Enhanced colonic nitric oxide generation and nitric oxide synthase activity in ulcerative colitis and Crohn's disease.

Recent studies have suggested that nitric oxide (NO.), the product of nitric oxide synthase in inflammatory cells, may play a part in tissue injury and inflammation through its oxidative metabolism. In this study the colonic generation of oxides of nitrogen (NOx) and nitric oxide synthase activity was determined in ulcerative colitis and Crohn's disease. Colonic biopsy specimens were obtained from inflammatory bowel disease patients and from normal controls. Mucosal explants were cultured in vitro for 24 hours and NOx generation was determined. Nitric oxide synthase activity was monitored by the conversion of [3H]-L-arginine to citrulline. Median NOx generation by inflamed colonic mucosa of patients with active ulcerative colitis and Crohn's colitis was 4.2- and 8.1-fold respectively higher than that by normal human colonic mucosa. In ulcerative colitis and Crohn's colitis nitric oxide synthase activity was 10.0- and 3.8-fold respectively higher than in normal subjects. Colonic NOx generation is significantly decreased by methylprednisolone and ketotifen. The decrease in NOx generation by cultured colonic mucosa induced by methylprednisolone suggests that NO synthase activity is induced during the culture and the steroid effect may contribute to its therapeutic effect. Enhanced colonic NOx generation by stimulated nitric oxide synthase activity in ulcerative colitis and Crohn's disease may contribute to tissue injury.     

Enhanced gastric and duodenal platelet-activating factor and leukotriene generation in duodenal ulcer patients

Platelet-activating factor (PAF), leukotriene B4 (LTB4), and leukotriene C4 (LTC4) generation by gastroduodenal mucosa was assessed in duodenal ulcer patients and in normal subjects, to elucidate their possible role in the pathogenesis of peptic ulcer disease. Endoscopic fundic, antral, and duodenal biopsy specimens were obtained from 35 duodenal ulcer patients on the day the diagnosis was established and from 42 normal controls. In duodenal ulcer patients PAF generation, determined by platelet aggregation, was two- to three-fold higher than its respective generation by normal subjects. LTB4 and LTC4 synthesis by cultured antral and duodenal mucosa obtained from duodenal ulcer patients was twofold higher than their synthesis by normal subjects. Fundic LTB4 and LTC4 generation was similar in ulcer patients and controls. In 11 patients PAF, LTB4, and LTC4 generation was also assessed after 4 weeks of treatment resulting in ulcer healing and found to be significantly reduced when compared with their synthesis when the ulcer was active. These results thus suggest that PAF, LTB4, and LTC4 may have a role in the pathogenesis of duodenal ulcer, and therefore their modulation may have therapeutic benefits.     

Bleeding duodenal ulcer and association with polymorphism of endothelial constitutive nitric oxide synthase gene

Nitric oxide (NO) exerts both protective and proinflammatory actions in the gastrointestinal tract. Enhanced gastric NO synthase (NOS) activity has been shown in duodenal ulcer patients. Recently, intron-4 polymorphism of the endothelial constitutive (ec) NOS gene has been associated with some pathological conditions. Our aim was to determine the genotype and allele frequencies of the ecNOS4 polymorphism in peptic ulcer patients. The distribution of the polymorphism ecNOS4a/b was studied in 188 ulcer patients and 120 healthy controls, from genomic DNA. Genotypes ab, bb, and aa and allele frequency were similar in both peptic ulcer patients and controls, and no differences were found when patients and controls were analyzed according to the presence of several etiological factors. However, alelle a carrier status was associated with decreased risk of bleeding in duodenal ulcer patients (OR = 0.49; 95% CI = 0.25–0.95; P = 0.03). In conclusion, this ecNOS4 polymorphism gene could be related to susceptibility of duodenal ulcer patients to bleeding.     

