Xuanfu Daizhe Tang alleviates reflux esophagitis in rats by inhibiting the STAT1/TREM-1 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Reflux esophagitis (RE) is a common chronic inflammatory disease of the esophageal mucosa with a high prevalence and recurrence rate, for which a satisfactory therapeutic strategy is still lacking. Chinese medicine has its characteristics and advantages in treating RE, and the clinical application of Xuanfu Daizhe Tang (XDT) in treating RE has achieved sound therapeutic effects. However, there needs to be more research on its mechanism of action. AIM OF THE STUDY: The present work aimed to investigate the mechanism of XDT action in RE through the Signal Transducer and Activator of Transcription 1 (STAT1)/Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) pathway. MATERIALS AND METHODS: The main active components of XDT were analyzed by ultra-performance liquid chromatography-mass spectrometer (UPLC-MS). The effect of XDT on RE was evaluated in a rat model of RE induced by "Cardioplasty + pyloric ligation + Roux-en-Y esophagojejunostomy". Each administration group was treated by gavage. The degree of damage to the esophageal mucosa was evaluated by visual observation, and the Potential of Hydrogen (PH) method and Hematoxylin-eosin staining (HE) staining were performed. Serum levels of Interleukin-1ß (IL-1ß), Interleukin-6 (IL-6), Tumor Necrosis Factor alpha (TNF-α), and Inducible Nitric Oxide Synthase (iNOS) were measured by ELISA. Quantitative Real-time PCR (qPCR), Western Blot (WB), and Immunofluorescence (IF) methods were used to detect Claudin-4, Claudin-5, TREM-1, and p-STAT1 in esophageal tissues for studying the mechanism of action and signaling pathway of XDT. Immunohistochemistry (IHC) analysis was used to detect the expression of TREM-1 and CD68 in esophageal tissues. Flow Cytometry (FC) was used to detect the polarization of macrophages in the blood. After conducting preliminary experiments to verify our hypothesis, we performed molecular docking between the active component of XDT and STAT1 derived from rats and parallel experiments with STAT1 inhibitor. The selective increaser of STAT1 transcription (2-NP) group was used to validate the mechanism by which XDT acts. RESULTS: XDT alleviated esophageal injury and attenuated histopathological changes in RE rats. XDT also inhibited the inflammatory response and decreased serum IL-1ß, IL-6, TNF-α, and iNOS levels in RE rats. qPCR and WB results revealed that XDT inhibited the expression of Claudin-4, Claudin-5, TREM-1, and STAT1 in the esophageal mucosa of RE rats. IHC and FC results showed that XDT reduced TREM-1 levels in esophageal tissues and polarized macrophages toward M2. The molecular docking results showed that rat-derived STAT1 can strongly bind to Isochronogenic acid A in XDT. The parallel experimental results of STAT1 inhibitor showed that XDT has anti-inflammatory effects similar to STAT1 inhibitors. The 2-NP group confirmed that XDT exerts its therapeutic effect on reflux esophagitis through the STAT1/TREM-1 pathway, with STAT1 as the upstream protein. CONCLUSIONS: This study suggests that XDT may treat reflux esophagitis by modulating the STAT1/TREM-1 pathway.

Elevated Pro-inflammatory Cytokine Levels in Acute Reflux Esophagitis Are Reduced by 1,25 Dihydroxy Vitamin D3.

BACKGROUND/AIM: Gastric acid reflux into the esophagus can cause irritation and inflammation of the esophagus and progress to reflux esophagitis (RE). Vitamin D3 (VitD3) has anti-inflammatory effects and plays an important regulatory role in adaptive and innate immunity. We hypothesized that VitD3 may play a protective role in RE. MATERIALS AND METHODS: Seventy male Sprague-Dawley rats were used, and acute RE (n=35) or chronic RE (n=35) were surgically induced. The effects of different doses of VitD3 on morphological changes and alteration of pro-inflammatory cytokine levels were examined in the rat models. Western blot analysis was performed to determine protein expression levels of IL-1ß, IL-6, and IL-8 in esophageal tissues. Serum levels of VitD3 and calcium were determined using enzyme-linked immunosorbent assays. RESULTS: The protein expression of pro-inflammatory cytokines IL-1ß, IL-6, and IL-8 was found significantly increased in RE. VitD3 treatment significantly reduced the levels of these pro-inflammatory cytokines in both the low-dose and high-dose VitD3 groups compared to control groups in acute RE, but not chronic RE. Macrographic and histopathological examination revealed various degrees of esophageal impairment in rats following surgical induction of acute or chronic RE in rats. These impairments were not improved by VitD3. Morphological grading of esophageal mucosa showed no significant differences between acute and chronic RE. Elevated serum levels of calcium were observed after VitD3 treatment. CONCLUSION: IL-1ß, IL-6, and IL-8 levels were significantly elevated in RE. The abnormal increase in these important pro-inflammatory cytokines was suppressed by VitD3 in the rat models of acute RE. These novel findings suggest a potential protective role of VitD3 in early-stage RE.

