇引起细胞内氧化反应并引起线粒体通透性改变及线粒体去极化, 这加速了胃黏膜细胞的死亡.
2.1.1.3 产生其它损伤性介质: 在胃黏膜损伤中, 炎性细胞尤其是活化的中性粒细胞极为重要[16,20]. 乙醇使白细胞浸润于胃黏膜, 并释放髓过氧化物酶(myelopero-xidase, MPO)、氧自由基、活性氧化代谢产物如超氧化阴离子(O2-)、蛋白酶并黏附于血管内皮造成大血管闭塞等方式导致黏膜损伤. 同时, 还激活胃肠道的肥大细胞使其释放组胺、血小板活性因子、内皮素、白三烯及各种超氧化物. 其中组胺、血小板活性因子可增加黏膜的通透性; 内皮素、白三烯可增加胃黏膜损伤的敏感性.
2.1.2 影响胃酸分泌: Lenz et al[21]的实验发现5%乙醇及威士忌酒明显增加基础胃酸分泌及五肽胃泌素峰值
(P<0.01), 10%及20%乙醇溶液比等热量、等渗透压的对照液明显增加3 h胃酸分泌量. 一般认为饮料的乙醇浓度与刺激胃酸分泌呈负相关, 低浓度乙醇(5%)是酸分泌的温和刺激剂, 而高浓度乙醇要么无此作用, 要么轻度抑制酸分泌[22,23]. 任何途径给予纯乙醇都不引起人胃泌素释放[24]. 低浓度酒精性饮料(啤酒、葡萄酒)通过两条途径促进胃泌素释放而强烈刺激胃酸分泌: 一是增加壁细胞内钙离子浓度, 二是刺激嗜铬细胞释放组织胺. 啤酒可致最大排酸量. 高浓度酒精性饮料不刺激胃酸分泌和胃泌素释放. 热稳定性物质和阴离子极性物质是否是存在于啤酒中的强有力的胃酸分泌刺激剂还有待证实. 慢性酗酒对胃酸分泌的作用不确定. 慢性饮酒病人酸分泌能力表现各异, 可正常、增强或减弱.
乙醇可降低食管下括约肌压力, 导致食管运动功能失调, 增加食管酸暴露时间, 利于胃食管反流病的发生. 有报道, 浓度为4%、10%和40%的乙醇溶液抑制胃排空, 啤酒和红酒对胃排空的抑制作用强于相同浓度的乙醇溶液. 胃排空功能障碍致胃内酸性胃液潴留过久, 增加了胃黏膜的损伤[25]. 乙醇还可降低Oddi氏括约肌基础压和抑制其位相收缩, 并呈乙醇浓度依赖关系. Oddi氏括约肌运动功能障碍可致十二指肠胃反流而使十二指肠内容物对胃黏膜的损伤机会增加.
2.3.1 胃黏膜屏障受损: 胃黏膜屏障指胃黏膜具有阻止胃腔内H+向组织内弥散及组织内Na+向胃腔内弥散的特性[26]. 其形态学基础包括黏膜表面的胃壁结合黏液层、黏膜表面的单层上皮及上皮细胞间紧密连接. 乙醇能引起胃黏膜上皮细胞肿胀, 溶解胃黏膜上皮脂蛋白层使上皮细胞之间的紧密连接受到损伤, 破坏胃黏膜屏障. 乙醇对胃黏液代谢的影响非常显著. 乙醇经过血流损害腺体的颈黏液细胞, 使胃黏液减少. 乙醇抑制黏液合成、转运和黏液糖蛋白的加工合成过程, 并且抑制黏液颗粒向上皮表面的转运过程. 这些均可引起胃黏膜屏障的损害, 导致氢离子逆向渗透, 引起炎症渗出、出血、溃疡. 陆震宇 et al[1]发现无水乙醇降低胃黏膜Na+-K+-ATPase活性, 而 Na+-K+-ATPase是位于细胞膜上的一种糖蛋白, 对维持细胞内外钠钾离子梯度, 保证细胞正常生理功能具有极重要的作用. 如果胃黏膜Na+-K+-ATPase活性受到抑制, 就会造成黏膜渗透性增加, 大量氢离子反流, 引起上皮细胞破坏. Iino et al[27]也发现无水乙醇灌胃后, 反映胃黏膜完整性的跨壁电位压也显著下降, Na+、K+向胃腔内弥散增加, 而胃腔内H+反渗也增加.