消化性溃疡胃粘膜组织一氧化氮合酶活性的改变及其与年龄的关系

目的通过比较消化性溃疡、胃炎患者及正常人胃粘膜组织一氧化氮合酶（ＮＯＳ）的活性，探讨ＮＯＳ和一氧化氮（ＮＯ）在消化性溃疡发病和转归过程中所起的作用，以及年龄因素对胃粘膜组织ＮＯＳ活性的影响。方法共收集了７８份胃粘膜标本，其中胃溃疡病人２３例，十二指肠球部溃疡２７例，浅表性胃炎１７例，正常志愿者１１例；采用高铁血红蛋白比色法检测ＮＯＳ的活性。结果胃溃疡患者ＮＯＳ活性显著高于正常对照组（Ｐ＜０．０２）；十二指肠球部溃疡患者及浅表性胃炎患者ＮＯＳ活性与正常对照组相比均无显著性差异；不同年龄组胃溃疡、十二指肠球部溃疡、胃炎患者胃粘膜组织中ＮＯＳ活性无显著性差异。结论胃溃疡患者ＮＯＳ活性升高，可能是机体为修复胃粘膜而引发的一种代偿反应，将有利于溃疡的愈合；年龄不是影响胃粘膜组织ＮＯＳ活性的主要因素     

Response of blood endothelin-1 and nitric oxide activity in duodenal ulcer patients undergoing Helicobacter pylori eradication

AIM: To investigate the effect of Helicobacter pylori eradication on endothelin-1 (ET-1) and nitric oxide (NO) in duodenal ulcer (DU) patients. METHODS: Sixty-six Hpylori-infected active DU patients were consecutively enrolled to receive one-week triple therapy (rabeprazole, amoxicillin and metronidazole) and then one-month rabeprazole therapy. They were asked back to determine ulcer and Hpylori status using endoscopy one month later. Thirty-seven healthy controls (H pylori +/-:17/20) were enrolled for comparison. Blood samples were collected in each visit to measure plasma ET-1 and nitrate/nitrite levels using an enzyme immunoassay kit. RESULTS: Sixty DU patients finished trial per protocol. The ulcer healing and Hpylori-eradication rates were 86.7% and 83.3%, respectively. Plasma ET-1 level in DU patients was higher than that of Hpylori-negative and positive controls (3.59±0.96 vs0.89±0.54 vs0.3±0.2 pg/mL,P<0.01), while nitrate/nitrite levels among them were also significantly different (8.55±0.71 vs5.27±0.68 vs 6.39±0.92 μmol/L, P<0.05). H pylori eradication diminished ET-1 levels (3.64±0.55 vs2.64±0.55 pg/mL, P<0.01) but elevated nitrate/ nitrite level (8.16±0.84 vs11.41±1.42 umol/L,P<0.05). CONCLUSION: Both plasma ET-1 and nitrate/nitrite levels increase in active DU patients. After an effective H pylori eradication, DU healing is associated with diminished blood ET-1 level and elevated nitrate/nitrite level.     

Cholecystokinin-like activity in the duodenal mucosa of duodenal ulcer patients.

Cholecystokinin-like activity in the duodenal mucosa was measured by the bioassay method described by Ljungberg to elucidate its significance in 14 duodenal ulcer patients as well as in 13 normal subjects with no evidence of gastrointestinal diseases. The stage of duodenal ulceration was determined endoscopically according to the criterion of the Japanese Gastroenterological Endoscopic Society. The cholecystokinin-like activity in the duodenal mucosa of duodenal ulcer patients in active stage 1, which was considered as an early stage of active open duodenal ulceration, did not differ statistically from that of normal subjects, whereas that of duodenal ulcer patients in active stage 2 began to show a significant increase (p less than 0.05), and the cholecystokinin-like activity in the duodenal mucosa of duodenal ulcer patients in healing stage 1 or healing stage 2 was significantly higher than that in normal subjects (p less than 0.01). The cholecystokinin-like activity in the duodenal mucosa of duodenal ulcer patients in the scarring stage, however, returned to the normal range. It is concluded that cholecystokinin may act physiologically in the cure of duodenal ulcer.     

