质子泵抑制剂对非甾体类抗炎药相关小肠黏膜损伤的影响

非甾体类抗炎药(non-steroidal anti-inflammatory drugs,NSAIDs)的主要不良反应是对食管、胃、十二指肠等消化道黏膜的损伤。随着胶囊内镜及小肠镜的日益普及,NSAIDs对小肠黏膜的损伤也开始受到大家的关注。目前,质子泵抑制剂(proton pump inhibitor,PPI)因对上消化黏膜有保护作用而被广泛应用,但其对NSAIDs相关小肠黏膜损伤的作用存在争议。本文系统回顾分析了PPI对服用NSAIDs的实验动物、健康志愿者及服用NSAIDs的患者小肠黏膜损伤的作用,发现PPI对服用NSAIDs的实验动物小肠黏膜损伤的作用与对健康志愿者或患者小肠黏膜损伤的作用不同。     

非甾体抗炎药引起小肠黏膜损伤机制及其治疗的研究进展

非甾体抗炎药(NSAIDs)是目前临床应用最广泛的药物之一,具有解热、镇痛、抗炎作用。随着NSAIDs的广泛应用,其胃肠道不良反应的报道日趋增多。目前NSAIDs对小肠黏膜损伤的机制未完全阐明。本文就NSAIDs引起小肠黏膜损伤的机制及其治疗的研究进展作一综述。     

非甾体消炎药小肠损伤机制以及云母防治作用的研究进展

非甾体消炎药(NSAIDs)临床应用广泛,其胃肠道不良反应日益受到关注。长期以来,人们比较重视NSAIDs引起的胃十二指肠黏膜损伤,然而近年发现NSAIDs相关小肠黏膜损伤亦有较高的发生率,其发生机制尚未完全阐明且缺乏有效防治方法。本文就NSAIDs相关小肠黏膜损伤机制以及云母的防治作用作一综述。     

小檗碱对非甾体消炎药相关性肠损伤的保护作用及其机制研究

背景：近年非甾体消炎药（NSAIDs）相关性肠损伤的发生率明显升高,但目前尚缺乏有效防治NSAIDs相关性肠损伤的药物。目的：研究中药小檗碱对NSAIDs相关性肠损伤的治疗作用及其机制。方法：将40只大鼠随机分为对照组、模型组以及低、中、高剂量小檗碱干预组（分别为25、50、75mg·kg-1·d-1）。采用7.5mg·kg-1·d-1双氯芬酸制备NSAIDs相关性肠损伤模型。造模第5d处死所有大鼠,行小肠黏膜大体、组织学评分。以ELISA法检测小肠黏膜前列腺素（PG）E2含量,硝酸还原酶法检测小肠黏膜和血清NO含量,免疫组化法检测小肠黏膜环氧合酶（COX）-1、COX-2表达。结果：与对照组相比,模型组大鼠小肠大体评分和组织学评分明显升高（P〈0．05）,小肠黏膜PGE,含量明显降低（P〈0．05）,小肠黏膜和血清NO含量明显升高（P〈0．05）,小肠黏膜COX-1表达明显降低（P〈0．05）,COX-2表达明显升高（P〈0．05）。给予低、中、高剂量小檗碱干预后,上述指标明显改善（P〈0．05）。结论：小檗碱对NSAIDs相关性肠损伤具有保护作用,其机制可能与小檗碱致小肠黏膜PGE：、COX-1表达升高以及组织和血清NO含量、COX-2表达降低有关。     

NSAIDs相关性小肠黏膜损伤机制及防治研究进展

非甾体类抗炎药(non-steroidal anti-in?ammatory drugs,NSAIDs)广泛应用于临床,胃黏膜损伤是其主要的不良反应.随着诊疗技术的进步,近年发现NSAIDs对小肠黏膜的损伤远比以往估计的严重.阐明NSAIDs对小肠黏膜的损伤机制对临床防治具有重要的意义,本文结合国内外文献综述此方面的研究进展.     