2.3.2 黏膜保护性物质含量减少: 巯基物质是体内一种重要的非酶类氧自由基清除剂, 分为非蛋白巯基物质和蛋白巯基物质. 巯基物质可以直接或间接与氧自由基和活性亲电子物质反应, 具有细胞保护作用: 可维持细胞骨架的完整; 有解毒作用; 非蛋白巯基物质的氧化先于蛋白巯基物质氧化, 前者明显保护了后者, 对维护细胞的结构与功能至关重要. 动物实验发现[28-32]乙醇处理后, 受试动物胃黏膜谷胱甘肽总浓度、谷胱甘肽还原酶和谷胱甘肽过氧化物酶(glutathione peroxidase, GSH-Px)活性下降. 谷胱甘肽是含巯基的非蛋白质化合物, 是细胞中的重要抗氧化剂, 对过氧化物造成黏膜损伤有保护作用. 胃黏膜保持充足谷胱甘肽(glutathione, GSH)含量对维持黏膜细胞的稳定和完整性有重要作用. 由于GSH含量减少, 使细胞内各种蛋白维持功能所必需的非蛋白巯基被氧化而减少. 补充巯基化合物半胱氨酸或GSH可防止乙醇所致的胃黏膜损伤.
实验研究[33,34]认为前列腺素(prostagladins, PGs)合成减少可能在乙醇引起胃黏膜损伤中起着重要作用. 陆震宇 et al [1]发现大鼠无水乙醇1 mL灌胃后, 血浆前列环素的稳定代谢产物6-酮-前列腺素F1a(6-Keto-PGF1a) 含量下降. PGs能增加胃黏膜上皮黏液和碳酸氢盐的分泌, 抑制胃酸分泌, 增加胃黏膜血流, 防止胃黏膜损伤, 刺激胃黏膜再生. 胃黏膜内的大量PGs是通过环氧合酶作用而合成, 但乙醇可灭活环氧合酶而阻碍PG合成[35-38].
2.3.3 胃黏膜微循环障碍: 胃黏膜微循环障碍被认为是乙醇引起胃损伤的主要致病机制. 乙醇可引起胃黏膜静脉收缩、胃黏膜血流量(gastric mucosal blood flow, GMBF)降低, 而且其损伤程度与GMBF呈负相关. GMBF减少, 将导致胃黏膜缺乏营养和不能及时清除有害物质, 因而造成胃黏膜损伤. GMBF降低被认为与乙醇促进胃动脉血管内皮释放内皮素(endothelin, ET)[39-43]及降低胃黏膜一氧化氮合成酶(nitric oxide synthase, NOS)活性使内源性NO合成减少有关[44-48]. ET是一种由血管内皮细胞产生的含有21个氨基酸的血管活性多肽, 是迄今所知最强烈而持久的缩血管因子, 它可引起胃黏膜损伤. Iaquinto et al [49]研究证实, 口服40%乙醇刺激人胃黏膜ET-1的释放, 引起人血浆ET-1水平迅速且呈时间依赖的升高. NOS是NO生物合成的关键因素, NO是新近发现的重要细胞信息分子, 它通过增加胃黏膜血流量、减轻炎症反应等机制, 在胃黏膜保护中起着重要作用. 该研究发现, 在胃黏膜损伤过程中NOS和ET含量呈负相关. NO可拮抗ET的作用, 并抑制ET的释放. 在乙醇损伤胃黏膜过程中, NO减少失去对ET的抑制作用, 使ET显著增加, 两者共同作用加剧胃黏膜损伤.