Protective Effects of Inflammation of Curcumae Longae Rhizoma 30% EtOH Extract on Acute Reflux Esophagitis Rats.

Gastroesophageal reflux disease (GERD) is induced by the reflux of stomach contents or gastric acid, pepsin into the esophagus for prolonged periods of time due to defection of the lower esophageal sphincter. Reflux esophagitis is a disease found in less than 50% of GERD patients. This study is aimed at evaluating the protective effect of Curcumae longae Rhizoma 30% EtOH extract (CLR) in acute reflux esophagitis (ARE) rats. CLR measured antioxidant activity through in vitro experiments. Based on the results, we performed experiments in vivo. Before 90 min ARE induction, CLR was administered orally by concentration. ARE was derived by linking the metastatic junction between pylorus and forestomach and corpus in Sprague-Dawley rats. And rats were sacrificed 5 h after surgery. We analyzed the expression of antioxidant and inflammatory-related markers by western blot and observed the production of alanine aminotransferase (ALT), aspartate aminotransferase (AST), reactive oxygen species (ROS), peroxynitrite (ONOO-), and thiobarbituric acid reactive substance (TBARS). The administration of CLR reduced esophagus tissue damage in rats with acute reflux esophagitis and decreased the elevated ALT, AST, ROS, ONOO-, and TBARS. In addition, CLR effectively increased antioxidant-related factors and reduced inflammatory protein. Overall, these results suggest that CLR would be used as a therapeutic material in protection and treatment for ARE. Overall, CLR treatment informed that markedly ameliorated inactivation of NF-κB led to the inhibition of the expressions of proinflammatory proteins. These results suggest that CLR would be used as a therapeutic material in protection and treatment for ARE.

Improvement of Inflammation through Antioxidant Pathway of Gardeniae Fructus 50% EtOH Extract (GE) from Acute Reflux Esophagitis Rats.

Gardeniae Fructus 50% EtOH extract (GE) is a traditional herb that has been used to treat a variety of diseases. In this study, we investigate the antioxidant, anti-inflammatory, and antiapoptotic properties of GE on acute reflux-induced esophagitis (RE) model in rats. 2,2'-Azino-bis (3-ethylbenzothiazolin-6-sulfonic acid) (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assays were performed to determine the antioxidant activity of GE. GE was given orally at 50 and 100 mg/kg body weight 1h 30 min prior to RE induction. And its effect was assessed in comparison with RE control and normal groups. The administration of the extract of the GE showed remarkable protection of mucosal damage in esophageal tissue, and the histologic observation showed that the gastric lesion was improved. Increased reactive oxygen species (ROS) levels in the serum were diminished by GE treatment. The antioxidative biomarkers including nuclear factor-erythroid 2-related factor 2 (Nrf-2), heme oxygenase-1 (HO-1), superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX) were significantly increased. GE administration significantly reduced the inflammatory protein expression through MAPK-related signaling pathways and the nuclear factor-kappa B (NF-κB) pathway. These results suggest that GE protects the esophagus mucosal membrane by attenuating oxidative stress and inflammatory response under reflux esophagitis condition through the antioxidant pathway. Therefore, it is suggested that GE may be a potential remedy for the treatment of reflux esophagitis.

Dichloromethane Extracts of Geranium Koreanum Kom. Alleviates Esophagus Damage in Acute Reflux Esophagitis-Induced Rats by Anti-Inflammatory Activities.