非甾体抗炎药肠道损害

非甾体抗炎药（NSAIDs)不仅引起胃十二指肠损害，还可引起小肠和大肠损害。NSAIDs小肠损害包括溃疡、穿孔、狭窄及NSAIDs肠病，以后者最为常见，表现为肠道失血、蛋白丢失及回肠吸收功能障碍。NSAIDs大肠损害包括非特异性结肠炎、溃疡、穿孔、狭窄，还可使原有结肠病变加重。其肠损害机制前期可能与NSAIDs抑制环氧合酶和线粒体氧化磷酸化，引起粘膜防御能力降低有关，后期则与肠腔内侵袭因素的作用有关。目前尚无有效的治疗方法，寻求副作用少的新型NSAIDs将可预防肠道损害的发生。     

非甾体抗炎药对小肠黏膜的损伤作用

研究显示非甾体抗炎药（NSAIDs）不仅可引起胃十二指肠黏膜损伤，还可引起小肠黏膜损伤。目的：探讨NSAIDs引起小肠黏膜损伤的发病机制及其病理生理变化。方法：50只大鼠随机分为空白对照组和四组模型组，以不同NSAID灌胃14d。另20只大鼠先分别行胆管结扎和假手术。再予吲哚美辛灌胃。观察各组大鼠一般情况和小肠黏膜大体、组织病理学改变，测定小肠组织髓过氧化物酶（MPO）、丙二醛（MDA）、超氧化物歧化酶（SOD）、一氧化氮（NO）含量。结果：四种NSAID均能造成大鼠小肠黏膜损伤，吲哚美辛、布洛芬和塞来昔布组累计损伤深度和面积显著高于空白对照组（P〈0．05），其中以吲哚美辛组损伤最重，阿司匹林组则与空白对照组无明显差异。各模型组小肠组织MPO含量均显著高于空白对照组，SOD活性则显著低于空白对照组（P〈0．05），MDA和NO含量均呈上升趋势，但分别仅吲哚美辛组和布洛芬组与空白对照组相比有显著差异（P〈0．05）。假手术组小肠黏膜损伤显著重于空白对照组（P〈0．05），胆管结扎组与空白对照组相比无明显差异。结论：NSAIDs可通过炎症反应、氧自由基损伤、NO过度产生以及药物的肝肠循环损害小肠上皮屏障，破坏小肠结构的完整性。     

非甾体类抗炎药对人大肠和小肠的副作用

大量研究表明,NSAIDs除引起胃十二指肠粘膜损害外,还对大肠和小肠有副作用。60％～70％。长期服用NSAIDs的病人可产生无症状性肠病,表现为少量出血及蛋白丢失。 NSAIDs与大肠 NSAIDs对“正常”结肠的损害:NSAIDs对大肠的损害多为个别病例报道。以Fenema-     

Ang(1-7)通过调节Treg/Th17平衡参与保护NSAIDs相关小肠损伤

背景:非甾体抗炎药(NSAIDs)广泛应用于临床。随着内镜技术的进步,NSAIDs相关小肠损伤越来越多见,但目前尚无明确有效的防治措施。目的:探讨调节性T细胞(Treg细胞)与Th17细胞失衡在NSAIDs相关小肠损伤中的作用以及血管紧张素1-7 [Ang(1-7)]的保护效应。方法:30只雄性Sprague-Dawley大鼠随机分为对照组、模型组和Ang(1-7)治疗组,后两组使用双氯芬酸钠诱导小肠损伤模型。5 d后处死大鼠,取小肠黏膜观察大体和组织学损伤情况;以ELISA法和(或)免疫组化法检测Ang(1-7)以及促炎和抗炎细胞因子水平;流式细胞术分析Treg、Th17细胞占CD4~+ T细胞的比例。结果:模型组大鼠小肠黏膜广泛充血、水肿,散在多发糜烂、小溃疡。Ang(1-7)治疗组小肠损伤明显减轻,黏膜轻度充血、水肿,散在少量小糜烂灶。治疗组小肠组织Ang(1-7)、抗炎细胞因子水平、Treg细胞数量和Treg/Th17比值较模型组显著升高,抗炎细胞因子水平和Th17细胞数量较模型组显著降低(P均0.05)。Pearson相关系数分析显示,小肠黏膜Ang(1-7)含量与Treg/Th17比值呈显著正相关(r=0.847,P0.05)。结论:Treg/Th17失衡可能是NSAIDs相关小肠损伤的重要发病机制,而Ang(1-7)可能通过调节Treg/Th17平衡参与保护NSAIDs相关小肠损伤。     