乙醇还可引起胃黏膜血管通透性升高、黏膜血流淤滞. 研究发现胃黏膜接触乙醇后出现肥大细胞脱颗粒[50-52], 并伴有胃黏膜组胺[53]及白三烯(leukotriene, LT)[54,55]含量升高, 以肥大细胞稳定剂酮替芬或组胺H1受体拮抗剂、LTC4合成抑制剂预处理, 则胃黏膜微循环明显改善, 胃黏膜损伤明显减轻. 表明肥大细胞及组胺、LTC4在乙醇引起的胃黏膜损伤中具有重要作用. 组胺和LT可扩张小动脉, 增加毛细血管通透性, 而乙醇又可使胃黏膜小静脉收缩, 所以毛细血管内压力增加, 黏膜出现淤血、水肿、出血, 继而组织坏死.
乙醇可降低胃黏膜疏水性及表面活性磷脂含量: 减慢胃黏膜上皮迁移和增殖, 损伤细胞内微丝、微管等细胞骨架系统, 破坏细胞间连接蛋白; 诱导细胞凋亡, 从而损伤胃黏膜的修复功能[56,57]; 通过刺激三磷酸酯产生, 引起细胞膜钙通道开放, 胞外钙内流, 造成细胞内钙超载[58]. 夏敏 et al [2]证明95%乙醇灌胃后,大鼠胃黏膜内Ca2+浓度升高. 乙醇对胃肠肽的影响也非常显著, 在乙醇性胃黏膜损伤中, 生长抑素(somatostatin, SS)和血管活性肠肽(vasoactive intestinal peptide, VIP)含量显著下降[59], 说明乙醇可破坏D细胞或抑制SS和VIP的分泌. 有研究证实[60,61]SS对胃黏膜具有保护作用, 可抑制胃酸、胃蛋白酶和胃泌素分泌, 促进胃黏液生成, 促进胃局部血液循环, 提高胃黏膜对氧自由基的清除能力, 预防细胞膜的脂质过氧化损伤. VIP可促进NO释放, 抑制ET-1的释放, 扩张血管, 抑制平滑肌收缩. 在乙醇所致的胃黏膜损伤中, VIP的减少可能通过减少NO释放和增加ET-1生成而参与胃黏膜的损伤过程. 酗酒者可出现原发性或继发性营养不良, 出现多种维生素和微量元素缺乏. 其中, 叶酸和锌的缺乏较常见. 叶酸缺乏影响蛋白合成, 锌缺乏可使谷胱甘肽转移酶减少, 这些都可以加重乙醇对胃黏膜的损伤作用.
少数学者认为[62]低浓度乙醇可能对胃黏膜产生适应性细胞保护作用. 适当浓度的乙醇刺激可引起胃黏膜干细胞热休克蛋白70(heat shock protein 70, HSP70)的表达[63,64]. Konturek et al [65]给大鼠100%乙醇灌胃处理后1 h, 测得大鼠胃黏膜HSP70表达明显上调, 而予阿司匹林组则黏膜HSP70表达减少. 夏玉亭 et al [66]通过体内外实验证明胃黏膜细胞中的HSP70具有保护作用. HSP70可帮助新生蛋白质成熟和移位, 帮助异常蛋白质降解; 作为"分子伴侣"对于维持胃黏膜细胞的稳定与生存至关重要[67]; 提高细胞SOD及过氧化氢酶活性, 减轻乙醇引起的过氧化反应损伤. 适当低浓度乙醇还可以防止非甾体抗炎药(nonsteroidal antiinflammatory drugs, NSAIDs)引起的细胞死亡而产生对胃黏膜的适应性细胞保护作用[68]. Uehigashi et al[69]研究表明适度的低浓度乙醇可通过提高胃黏膜的前列腺素的水平而对胃黏膜有保护作用. 一些酒精性饮料, 像红葡萄酒, 有抗幽门螺杆菌活动性感染的保护作用[22], 这一作用可能与饮料中所含乙醇的抗微生物效应有关.