Rapid gastric emptying in duodenal ulcer patients

Isosmotic liquid peptone meals adjusted to pH 7, 3, and 1.5 were instilled on separate days into the stomachs of 8 duodenal ulcer patients and 7 healthy controls. Using a marker-dilution method, duodenal acid load (DAL) was measured as the amount of unbuffered hydrogen ions delivered to the duodenum per unit time. Gastric emptying was measured as the total volume of gastric contents, including meal plus gastric secretion, passing through the pylorus per unit time (VPP). Mean pentagastrin-stimulated acid output was not significantly different between the two groups. However, after all three test meals, mean DAL was significantly greater in duodenal ulcer than in normal subjects in both hours of the test, and VPP was significantly greater in ulcer than in normal subjects in the first 40 min. In both groups, following peptone meals of pH 7 and 3, the volume of gastric contents delivered through the pylorus decreased as the amount of free hydrogen ions entering the duodenum increased, but a given load of acid was less effective in slowing emptying in duodenal ulcer patients than in controls. These studies indicate that duodenal ulcer patients empty liquid meals more rapidly than do normal subjects, independent of the initial pH of the meals, and that, in addition, acid inhibition of gastric emptying is defective in duodenal ulcer.Dr. Grossman died May 26, 1981.S. K. Lam was a visiting scientist from the Department of Medicine, University of Hong Kong. Queen Mary Hospital, Hong Kong. M.I. Grossman holds a Veterans Administration Senior Medical Investigatorship.These studies were supported by National Institutes of Arthritis, Metabolism and Digestive Diseases grant AM 17328 to the Center for Ulcer Research and Education and by Veterans Administration Research Funds.This work was presented in part in abstract form at the 80th Annual Meeting of the American Gastroenterological Association, New Orleans, Louisiana, May 19–25, 1979.     

Histamine and duodenal ulcer: effect of omeprazole on gastric histamine in patients with duodenal ulcer.

Gastric mucosal concentrations of histamine and of its metabolic enzyme, histamine methyltransferase activity, were measured in patients with duodenal ulcer disease and patients with an apparently normal stomach and duodenum. Patients with duodenal ulcer had significantly less (p less than 0.05) mucosal histamine (median 204 nmol/g) than control subjects (median 252 nmol/g). There was no significant difference between the two groups in their histamine methyltransferase activity values. Omeprazole therapy did not significantly change mucosal histamine (+23%), histamine methyltransferase activity (+5%), histamine release before (+5%) or during (+7%) pentagastrin infusion. It significantly decreased acid secretion during pentagastrin stimulation (median -73%, p less than 0.001). Omeprazole, like cimetidine, does not stop histamine release during pentagastrin stimulation.     

幽门螺杆菌阳性胃炎患者胃粘膜-氧化氮合酶活力变化的意义

目的探讨幽门螺杆菌(Hp)感染时胃粘膜内一氧化氮合酶(NOS)活性和一氧化氮(NO)含量与细胞凋亡改变的意义.方法选择慢性活动性胃炎病人27例,其中Hp阳性者15例,Hp阴性者12例正常对照组10例.应用生物化学方法和切口末端标记法(Tunel)检测胃粘膜组织中一氧化氮产物N0-2水平、NOS活性及细胞凋亡指数.结果Hp感染时,胃粘膜NOS活性、NO-2水平及细胞凋亡指数明显升高,较Hp阴性组差异显著(P＜0.01),胃炎积分数与胃粘膜组织中NOS活性和NO-2水平呈明显正相关(r=0.66和0.84,P＜0.01).当根除Hp后,胃粘膜组织NOS活性,NO-2水平及细胞凋亡指数则显著降低,细胞凋亡指数与NOS活性和N0-2水平呈明显正相关(r=0.68和0.79,P＜0.01).结论Hp感染时可引起胃粘膜组织NOS活化,NO过量产生,细胞凋亡增加,这从又一方面说明Hp感染在胃腺癌发病机制中作用.     

人胃癌组织中一氧化氮合酶的表达

目的探讨NOS与胃癌的关系.方法用NADPH-d组织化学法测定了正常胃组织、癌旁组织和癌组织中一氧化氮合酶(NOS)表达水平.结果正常胃组织中粘膜上皮细胞、各种有分泌功能的细胞及肌层神经纤维中均有NOS表达,测一个视野NOS阳性细胞的平均灰度,正常胃组织为112、癌旁组织为120、胃癌组织为145.各组间差异有显著意义.表明正常胃组织NOS活性最高,胃癌组织NOS活性最低.结论①正常胃组织有广泛的NOS分布,提示NO对维持正常胃功能具有重要作用;②胃粘膜细胞癌变过程中,NOS活性明显降低,提示NOS活性与胃粘膜细胞癌变有高度相关性.     