Reflux esophagitis (RE) is a gastrointestinal disease caused by the reflux of gastric acid and stomach contents, and it leads to esophageal damage. Therefore, it is necessary to study the improvement of esophageal damage on a RE-induced model. The present study was accomplished to demonstrate the protective effects of a dichloromethane fraction of Geranium koreanum (DGK) plant on esophageal damage in an acute RE rat model. First, we examined the potential of anti-inflammatory effects of various fractions measured by cell cytotoxicity, morphological changes and nitric oxide (NO) production on lipopolysaccharide (LPS)-induced Raw 264.7 macrophage cells. Then, to evaluate the protective effects on RE, rats were partitioned into the following groups: normal control, RE-induced control and RE rats pre-treated with DGK 100 and 200 mg/kg body weight. The esophageal mucosal ulcer ratio was measured by the Image J program and histological changes were examined using a hematoxylin and eosin staining of the esophageal mucosa. The expression of pro-inflammatory proteins, cytokines and tight junction proteins involved in the esophageal mucosal damage were investigated using Western blotting and an enzyme-linked immunosorbent assay (ELISA) kit with esophagus tissue. DGK chemical profile and phenolic contents were analyzed by liquid chromatography-mass spectrometry (LC-MS/MS). The results showed that DGK exhibited anti-inflammatory effects against LPS-stimulated cells by significantly inhibiting NO production. Additionally, the results in vivo showed that improvement effects of DGK on esophageal mucosal damage. The expression of inflammatory proteins involved in nuclear factor κB (NF-κB) signaling pathways and tight junction protein (claudin-4 and -5) were significantly decreased in esophageal mucosa. We found the potential of DGK as source of replacement therapy products for inflammatory and RE disease.

Estrogen-Dependent Nrf2 Expression Protects Against Reflux-Induced Esophagitis.

BACKGROUND: Gastroesophageal reflux disease is more common in males than in females. The enhanced antioxidative capacity of estrogen in females might account for the gender difference. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a pivotal role in the host defense mechanism against oxidative stress. AIMS: This study aimed to clarify the role of Nrf2 in reflux-induced esophageal inflammation, focusing on the gender difference and nitric oxide. METHODS: Gastroesophageal reflux was surgically induced in male and female rats. Nitrite and ascorbic acid were administered for 1 week to provoke nitric oxide in the esophageal lumen. Male rats with gastroesophageal reflux were supplemented with 17ß-estradiol or tert-butylhydroquinone, an Nrf2-inducing reagent. Esophageal squamous cell carcinoma KYSE30 cells were treated with 17ß-estradiol. Nrf2 expression was examined by Western blotting and quantitative real-time PCR. Antioxidant gene expression profiles were examined by a PCR array. RESULTS: In the presence of nitric oxide, reflux-induced esophageal damage was less evident, whereas esophageal expression of Nrf2 and its target genes such as Nqo1 was more evident in female or male rats supplemented with 17ß-estradiol than in male rats. 17ß-Estradiol increased nuclear Nrf2 expression in KYSE30 cells. tert-Butylhydroquinone increased tissue Nqo1 mRNA expression, leading to a reduction in reflux-induced esophageal damage. CONCLUSIONS: Estrogen-dependent Nrf2 expression might contribute to protection against the development of gastroesophageal reflux disease in females.

Anti-apoptotic effect of banhasasim-tang on chronic acid reflux esophagitis.

AIM: To evaluate the anti-apoptotic effect of banhasasim-tang (BHSST) on chronic acid reflux esophagitis (CARE) using a rat model. METHODS: A surgically-induced CARE model was established in Sprague-Dawley rats. The modeled rats were divided into a treatment group or untreated group, and given BHSST (1 g/kg body weight per day) or water, respectively, for 15 consecutive days (n = 7 each group). Changes in expression of proteins related to nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and apoptosis were assessed by western blotting. Changes in esophageal pathology were analyzed by gross and histological examinations. RESULTS: The CARE exposure modeled rats showed increased levels of the NADPH oxidase subunit, NOX4 and p47phox in the esophagus. The BHSST treatment completely resolved these CARE-related increases. The CARE rats also showed markers of cytokine stress, including elevated levels of TNF-α and reactive oxygen species as well as of the consequent increase in JNK activation, and subsequent decrease in pro-survival gene expression, such as of Bcl-2. BHSST treatment resolved the CARE-related changes. BHSST also exerted an anti-apoptotic effect, as evidenced by altered expression of the apoptosis-related genes for bax, cytochrome c, and caspase 3. Finally, the BHSST treatment markedly ameliorated the CARE-related esophageal mucosal ulcerations. CONCLUSION: In the rat model of CARE, BHSST can suppress development of esophageal mucosal ulceration via regulation of reactive oxygen species-dependent apoptosis.