乙醇引起的胃黏膜急性损伤明确, 临床上利用无水乙醇或高浓度乙醇能使组织蛋白凝固的特点, 采用内镜下局部注射无水酒精来治疗上消化道出血, 达到止血目的. 在动物实验模型中, 用于探讨胃黏膜急性损伤的病理生理机制, 并被广泛用于药理学研究, 用于药物的疗效评估. 但慢性饮酒对胃黏膜的影响还存在争议, 其与慢性胃炎的关系研究报道不一致. 慢性饮酒是否会引起胃、十二指肠溃疡也无定论. 乙醇与胃癌的关系, 人们认为乙醇不是直接致癌物质, 但在一定实验条件下是一种辅助致癌物质. 乙醇代谢产生乙醛和自由基, 乙醛具致癌作用和致突变作用, 可与DNA和蛋白质相结合, 破坏叶酸, 引起继发性过度增生. 有证据表明乙醛是乙醇致癌的主要原因. 近期研究发现乙醇对胃黏膜有适应性细胞保护作用, 可抗H pylori感染、促进胃黏膜上皮细胞更新及HSP70表达, 但这些保护作用的分子机制尚不清楚. 乙醇对胃黏膜的影响较为复杂, 深入研究其对胃黏膜的作用机制, 对于胃黏膜保护有积极意义.
电编:张勇 编辑:菅鑫妍 审读:张海宁
| 3. | Sibilia V, Rindi G, Pagani F, Rapetti D, Locatelli V, Torsello A, Campanini N, Deghenghi R, Netti C. Ghrelin protects against ethanol-induced gastric ulcers in rats: studies on the mechanisms of action. Endocrinology. 2003;144:353-359. [PubMed] [DOI] |
| 4. | Knoll MR, Kolbel CB, Teyssen S, Singer MV. Action of pure ethanol and some alcoholic beverages on the gastric mucosa in healthy humans: a descriptive endoscopic study. Endoscopy. 1998;30:293-301. [PubMed] [DOI] |
| 5. | Keshavarzian A, Fields JZ, Vaeth J, Holmes EW. The differing effects of acute and chronic alcohol on gastric and intestinal permeability. Am J Gastroenterol. 1994;89:2205-2211. [PubMed] |
| 6. | Bienia A, Sodolski W, Luchowska E. The effect of chronic alcohol abuse on gastric and duodenal mucosa. Ann Univ Mariae Curie Sklodowska. 2002;57:570-582. [PubMed] |
| 7. | Iishi H, Tatsuta M, Baba M, Taniguchi H. Promotion by ethanol of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats. Br J Cancer. 1989;59:719-721. [PubMed] [DOI] |
| 8. | Vakevainen S, Mentula S, Nuutinen H, Salmela KS, Jousimies-Somer H, Farkkila M, Salaspuro M. Ethanol-derived microbial production of carcinogenic acetaldehyde in achlorhydric atrophic gastritis. Scand J Gastroenterol. 2002;37:648-655. [PubMed] [DOI] |
| 9. | Borriello SP, Reed PJ, Dolby JM, Barclay FE, Webster AD. Microbial and metabolic profile of achlorhydric stomach: comparison of pernicious anaemia and hypogammaglobulinaemia. J Clin Pathol. 1985;38:946-953. [PubMed] [DOI] |
| 10. | Ko JK, Cho CH. Alcohol drinking and cigarette smoking: a "partner" for gastric ulceration. Zhonghua YiXue ZaZhi. 2000;63:845-854. [PubMed] |
| 11. | Brzozowski T, Konturek PC, Konturek SJ, Kwiecien S, Sliwowski Z, Pajdo R, Duda A, Ptak A, Hahn EG. Implications of reactive oxygen species and cytokines in gastroprotection against stress-induced gastric damage by nitric oxide releasing aspirin. Int J Colorectal Dis. 2003;18:320-329. [PubMed] [DOI] |
| 12. | Kwiecien S, Brzozowski T, Konturek SJ. Effects of reactive oxygen species action on gastric mucosa in various models of mucosal injury. J Physiol Pharmacol. 2002;53:39-50. [PubMed] |
| 13. | Huh K, Kwon TH, Shin US, Kim WB, Ahn BO, Oh TY, Kim JA. Inhibitory effects of DA-9601 on ethanol-induced gastrohemorrhagic lesions and gastric xanthine oxidase activity in rats. J Ethnopharmacol. 2003;88:269-273. [PubMed] [DOI] |