小肠出血损伤对大鼠肠黏膜内跨细胞白蛋白转运的影响

目的探讨小肠出血损伤对大鼠肠黏膜内跨细胞白蛋白转运的影响。方法选取40只SD雄性大鼠,体重240~280 g,随机分为对照组和模型组,每组20只。采用7.5 mg/kg双氯芬酸灌胃,诱导大鼠小肠黏膜损伤模型,建立大鼠非甾体类抗炎药(NSAIDs)肠黏膜损伤模型。将以上两组再随机分为急性期(T1)和亚急性期(T2)亚组,每组10只。对照组以1 ml纯化水灌胃;模型组以7.5 mg/kg双氯芬酸灌胃。T1亚组在灌胃1 d后处死,T2亚组灌胃5 d后处死。根据小肠损伤程度病理评分进行评价。测定大鼠血清中一氧化氮(NO)、白蛋白含量,同时测定荧光标记白蛋白,研究大鼠肠黏膜中白蛋白跨细胞转运的情况。结果7.5 mg/kg双氯芬酸能引起大鼠小肠黏膜严重的出血性损伤,小肠黏膜可见糜烂、溃疡、红斑,局部肠腔见囊样扩张,且T1、T2模型组小肠的损伤程度均大于T1、T2对照组(P<0.05),T2模型组小肠的损伤程度大于T1模型组(P<0.05)。T1模型组血清NO含量显著低于T1对照组(P<0.05),T2模型组NO含量显著高于T1对照组和T1模型组(P<0.05)。T1、T2模型组血清白蛋白显著低于T1、T2对照组(P<0.05),T2模型组较T1模型组显著降低(P<0.05)。结论短期小剂量的双氯芬酸能引起大鼠小肠黏膜损伤出血,并随着时间的延长而加重;小肠出血损伤会影响大鼠肠黏膜内跨细胞白蛋白的转运,从而导致NSAIDs性肠黏膜损伤。     

Present status and strategy of NSAIDs-induced small bowel injury

Non-steroidal anti-inflammatory drugs (NSAIDs) are well known to cause gastroduodenal mucosal lesions as an adverse effect. Recently, the serious problem of NSAID-induced small intestinal damage has become a topic of great interest to gastroenterologists, since capsule endoscopy and balloon enteroscopy are available for the detection of small intestinal lesions. Such lesions have been of great concern in clinical settings, and their treatment and prevention must be devised as soon as possible. The prevalence of NSAIDs-induced small intestinal injury is higher than had been expected. Recent studies show that more than 50% of patients taking NSAIDs have some mucosal damage in the small intestine. The gross appearance of NSAID-induced enteropathy varies, appearing variously as diaphragm-like strictures, ulcers, erosions, and mucosal redness. To investigate NSAID-induced enteropathy, and to rule out other specific enteropathies, other useful methods (in addition to capsule endoscopy and balloon enteroscopy) include such modalities as radiological examination of the small intestine, the permeability test, scintigraphy or the fecal excretion test using ¹¹¹Indium-labeled white blood cells, and measurement of the fecal calprotectin concentration. Diaphragm-like strictures and bleeding from mucosal breaks may be treatable with interventional enteroscopy. Misoprostol, metronidazole, and sulfasalazine are frequently used to treat NSAID-induced enteropathy, but have undesirable effects in some cases. In the experimental model, we confirmed that several existing drugs for gastroduodenal ulcers prevented indomethacin-induced small intestinal injury. Such drugs may be useful for preventing the adverse effects of NSAIDs not only in the stomach but also in the small intestine. We hope to examine these drugs in future clinical studies.     

NSAID enteropathy: could probiotics prevent it?

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs in the world; nevertheless, about 50–70 % of patients on long-term NSAIDs develop small intestine injury, namely NSAID enteropathy, sometimes with serious outcomes. No medications with proven efficacy are yet available to prevent NSAID enteropathy. A series of therapeutic strategies targeting the different mechanisms involved in small bowel injury have been investigated, but without definitive results. Intestinal bacteria and their degradation products are essential for the development of NSAID-induced small bowel lesions, because “germ-free” animals were found to be resistant to indomethacin injuries. Therefore, it has been suggested that modulating the intestinal flora, for example by using probiotics, could protect against NSAID enteropathy. In this work, we reviewed the main therapeutic strategies for NSAID enteropathy, in particular analyzing the available studies relating to the eventual protective role of probiotics. We found that results are not all concordant; nevertheless, the more recent studies provide better understanding about pathogenetic mechanisms involved in small intestinal injury and the role of probiotics, and show encouraging results. Larger and well-designed studies should be performed to evaluate the actual role of probiotics in NSAID enteropathy, the eventual differences among probiotic strains, dose-responses, and optimal duration of therapy.     