The effect of n-3/n-6 polyunsaturated fatty acids on acute reflux esophagitis in rats.

BACKGROUND: Polyunsaturated fatty acids (PUFAs) play various roles in inflammation. However, the effect of PUFAs in the development of reflux esophagitis (RE) is unclear. This study is to investigate the potential effect of n-3/n-6 PUFAs on acute RE in rats along with the underlying protective mechanisms. METHODS: Forty Sprague Dawley rats were randomly divided into four groups (n = 10 in each group). RE model was established by pyloric clip and section ligation. Fish oil- and soybean oil-based fatty emulsion (n-3 and n-6 groups), or normal saline (control and sham operation groups) was injected intraperitoneally 2 h prior to surgery and 24 h postoperatively (2 mL/kg, respectively). The expressions of interleukin (IL)-1ß, IL-8, IL-6 and myeloid differentiation primary response gene 88 (MyD88) in esophageal tissues were evaluated by Western blot and immunohistochemistry after 72 h. The malondialdehyde (MDA) and superoxide dismutase (SOD) expression in the esophageal tissues were determined to assess the oxidative stress. RESULTS: The mildest macroscopic/microscopic esophagitis was found in the n-3 group (P < 0.05). The expression of IL-1ß, IL-8, IL-6 and MyD88 were increased in all RE groups, while the lowest and highest expression were found in n-3 and n-6 group, respectively (P < 0.05). The MDA levels were increased in all groups (P < 0.05), in an ascending trend from n-3, n-6 groups to control group. The lowest and highest SOD levels were found in the control and n-3 group, respectively (P < 0.05). CONCLUSION: n-3 PUFAs may reduce acute RE in rats, which may be due to inhibition of the MyD88-NF-kB pathway and limit oxidative damage.

Protective effect of Rhei Rhizoma on reflux esophagitis in rats via Nrf2-mediated inhibition of NF-κB signaling pathway.

BACKGROUND: Rhei Rhizoma has been widely used as a traditional herbal medicine to treat various inflammatory diseases. The present study was conducted to evaluate its anti-inflammatory activity against experimental reflux-induced esophagitis (RE) in SD rats. METHODS: Rhei Rhizoma was administered at 125 or 250 mg/kg body weight per day for 7 days prior to the induction of reflux esophagitis, and its effect was compared with RE control and normal rats. RESULTS: Rhei Rhizoma administration markedly ameliorated mucosal damage on histological evaluation. The elevated reactive oxygen species in the esophageal tissue of RE control rats decreased with the administration of Rhei Rhizoma. RE control rats exhibited the down-regulation of antioxidant-related proteins, such as nuclear factor-erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression levels, in the presence of esophagitis; however, the levels with Rhei Rhizoma treatment were significantly higher than those in RE control rats. Moreover, RE control rats exhibited the up-regulation of protein expressions related to oxidative stress in the presence of esophagitis, but Rhei Rhizoma administration significantly reduced the expression of inflammatory proteins through mitogen-activated protein kinase (MAPK)-related signaling pathways. The protein expressions of inflammatory mediators and cytokines by nuclear factor-kappa B (NF-κB) activation were modulated through blocking the phosphorylation of inhibitor of nuclear factor kappa B (IκB)α. CONCLUSION: Our findings support the therapeutic evidence for Rhei Rhizoma ameliorating the development of esophagitis via regulating inflammation through the activation of the antioxidant pathway.

Effect of freeze-dried berries on the development of reflux-induced esophageal adenocarcinoma.