| 14. | Chow JY, Ma L, Cho CH. Involvement of free radicals and histamine in the potentiating action of cigarette smoke exposure on ethanol-induced gastric mucosal damage in rats. Free Radic Biol Med. 1998;24:1285-1293. [PubMed] [DOI] |
| 15. | Bagchi D, Carryl OR, Tran MX, Krohn RL, Bagchi DJ, Garg A, Bagchi M, Mitra S, Stohs SJ. Stress, diet and alcohol-induced oxidative gastrointestinal mucosal injury in rats and protection by bismuth subsalicylate. J Appl Toxicol. 1998;18:3-13. [PubMed] [DOI] |
| 16. | Repetto M, Maria A, Guzman J, Giordano O, Llesuy S. Protective effect of Artemisia douglasiana Besser extracts in gastric mucosal injury. J Pharm Pharmacol. 2003;55:551-557. [PubMed] [DOI] |
| 17. | Khosla P, Karan RS, Bhargava VK. Effect of garlic oil on ethanol induced gastric ulcers in rats. Phytother Res. 2004;18:87-91. [PubMed] [DOI] |
| 18. | Ozdil S, Yanardag R, Koyuturk M, Bolkent S, Arbak S. Protective effects of ascorbic acid, DL-alpha-tocopherol acetate, and sodium selenate on ethanol-induced gastric mucosal injury of rats. Biol Trace Elem Res. 2004;99:173-189. [PubMed] [DOI] |
| 19. | Liu MY, Chiang JP, Hsu DZ, Deng JF. Abamectin attenuates gastric mucosal damage induced by ethanol through activation of vagus nerve in rats. Alcohol. 2003;30:61-65. [PubMed] [DOI] |
| 21. | Lenz HJ, Ferrari-Taylor J, Isenberg JI. Wine and five percent ethanol are potent stimulants of gastric acid secretion in humans. Gastroenterology. 1983;85:1082-1087. [PubMed] |
| 22. | Stermer E. Alcohol consumption and the gastrointestinal tract. Isr Med Assoc J. 2002;4:200-202. [PubMed] |
| 23. | Chari S, Teyssen S, Singer MV. Alcohol and gastric acid secretion in humans. Gut. 1993;34:843-847. [PubMed] [DOI] |
| 24. | Matsuno K, Tomita K, Okabe S. Wine stimulates gastric acid secretion in isolated rabbit gastric glands via two different pathways. Aliment Pharmacol Ther. 2002;16 Suppl 2:107-114. [PubMed] [DOI] |
| 27. | Iino T, Nakahara K, Miki W, Kiso Y, Ogawa Y, Kato S, Takeuchi K. Less damaging effect of whisky in rat stomachs in comparison with pure ethanol. Role of ellagic acid, the nonalcoholic component. Digestion. 2001;64:214-221. [PubMed] [DOI] |
| 28. | Bilici D, Suleyman H, Banoglu ZN, Kiziltunc A, Avci B, Ciftcioglu A, Bilici S. Melatonin prevents ethanol-induced gastric mucosal damage possibly due to its antioxidant effect. Dig Dis Sci. 2002;47:856-861. [PubMed] [DOI] |
| 29. | La Casa C, Villegas I, Alarcon de la Lastra C, Motilva V, Martin Calero MJ. Evidence for protective and antioxidant properties of rutin, a natural flavone, against ethanol induced gastric lesions. J Ethnopharmacol. 2000;71:45-53. [PubMed] [DOI] |
| 30. | Ajaikumar KB, Asheef M, Babu BH, Padikkala J. The inhibition of gastric mucosal injury by Punicagranatum L. (pomegranate) methanolic extract. J Ethnopharmacol. 2005;96:171-176. [PubMed] [DOI] |