Prevalence of non-steroidal anti-inflammatory drug-induced enteropathy determined by double-balloon endoscopy: A Japanese multicenter study

Objective. Capsule endoscopy has shown that non-steroidal anti-inflammatory drugs (NSAIDs) can damage the small intestine. The aim of this study was to determine the prevalence of NSAIDs enteropathy in subjects indicated for double-balloon endoscopy (DBE). Material and methods. The Japanese Study Group for Double-Balloon Endoscopy (JSG-DBE) established a database for the practical use of DBE in the Japanese population during a 2-year period from 2004 to 2005. Using this database, we identified subjects who had been taking NSAIDs within a month prior to DBE (NSAIDs group) and those free from NSAIDs use (control group). The clinical background and DBE findings were compared between the two groups. Results. Among 1035 patients registered in the JSG-DBE database, 61 subjects were classified as the NSAIDs group and 600 served as the control group. Patients in the NSAIDs group were older (62±18 versus 51±19 years, p<0.0001) and gastrointestinal bleeding was a more frequent indication for DBE (79% versus 44%, p<0.001) compared with in the control group. Non-specific mucosal breaks were detected by DBE in 31 patients in the NSAIDs group (51%) and 29 patients in the control group (5%, p <0.0001). Aspirin was less frequently prescribed and cardiovascular disease was a less frequent indication for NSAIDs use in patients with mucosal breaks than in those without breaks. Conclusions. In the cases indicated for enteroscopy, NSAIDs enteropathy occurred in half of the patients taking NSAIDs. Aspirin seems to be less harmful to the small intestine than other NSAIDs.     

Role of COX-2 in nonsteroidal anti-inflammatory drug enteropathy in rodents

Abstract

Objective. It is widely thought that cyclooxygenase 1 (COX-1) inhibition with consequential decreases in mucosal prostaglandins, along with concomitant inhibition of COX-2, is pivotal in nonsteroidal anti-inflammatory drug-induced (NSAID) enteropathy. We examined the role of COX-1, COX-2 and topical effects of drugs in NSAID enteropathy. Material and methods. We quantified small intestinal damage and prostaglandin E₂ levels in wild-type, COX-1 and COX-2 deficient mice after administration of R-2-phenylpropionic acid (which has the same topical characteristics as conventional NSAIDs but does not affect the COX enzymes), the conventional NSAIDs flurbiprofen and the selective COX-2 inhibitor celecoxib. We also measured intestinal permeability and inflammation in rats given the selective COX-1 inhibitor SC-560 and NSAIDs. The parameters were assessed at baseline and after administration of the drugs. Results. R-2-phenylpropionic acid caused small intestinal damage in COX-2^-/- and wild-type mice given celecoxib, but not in wild type or COX-1^-/- mice. PGE₂ levels in mice dosed with R-2-phenylpropionic acid were elevated. Indomethacin raised permeability and caused inflammation in rats. Conclusions. The combination of COX-2 absence (or inhibition) and the topical effect of NSAIDs lead to changes characteristic of NSAID enteropathy without concomitant COX-1 inhibition and/or associated decreases in mucosal prostaglandins. COX-2 appears to be more important for maintaining small bowel integrity than COX-1.     

High prevalence of NSAID enteropathy as shown by a simple faecal test

BACKGROUND: The diagnosis of non-steroidal anti-inflammatory drug (NSAID) induced enteropathy is difficult, requiring enteroscopy or the use of four day faecal excretion of (111)In labelled white cells. AIMS: To assess faecal calprotectin (a non-degraded neutrophil cytosolic protein) as a method for diagnosing NSAID enteropathy. METHODS: Single stool faecal calprotectin concentrations were compared with the four day faecal excretion of (111)In labelled white cells in 47 patients taking NSAIDs. The prevalence and severity of NSAID enteropathy was assessed using this method in 312 patients (192 with rheumatoid arthritis, 65 with osteoarthritis, 55 with other conditions) taking 18 different NSAIDs. RESULTS: The four day faecal excretion of (111)In white cells correlated significantly with faecal calprotectin concentrations. In the group of 312 patients on NSAIDs faecal calprotectin concentrations were significantly higher than in controls, the prevalence of NSAID enteropathy being 44%. The prevalence and severity of NSAID enteropathy was independent of the particular type or dose of NSAID being taken or other patient variables. CONCLUSIONS: Assay of faecal calprotectin provides a simple practical method for diagnosing NSAID enteropathy in man. Forty four per cent of patients receiving these drugs had NSAID induced enteropathy when assessed by this technique; 20% of these had comparable levels of inflammation to that previously reported in patients with inflammatory bowel disease.     