The incidence of esophageal adenocarcinoma in humans is increasing more rapidly than any other malignancy in the United States. Animal studies have demonstrated the efficacy of freeze-dried berry supplementation on carcinogen-induced esophageal squamous cell carcinoma in rats; however, no such studies have been done in esophagoduodenal anastomosis (EDA), an animal model for reflux-induced esophageal adenocarcinoma (EAC) development. Eight-week-old male Sprague-Dawley rats were randomized into 3 groups: EDA + control diet (EDA-CD; n = 10); EDA + 2.5% black raspberry diet (EDA-BRB; n = 11) and EDA + 2.5% blueberry diet (EDA-BB; n = 12). After 2 wk of feeding the respective diets, the rats underwent EDA surgery to induce gastroesophageal reflux and then continued the diet. Measurement of feed intake suggested that all EDA-operated animals had lower feed intake starting at 10 wk after surgery and this was significant close to termination at 24 wk. There were no significant differences in either reflux esophagitis (RE), intestinal metaplasia (IM) (70% in CD, 64% in BRB, and 66% in BB; P = 0.1) or EAC incidence (30% for CD, 34% for BRB, and 25% for BB; P = 0.2) with supplementation. Berry diets did not alter COX-2 levels, but BB diet significantly reduced MnSOD levels (1.23 ± 0.2) compared to control diet (2.05 ± 0.14; P < 0.05). We conclude that a dietary supplementation of freeze-dried BRB and BB at 2.5% (w/w) was not effective in the prevention of reflux-induced esophageal adenocarcinoma in this EDA animal model.

Dietary freeze-dried black raspberry's effect on cellular antioxidant status during reflux-induced esophagitis in rats.

INTRODUCTION: Esophageal cancer consists of two distinct types, esophageal adenocarcinoma (EAC) and squamous cell carcinoma, both of which differ significantly in their etiology. Freeze-dried black raspberry (BRB) has been consistent in its ability to modulate the biomarkers and reduce the incidence of carcinogen-induced squamous cell carcinoma in rats. In our previous studies in the esophagoduodenal anastomosis (EDA) model, we have shown that the early modulation of manganese superoxide dismutase (MnSOD) significantly correlates with the development of reflux-induced EAC in rats. In this study we looked at the short-term effects of a BRB-supplemented diet on the modulation of antioxidant enzymes in reflux-induced esophagitis. METHODS: Male SD rats (8 wk old; n = 3-5) were randomized into three groups--sham-operated, fed control AIN-93M diet (SH-CD), EDA operated and fed either control diet (EDA-CD) or 2.5% (w/w) BRB diet (EDA-BRB). The effect of both reflux and dietary supplementation was analyzed 2 and 4 wk after EDA surgery. RESULTS: Animals in the EDA groups had significantly lower weight gain and diet intake compared to SH-CD (P < 0.05). The sham-operated animals received an average esophagitis score of 0.1 ± 0.1; this increased significantly in EDA-CD animals to 1.8 ± 0.14 (P < 0.001 versus SH-CD) and in EDA-BRB group to 1.7 ± 0.06 (P < 0.001 versus SH-CD), with BE changes also present. However, dietary supplementation of BRB did not alter or ameliorate the grade of esophagitis or the induction of BE. BRB diet caused a 43% increase in MnSOD levels compared to EDA-CD (0.73 ± 0.16; P = 0.09); however, this effect was not statistically significant and at 4 wk, EDA-CD (0.58 ± 0.12) showed an increase in MnSOD expression compared to SH-CD (0.34 ± 0.01). CONCLUSIONS: In conclusion, our data suggest that dietary BRB does not increase the levels of cellular antioxidant enzymes or reduce the levels of lipid peroxidation compared to a control diet, in a short-term study of gastroesophageal reflux induction in the EDA animal model. However, it remains to be tested whether this is indicative of its ineffectiveness to inhibit reflux-induced EAC incidence over the long term.

[Clinical observation on acupuncture for treatment of reflux esophagitis of heat stagnation of liver and stomach type].