| 31. | Arafa HM, Sayed-Ahmed MM. Protective role of carnitine esters against alcohol-induced gastric lesions in rats. Pharmacol Res. 2003;48:285-290. [PubMed] [DOI] |
| 32. | Raphael KR, Kuttan R. Inhibition of experimental gastric lesion and inflammation by Phyllanthus amarus extract. J Ethnopharmacol. 2003;87:193-197. [PubMed] [DOI] |
| 33. | Liu ES, Wong BC, Cho CH. Influence of gender difference and gastritis on gastric ulcer formation in rats. J Gastroenterol Hepatol. 2001;16:740-747. [PubMed] [DOI] |
| 34. | Saeki T, Ohno T, Kamata K, Arai K, Mizuguchi S, Katori M, Saigenji K, Majima M. Mild irritant prevents ethanol-induced gastric mucosal microcirculatory disturbances through actions of calcitonin gene-related peptide and PGI2 in rats. Am J Physiol Gastrointest Liver Physiol. 2004;286:G68-G75. [PubMed] [DOI] |
| 35. | Kawabata A, Nishikawa H, Saitoh H, Nakaya Y, Hiramatsu K, Kubo S, Nishida M, Kawao N, Kuroda R, Sekiguchi F. A protective role of protease-activated receptor 1 in rat gastric mucosa. Gastroenterology. 2004;126:208-219. [PubMed] [DOI] |
| 36. | Brzozowski T, Konturek PC, Konturek SJ, Kwiecien S, Drozdowicz D, Bielanski W, Pajdo R, Ptak A, Nikiforuk A, Pawlik WW. Exogenous and endogenous ghrelin in gastroprotection against stress-induced gastric damage. Regul Pept. 2004;120:39-51. [PubMed] [DOI] |
| 37. | Komori M, Tsuji S, Sun WH, Tsujii M, Kawai N, Yasumaru M, Kakiuchi Y, Kimura A, Sasaki Y, Higashiyama S. Gastrin enhances gastric mucosal integrity through cyclooxygenase-2 upregulation in rats. Am J Physiol Gastrointest Liver Physiol. 2002;283:G1368-G1378. [PubMed] [DOI] |
| 38. | Miyake K, Tsukui T, Wada K, Tatsuguchi A, Futagami S, Hiratsuka T, Shinoki K, Iizumi T, Akamatsu T, Sakamoto C. Irritant-induced cyclooxygenase-2 is involved in the defense mechanism of the gastric mucosa in mice. J Gastroenterol. 2002;37:164-171. [PubMed] [DOI] |
| 39. | Kawano S, Tsuji S. Role of mucosal blood flow: a conceptional review in gastric mucosal injury and protection. J Gastroenterol Hepatol. 2000;15 Suppl:D1-D6. [PubMed] [DOI] |
| 40. | Ohta M, Nguyen TH, Tarnawski AS, Pai R, Kratzberg YP, Sugimachi K, Sarfeh IJ. Overexpression of endothelin-1 mRNA and protein in portal hypertensive gastric mucosa of rats: a key to increased susceptibility to damage? Surgery. 1997;122:936-942. [PubMed] [DOI] |
| 41. | Masuda E, Kawano S, Nagano K, Tsuji S, Takei Y, Hayashi N, Tsujii M, Oshita M, Michida T, Kobayashi I. Role of endogenous endothelin in pathogenesis of ethanol-induced gastric mucosal injury in rats. Am J Physiol. 1993;265:G474-G481. [PubMed] |
| 42. | Masuda E, Kawano S, Nagano K, Tsuji S, Ishigami Y, Tsujii M, Hayashi N, Fusamoto H, Kamada T. Effect of intravascular ethanol on modulation of gastric mucosal integrity: possible role of endothelin-1. Am J Physiol. 1992;262:G785-G790. [PubMed] |