Enhanced mucosal permeability and nitric oxide synthase activity in jejunum of mast cell deficient mice

Background—Recent reports have described amodulating influence of nitric oxide (NO) on intestinal mucosalpermeability and have implicated a role for mast cells in this NOmediated process.
Aims—To assess further the contribution of mastcells to the mucosal permeability changes elicited by the NO synthase(NOS) inhibitor N^G-nitro-L-arginine methylester(L-NAME), using mast cell deficient (W/W^V) andmast cell replete mice (+/+).
Methods—Chromium-51 EDTA clearance (from blood tojejunal lumen), jejunal NOS and myeloperoxidase (MPO) activities, andplasma nitrate/nitrite levels were monitored.
Results—The increased EDTA clearance elicited byintraluminal L-NAME in W/W^V mice (4.4-fold) wassignificantly greater than the response observed in control (+/+) mice(1.8-fold). The exacerbated response in W/W^v mice wasgreatly attenuated by pretreatment with either dexamethasone (1.3-fold)or the selective inducible NOS inhibitor, aminoguanidine (1.4-fold),and partially attenuated by the mast cell stabiliser, lodoxamide(2.9-fold). Jejunal inducible NOS activity was significantly higher inW/W^V than in +/+ mice, while jejunal MPO was lower inW/W^V mice than in +/+ mice, suggesting that the higherinducible NOS in W/W^V does not result from the recruitmentof inflammatory cells into the gut. The higher inducible NOS activityin the jejunum of W/W^V was significantly reduced bydexamethasone treatment.
Conclusions—Our results suggest that mast cellsnormally serve to inhibit inducible NOS activity tonically in the gutand that inhibitors of NOS elicit a larger permeability response when this tonic inhibitory influence is released by mast cell depletion.

Keywords:aminoguanidine; c-kit; dexamethasone; epithelium; neutrophils

     

梅毒患者血清一氧化氮和一氧化氮合酶水平测定

目的　检测梅毒螺旋体感染者血清中一氧化氮 (NO)和一氧化氮合酶 (NOS)的水平。方法　用分光光度法测定血清中NO水平和NOS活性 ,血清中NO3 和NO2 总量代表体内NO水平 ,NOS催化L 精氨酸和氧的反应生成NO的多少代表血清NOS活性。结果　梅毒患者NO浓度为 115± 36 3nmol/L ,NOS活性为 35 8± 7 3U/ml,二者均远远高于正常对照组。结论　梅毒螺旋体的感染引起患者体内NO水平和NOS活性升高 ,NO在梅毒感染中可能发挥重要的作用。     

Decreased nitric oxide synthase activity in platelets from IDDM and NIDDM patients

Summary Nitric oxide (NO) produced by platelet nitric oxide synthase (NOS) inhibits platelet activation by increased cytoplasmic cGMP levels. The aim of this study was to investigate platelet NOS activity in insulin-dependent (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM), which are characterized by enhanced platelet activation. HbA_{1 c} levels, platelet NOS and platelet membrane Na⁺/K⁺ ATPase activity were determined in 19 IDDM patients, 21 NIDDM patients and 31 healthy control subjects. NOS activity was measured by a spectrophotometric method based on NO-dependent oxidation of oxyhaemoglobin to met-haemoglobin. Na⁺/K⁺ ATPase activity was measured by the method of Kitao and Hattori. Both NOS and Na⁺/K⁺ ATPase activity were significantly reduced in diabetic subjects compared with control subjects. NOS showed a significant negative relation with HbA_{1 c} levels and a positive relation with Na⁺/K⁺ ATPase activity in diabetic patients. It is hypothesized that the decreased NOS activity might play a role in the pathogenesis of diabetic vascular complications. [Diabetologia (1998) 41: 101–104] Received: 30 June 1997 and in revised form: 3 September 1997     

Serum group I pepsinogens in unoperated duodenal ulcer patients and in duodenal ulcer patients after proximal gastric vagotomy

Thirty-three duodenal ulcer patients (group A) were examined for gastric acid secretion capacity and serum group I pepsinogens (PG I) under basal conditions. Another group of 36 duodenal ulcer patients (group B), who had undergone proximal gastric vagotomy (PGV) 1 year previously, were similarly examined. Mean basal acid output, mean insulin-stimulated peak acid output, and mean pentagastrin-stimulated peak acid output in the conservatively treated group were 4.5 meq/h, 25.1 meq/h, and 34.4 meq/h, respectively. The corresponding values in the PGV group were 2.5 meq/h, 6.7 meq/h, and 18.5 meq/h. The mean serum PG I concentration in group A was 103.6 ng/ml and in group B 69.9 ng/ml, whereas the mean serum PG I concentration in 34 healthy control subjects was 47.9 ng/ml. The differences in serum PG I concentrations between all three groups were statistically significant (p less than 0.05). An elevated concentration of serum PG I is associated with clinical ulcer disease in unoperated patients, but the wide overlap in the PG I concentration area between duodenal ulcer patients and healthy persons limits the use of PG I determinations in disturbances of gastric acid secretion.     