OBJECTIVE: To observe the clinical therapeutic effect of acupuncture for treatment of reflux esophagitis of heat stagnation of liver and stomach type. METHODS: Sixty-one cases were randomly divided into an acupuncture group (31 cases) and a medication group (30 cases). The acupuncture group was treated with needles at Zusanli (ST 36), Zhongwan (CV 12), Weishu (BL 21) and Neiguan (PC 6) mainly, once a day; and the medication group was treated with oral administration of 20 mg Omeprazole, once a day. The scores of clincial symptoms, comprehensive therapeutic effect, results of gastroscopy and pathology as well as recurrence rate etc. were observed before and after treatment. RESULTS: After treatment, the scores of symptoms significantly decreased in the two groups (both P < 0.01). The total effective rate of the acupuncture group was 90.3% (28/31), and 90.0% (27/30 )in the medication group, there was no statistical difference between two groups (P > 0.05); results of gastroscopy and esophageal mucosa pathology showed no statistical difference between two groups (both P > 0.05), the recurrence rate 12 weeks after treatment of 9.1% in the acupuncture group was lower than that of 42.9% in the medication grou p (P < 0.05). CONCLUSION: Acupuncture has preferable short and long-term therapeutic effects for treatment of reflux esophagitis of heat stagnation of liver and stomach type.

Rikkunshito, a traditional Japanese medicine, may relieve abdominal symptoms in rats with experimental esophagitis by improving the barrier function of epithelial cells in esophageal mucosa.

BACKGROUND: A traditional Japanese medicine, rikkunshito, has been reported to relieve dyspepsia symptoms. We investigated the effect of rikkunshito on RE-induced abdominal dyspepsia, and performed experiments to elucidate the mechanism of that effect. METHODS: RE model rats were prepared using 8-week-old male Wistar rats, and rikkunshito was administered in drinking water. Voluntary movement was used as an index of RE-induced abdominal dyspepsia, which was monitored by an infrared sensor. On the tenth day after surgery, the total area of esophageal erosion was measured, and samples of nonerosive mucosa were collected. Using those samples, intercellular spaces of epithelial mucosa were examined by transmission electron microscopy, and the NP-40-soluble and -insoluble levels of the tight junction proteins claudin-1, -3 and -4 and their mRNAs were determined. RESULTS: Rikkunshito did not reduce the average total area of erosive lesions in the esophageal mucosa of RE model rats. On day 10, voluntary movement was significantly decreased in the RE model rats and rikkunshito significantly increased it. Nonerosive esophageal mucosa from RE rats showed dilation of intercellular spaces in epithelium, and significantly decreased claudin-3 mRNA and protein levels. Rikkunshito significantly suppressed intercellular space dilation and significantly increased the level of NP-40-insoluble claudin-3, but it did not affect the mRNA level, suggesting that it promoted tight junction formation by facilitating the translocation of proteins. CONCLUSION: Rikkunshito increased voluntary movement in RE model rats. This may have been because rikkunshito ameliorated the symptoms of RE by improving the barrier function of esophageal mucosa.

[Optimal extraction of Dingxiang jiangqi granules].

OBJECTIVE: To screen and optimize the extraction of Dingxiangjiangqi granules. METHOD: The extraction route was screened by using pharmacodynamic experiment and the extraction conditions were optimized by orthogonal design and taking extract yield, content of naringin and tetrahydropalmatine as indexes. RESULT: The pharmacodynamic result showed that aqueous extract had the best effect to cure the esophagitis of rats and the optimized extraction technique was adding 12 times water, extracting 0. 5 hour for 3 times. CONCLUSION: The optimum extraction was simple, reasonable, stable and useful for further development.

[Assessment on effects of tongjiang granule on experimental reflux esophagitis in rats].

OBJECTIVE: To study the effects of tongjiang granule (TJG) on reflux esophagitis (RE) in rats. METHODS: Two rat models of RE were established respectively by cardioplasty + pyloric ligation + Roux-en-Y gastro-jejunum anastomosis and by placed a fixed steel ring into the gastric cardia, and the model rats were treated with various dosages of TJG or cisapride by gastric perfusion. RESULTS: Rat models were established successfully by both methods. The score of pathological changes of esophagus mucosa in the model rats, made by either method, after high-dosage TJG treatment was lower than that in the model rats (P < 0.05), but equal to that in the cisapride treated model rats. High and moderate dosages of TJG were shown by transmission electron microscope to have effects of alleviating heckle cells and inflammatory reaction. They could reduce the level of gastric acid, more significant in high and moderate dosage groups (P < 0.05), while cisapride couldn't. CONCLUSION: TJG is effective in treating experimental RE in rats to a certain extent.