13例以下消化道出血为主要表现的NSAIDs肠病临床分析

目的研究NSAIDs相关性肠病的临床特征,以期提高对其认识,减少漏诊和误诊。方法回顾性分析解放军总医院消化内科13例NSAIDs相关性肠病患者的用药史、临床表现、实验室及影像学检查、胃肠镜检查及治疗。结果 13例NSAIDs相关性肠病均以下消化道出血为主要表现,均有NSAIDs长期服药史,胃镜检查多无异常发现,肠镜检查远端回肠和结肠可见非特异性的黏膜糜烂。停药后,给予PPI、黏膜保护剂可治愈。结论 NSAIDs相关性肠病临床表现及各项检查表现均不典型,易误诊,应结合用药史、临床表现和胃肠镜、胶囊内镜、小肠镜等提高诊断率。     

Psychological stress exacerbates NSAID-induced small bowel injury by inducing changes in intestinal microbiota and permeability via glucocorticoid receptor signaling

Background

Nonsteroidal anti-inflammatory drugs (NSAIDs) are popular painkillers, but they have serious side effects, not only in the upper gastrointestinal tract but also in the small intestine. It is well known that psychological stress may exacerbate various gastrointestinal diseases. The aim of this study was to determine whether psychological stress exacerbates NSAID enteropathy and to determine the possible underlying mechanisms for this.

Methods

Experiment 1: mice were exposed to water avoidance stress (WAS) or sham stress for 1 h per day for 8 consecutive days, and then enteropathy was induced by indomethacin. Experiment 2: cecal contents from stress (−) or (+) mice were transplanted into mice that had received antibiotics and in which NSAID enteropathy had been induced without WAS. Experiment 3: mifepristone, a glucocorticoid receptor antagonist, was injected before WAS for 8 days. Small intestinal injury, mRNA expression of TNFα, intestinal permeability, and the microbial community were assessed.

Results

Psychological stress exacerbated NSAID enteropathy and increased intestinal permeability. Psychological stress induced changes in the ileal microbiota that were characterized by increases in the total number of bacteria and the proportion of Gram-negative bacteria. The increased susceptibility to NSAIDs and intestinal permeability due to WAS was transferable via cecal microbiota transplantation. The increased permeability and aggravation of NSAID enteropathy caused by WAS were blocked by the administration of mifepristone.

Conclusions

This study demonstrated a relationship between NSAID enteropathy and psychological stress, and showed the utility of studying the intestinal microbiota in order to elucidate the pathophysiology of NSAID enteropathy. It also showed the impact of stress on the intestinal microbiota and the mucosal barrier in gastrointestinal diseases.

     

Diaphragm disease compared with cryptogenic multifocal ulcerous stenosing enteritis

As the use of drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs) increases,so too do gastrointestinal ulcers,bleeding,perforation and obstruction.Diaphragm disease of the small intestine is formed by submucosal fibrosis and destruction of lamina muscularis due to chronic ulceration,which corresponds to the most severe stage of NSAID enteropathy.It may lead to stricture of the small intestine.If such ulcerations and strictures in the small intestine are multiple,differential diagnosis is between dia...     

Nonsteroidal antiinflammatory drug–induced enteropathy and severe chronic anemia in a patient with rheumatoid arthritis

This report describes the case of a woman who was admitted to the hospital with severe anemia and refractory rheumatoid arthritis. She had been transfusion dependent for 8 years and was receiving a combination of indomethacin and naproxen. An indium-111 white blood cell scan revealed small bowel inflammation. Salsalate was substituted for her previous nonsteroidal antiinflammatory drugs (NSAIDs), and metronidazole was initiated. This resulted in maintenance of a normal hemoglobin level for at least 1 year after discharge. Small intestine inflammation and bleeding (enteropathy) due to NSAIDs must be considered in the evaluation of anemia in patients with arthritis.