Regression of duodenal gastric metaplasia in Helicobacter pylori positive patients with duodenal ulcer disease.

BACKGROUND: It is unclear whether the extent of duodenal gastric metaplasia is due to Helicobacter pylori and/or acid. AIMS: To investigate the role of Helicobacter pylori eradication in the regression of duodenal gastric metaplasia in patients with duodenal ulcer maintained in acid suppression conditions. METHODS:. Duodenal (anterior, superior inferior walls of first part of duodenum) and gastric antrum biopsies were obtained from 44 Helicobacter pylori positive duodenal ulcer patients. Helicobacter pylori infection was diagnosed by rapid urease test, histology and 13C-Urea Breath Test. Patients were treated with 20 mg omeprazole tid associated with 250 mg clarithromycin and 500 mg amoxycillin four times daily for 10 days and maintained with 20 mg omeprazole daily for 18 weeks. Control endoscopies were performed at 6 and 18 weeks after beginning treatment. RESULTS: Duodenal gastric metaplasia regression was observed in all (32/32) patients in whom Helicobacter pylori was eradicated, but in only 3 out of 6 patients in whom eradication was not achieved (p<0. 001). CONCLUSIONS:. The present results suggest that Helicobacter pylori eradication associated with prolonged acid suppression may represent a good therapeutic strategy to achieve duodenal gastric metaplasia regression and highlight the combined role of acid and Helicobacter pylori in the pathogenesis of duodenal gastric metaplasia.     

十二指肠溃疡患者夜间酸突破现象分析

目的探讨十二指肠溃疡患者(DU)的夜间酸突破(NAB)现象及其与幽门螺杆菌(Hp)感染之间的关系.方法十二指肠溃疡患者随机分为五组,每组8例,分别接受A组静脉注射奥美拉唑40 mg,每日2次;B组静脉注射奥美拉唑40 mg,每日1次;C组口服奥美拉唑20 mg,每日2次;D组口服奥美拉唑20 mg,每日1次;E组静脉注射西米替丁600 mg,每日2次.均用药5 d并于第5天早上8时起连续24 h监测其胃内pH值.结果五组患者的平均胃内pH、平均中位pH、夜间平均胃内pH和夜间平均中位pH均有不同程度升高,A组升高明显,显著高于B、D、E组,差异有显著性(P＜0.05);B、D、E组夜间pH＜4.0的时间占夜间监测时间的百分比显著高于A、C组(P＜0.05);五组分别有0例(A组,0%)、4例(B组,50.0%)、1例(C组,12.5%)、4例(D组,50.0%)、3例(E组,37.5%)患者发生NAB;奥美拉唑2次用药组(包括静脉和口服用药组)仅有1例NAB发生(6.3%),显著低于1次用药组(包括静脉和口服用药组,56.3%,P＜0.05);合计18例Hp阴性者中有10例(55.6%)发生NAB,22例Hp阳性者中只有3例(13.6%,P＜0.05).结论 DU患者中,中国人的NAB发生率低,NAB与奥美拉唑剂量、用药方法及Hp感染相关.     

十二指肠溃疡患夜间酸突破现象初探

目的探讨十二指肠溃疡患者的夜间酸突破现象及其与Hp感染之间的关系.方法十二指肠溃疡患者随机分为三组,每组8例,分别接受①每12h一次静注奥美拉唑40mg(静注1组);②每24h一次静注奥美拉唑40mg(静注2组);③每日二次口服奥美拉唑20mg(口服组).均用药5日并于第5天早上7.30时起连续24小时监测其胃内pH值.结果三组的平均胃内pH、平均中位pH、夜间平均胃内pH、和夜间平均中位pH均升高,以静注1组显著高于其它二组静注2组的夜间pH＜4.0的时间占夜间监测时间的百分比(35.7%±40.3%)显著长于口服组(1.5%±1.9%)和静注2组(1.2±2.3)(p＜0.05);静注2组和口服组分别有4例(50.0%)和1例(12.5%)发生NAB,而静注1组无酸突破发生;合计9例Hp阴性中4例(44.4%)发生NAB,15例Hp阳性中只有1例(6.7%)出现NAB(p＜0.05).结论十二指肠溃疡患者中,中国人的NAB发生率低,可能与国人对奥美拉唑高敏感,且Hp感染率高有关.