Protective effect of lafutidine, a novel H2-receptor antagonist, on reflux esophagitis in rats through capsaicin-sensitive afferent neurons.

We examined the effect of lafutidine, a novel histamine H(2)-receptor antagonist, on acid reflux esophagitis in rats in relation to capsaicin-sensitive afferent neurons. The esophagitis was induced in rats by ligating both the pylorus and forestomach for 4 h. Lafutidine (1 - 30 mg/kg) and cimetidine (100 mg/kg) were administered either intragastrically or intraduodenally, while capsaicin (1 - 30 mg/kg) was administered intragastrically after the dual ligation. Intragastrical administered lafutidine at >3 mg/kg significantly prevented the hemorrhagic esophageal damage induced by the dual ligation, and this effect was mimicked by neither capsaicin nor cimetidine given intragastrically, but totally abolished by sensory deafferentation. In contrast, lafutidine and cimetidine given intraduodenally were both protective against the esophageal damage in a sensory deafferentation-resistant manner. The acid secretion in pylorus-ligated stomachs was significantly inhibited by these agents given intraduodenally, but not intragastrically. Vanilloid receptor subtype 1 (VR1) was expressed abundantly in the stomach, but very weakly expressed in the esophagus as assessed by Western blotting. These results suggest that lafutidine is effective against the esophageal lesions induced by acid reflux through inhibition of acid secretion and capsaicin-sensitive afferent neurons. The latter mechanism, not shared by cimetidine, may be due to the interaction of lafutidine with unidentified sites on sensory neurons other than VR1.

[Complementary observational study of the efficacy, tolerance and safety of lansoprazole 15 mg as maintenance therapy of reflux esophagitis in daily medical practice in Belgium (record RU49749/R002]. / Etude casuistique complémentaire de l'efficacité, la tolérance et la sécurité du lansoprazole 15 mg dans le traitement d'entretien de l'oesophagite de reflux en pratique médicale quotidienne en Belgique (record RU49749/R002).

Gastroesophageal reflux disease is a frequent illness with important implications on quality of life. In order to evaluate in a general population the efficacy and safety of lansoprazole 15 mg in maintenance therapy of reflux oesophagitis in current medical practice, an open label observational study was conducted in Belgium. 1.709 patients were included by 429 general practitioners during 3 to 6 months from 1997 to 1999. At the end of the study, symptoms improved or disappeared in 88% of patients. No drug related severe adverse event was reported. This study confirmed that lansoprazole 15 mg is effective and safe in maintenance treatment of reflux oesophagitis.

Oxidative damages are critical in pathogenesis of reflux esophagitis: implication of antioxidants in its treatment.

BACKGROUND: The facts that the severity of reflux esophagitis cannot be accurately predicted on the basis of acid exposure and acid suppression treatment is not enough for the complete healing, suggested that other damaging factors might be involved in pathogenesis of reflux esophagitis. AIMS: The present study was designed to evaluate the oxidative stress as the major pathogenic factor of reflux esophagitis and the importance of antioxidant in treatment of reflux esophagitis. MATERIALS AND METHODS: Reflux esophagitis was induced by the insertion of small caliber ring (3 mm in diameter) into the duodenum 1 cm distal to the ligament of Treitz in rats. RESULTS: DA-9601, a novel antioxidant substance, attenuated the gross esophagitis significantly compared to that treated with ranitidine, histamine-2 receptor antagonist (H2-RA), in a dose-dependent manner. Severe, hemorrhagic, and longitudinal ulcerations were developed in H2-RA pretreated group, whereas mildly scattered erosions were observed in antioxidant-pretreated group. Significantly increased amounts of malondialdehyde (MDA), increased NF-kappaB activation, and the mucosal depletion of reduced glutathione (GSH) were observed in the esophagus of reflux esophagitis. H2-RA treatment didn't affect the levels of GSH and MDA, whereas DA-9601 attenuated the decrement of the GSH levels and significantly decreased lipid peroxides in the esophagus. Antioxidants treatment showed significant reductions in the activation of NF-kappaB, inflammation-associated transcription factor, especially p50 component in accordance with significant higher levels of NF-kappaB repressor, IkappaBalpha expression. CONCLUSION: Oxygen-derived free radicals seem to be one of the important mediators in generation of reflux esophagitis, which suggests that the combination of antioxidant and anti-secretory medications will be ideal and more beneficial in the prevention and treatment of reflux esophagitis than currently prescribed antisecretory treatment alone.