| 43. | Morales RE, Johnson BR, Szabo S. Endothelin induces vascular and mucosal lesions, enhances the injury by HCl/ethanol, and the antibody exerts gastroprotection. Faseb J. 1992;6:2354-2360. [PubMed] |
| 44. | Zayachkivska OS, Konturek SJ, Drozdowicz D, Konturek PC, Brzozowski T, Ghegotsky MR. Gastroprotective effects of flavonoids in plant extracts. J Physiol Pharmacol. 2005;56 Suppl 1:219-231. [PubMed] |
| 45. | Pan LR, Tang Q, Fu Q, Hu BR, Xiang JZ, Qian JQ. Roles of nitric oxide in protective effect of berberine in ethanol-induced gastric ulcer mice. Acta Pharmacol Sin. 2005;26:1334-1338. [PubMed] [DOI] |
| 46. | Zayachkivska OS, Konturek SJ, Drozdowicz D, Brzozowski T, Gzhegotsky MR. Influence of plant-originated gastroproteciive and antiulcer substances on gastric mucosal repair. Fiziol Zh. 2004;50:118-127. [PubMed] |
| 47. | Sibilia V, Torsello A, Pagani F, Rapetti D, Lattuada N, Locatelli V, Bulgarelli I, Guidobono F, Netti C. Effects of hexarelin against acid-independent and acid-dependent ulcerogens in the rat. Peptides. 2004;25:2163-2170. [PubMed] [DOI] |
| 48. | Li YH, Li J, Huang Y, Lu XW, Jin Y. Gastroprotective effect and mechanism of amtolmetin guacyl in mice. World J Gastroenterol. 2004;10:3616-3620. [PubMed] [DOI] |
| 49. | Iaquinto G, Giardullo N, Taccone W, Leandro G, Pasquale L, De Luca L, Szabo S. Role of endogenous endothelin-1 in ethanol-induced gastric mucosal damage in humans. Dig Dis Sci. 2003;48:663-669. [PubMed] [DOI] |
| 50. | Kalia N, Bardhan KD, Reed MW, Jacob S, Brown NJ. Mast cell stabilization prevents ethanol-induced rat gastric mucosal injury: mechanisms of protection. J Gastroenterol Hepatol. 2000;15:133-141. [PubMed] [DOI] |
| 51. | Ishizuka Y, Kamisaki T, Sato M. Anti-gastric acid secretory mechanism of 1,6-dihydro-2-[2-(2-methylpropoxy)anilino]-6-oxo-5-pyrimidinecarboxylic acid. Effect on mucosal mast cell. Arzneimittelforschung. 1996;46:919-922. |
| 52. | Erkasap S, Erkasap N, Aral E, Koken T, Kahraman A, Aydin Y, Yilmaz S, Ates E. Mast cell stabilizator and antioxidant effects of epidermal growth factor (EGF) on gastric mucosal injury induced by ethanol in rats. Chin J Physiol. 2005;48:1-6. [PubMed] |
| 53. | Kahraman A, Erkasap N, Koken T, Serteser M, Aktepe F, Erkasap S. The antioxidative and antihistaminic properties of quercetin in ethanol-induced gastric lesions. Toxicology. 2003;183:133-142. [PubMed] [DOI] |
| 54. | Ko JK, Cho CH, Lam SK. Adaptive cytoprotection through modulation of nitric oxide in ethanol-evoked gastritis. World J Gastroenterol. 2004;10:2503-2508. [PubMed] [DOI] |
| 55. | Karmeli F, Eliakim R, Okon E, Rachmilewitz D. Role of vasoactive intestinal peptide (VIP) in pathogenesis of ethanol-induced gastric mucosal damage in rats. Dig Dis Sci. 1993;38:1210-1219. [PubMed] [DOI] |