Lansoprazole versus ranitidine in the maintenance treatment of reflux oesophagitis.

AIMS: To assess the relative efficacies of lansoprazole 15 mg once daily, lansoprazole 30 mg once daily and ranitidine 300 mg b.d. in the maintenance treatment of reflux oesophagitis for 12 months. METHODS: Multicentre, out-patient, double-blind, parallel group, prospectively randomized clinical trial. Patients with grade 0, asymptomatic oesophagitis after 8 weeks of treatment with lansoprazole 30 mg once daily were randomized to receive lansoprazole 30 mg once daily (L30) (n = 75), lansoprazole 15 mg once daily (L15) (n = 86) or ranitidine 300 mg b.d. (R600) (n = 74) for 12 months. Endoscopy was repeated at 6 and 12 months, and symptomatic assessment was made every 3 months. Efficacy was primarily assessed by the time to endoscopically confirmed relapse (oesophagitis grade > or = 1) and the proportion of patients who relapsed during the 12-month study period. Severity of symptoms were secondary efficacy measures. RESULTS: For all patients randomized with at least one post-baseline endoscopy (intent-to-treat principle) both lansoprazole 15 mg (P < 0.001) and lansoprazole 30 mg (P < 0.001) were significantly superior to ranitidine 600 mg with respect to time to endoscopic relapse. There was no difference between the lansoprazole groups (P = 0.11). There was evidence of relapse in 27 of 86 (31.4%), 15 of 75 (20.0%) and 50 of 74 (67.6%) of the patients treated with lansoprazole 15 mg and 30 mg and ranitidine 600 mg, respectively. Patients receiving treatment with either lansoprazole dosages experienced significantly less severe heartburn and regurgitation than those patients treated with ranitidine. There were no differences between the treatment groups with respect to the severity or incidence of adverse events. No clinically significant laboratory changes were observed in any of the treatment groups. Serum gastrin levels were elevated in all treatment groups, and most markedly in those patients receiving lansoprazole, but there was no significant difference between the treatments. Morphological and immunohistochemical examination of the gastric biopsies revealed no clinically relevant changes from baseline in any of the treatment groups. CONCLUSION: Both lansoprazole 15 mg and lansoprazole 30 mg once daily are significantly more effective than high-dose ranitidine in maintaining reflux oesophagitis in remission.

Esophagitis in Sprague-Dawley rats is mediated by free radicals.

Free radical-mediated esophagitis was studied during duodenogastroesophageal reflux (mixed reflux) or acid reflux in rats. The influence of reflux on esophageal glutathione levels was also examined. Mixed reflux caused more gross mucosal injury than acid reflux. Gross mucosal injury occurred in the mid-esophagus. Total glutathione (GSH) in the esophageal mucosa of control rats was highest in the distal esophagus. The time course of esophageal GSH in rats treated by mixed reflux showed a significant decrease 4 hr after initiation of reflux, followed by a significant increase from the 12th hour on. Mucosal GSH was increased in both reflux groups after 24 hr but significantly more so in the mixed than in the acid reflux group. The free radical scavenger superoxide dismutase (SOD) prevented esophagitis and was associated with decreased GSH levels. GSH depletion by buthionine sulfoximine (BSO) prevented esophagitis and stimulated SOD production in the esophageal mucosa. It is concluded that gastroesophageal reflux is associated with oxidative stress in the esophageal mucosa. The lower GSH levels in the mid-esophagus may predispose to damage in this area. Duodenogastroesophageal reflux causes more damage than pure acid reflux. Oxidative stress leads to GSH depletion of the esophageal mucosa in the first few hours following damage but then stimulates GSH production. GSH depletion by BSO does not worsen esophagitis since it increases the esophageal SOD concentration.