| 56. | Asai K, Buurman WA, Reutelingsperger CP, Schutte B, Kaminishi M. Modular effects of estradiol on ethanol-induced apoptosis in human intestinal epithelial cells. Scand J Gastroenterol. 2005;40:326-335. [PubMed] [DOI] |
| 57. | Tsutsumi S, Tomisato W, Takano T, Rokutan K, Tsuchiya T, Mizushima T. Gastric irritant-induced apoptosis in guinea pig gastric mucosal cells in primary culture. Biochim Biophys Acta. 2002;1589:168-180. [PubMed] [DOI] |
| 58. | Mustonen H, Kiviluoto T, Paimela H, Puolakkainen P, Kivilaakso E. Calcium signaling is involved in ethanol-induced volume decrease and gap junction closure in cultured rat gastric mucosal cells. Dig Dis Sci. 2005;50:103-110. [PubMed] [DOI] |
| 59. | Koko V, Todorovic V, Varagic J, Micev M, Korac A, Bajcetic M, Cakic-Milosevic M, Nedeljkovic M, Drndarevic N. Gastrin producing G-cells after chronic ethanol and low protein nutrition. Indian J Exp Biol. 1998;36:1093-1101. [PubMed] |
| 60. | Ancha H, Ojeas H, Tedesco D, Ward A, Harty RF. Somatostatin-induced gastric protection against ethanol: involvement of nitric oxide and effects on gastric mucosal blood flow. Regul Pept. 2003;110:107-113. [PubMed] [DOI] |
| 61. | Karmeli F, Eliakim R, Okon E, Rachmilewitz D. Somatostatin effectively prevents ethanol- and NSAID-induced gastric mucosal damage in rats. Dig Dis Sci. 1994;39:617-625. [PubMed] [DOI] |
| 62. | Sikiric P, Seiwerth S, Deskovic S, Grabarevic Z, Marovic A, Rucman R, Petek M, Konjevoda P, Jadrijevic S, Sosa T. New model of cytoprotection/adaptive cytoprotection in rats: endogenous small irritants, antiulcer agents and indomethacin. Eur J Pharmacol. 1999;364:23-31. [PubMed] [DOI] |
| 63. | Ueyama T, Saika M, Senba E. Distinct gene expression in the stomach following stress and alcohol exposure. Kaibogaku Zasshi. 2001;76:435-441. [PubMed] |
| 64. | Tsukimi Y, Okabe S. Recent advances in gastrointestinal pathophysiology: role of heat shock proteins in mucosal defense and ulcer healing. Biol Pharm Bull. 2001;24:1-9. [PubMed] [DOI] |
| 65. | Konturek PC, Brzozowski T, Kania J, Konturek SJ, Hahn EG. Nitric oxide-releasing aspirin protects gastric mucosa against ethanol damage in rats with functional ablation of sensory nerves. Inflamm Res. 2003;52:359-365. [PubMed] [DOI] |
| 67. | Rokutan K. Role of heat shock proteins in gastric mucosal protection. J Gastroenterol Hepatol. 2000;15 Suppl:D12-D19. [PubMed] [DOI] |
| 68. | Tanaka K, Nishimoto K, Tomisato W, Tsutsumi S, Hoshino T, Tsuchiya T, Mizushima T. Adaptive cytoprotection induced by pretreatment with ethanol protects against gastric cell damage by NSAIDs. Dig Dis Sci. 2004;49:210-217. [PubMed] [DOI] |
| 69. | Uehigashi Y, Yakabi K, Nakamura T. Pretreatment with mild irritant enhances prostaglandin E2 release from isolated canine gastric mucosal mast cells. Dig Dis Sci. 1999;44:1384-1389. [PubMed] [DOI] |