Pathophysiology of reflux oesophagitis: role of Toll-like receptors 2 and 4 and Farnesoid X receptor.

The pathogenesis of gastroesophageal reflux disease (GERD) is not fully understood. It involves the activation of mucosal immune-mediated and inflammatory responses. Toll-like receptors (TLR) 2 and TLR4 are pattern-recognition receptors of the innate immune system; they recognize microbial and endogenous ligands. Farnesoid X receptor (FXR) is a bile acid receptor that regulates the inflammatory response. We aimed to evaluate TLR2, TLR4 and FXR expression patterns in GERD. We re-evaluated 84 oesophageal biopsy samples according to the global severity (GS) score, including 26 cases with histologically normal oesophagus, 28 with histologically mild oesophagitis and 30 with severe oesophagitis. We used immunohistochemistry and in situ hybridization to assess the expression patterns of TLR2, TLR4 and FXR in oesophageal squamous cells. Immunohistochemistry showed that nuclear and cytoplasmic TLR2 was expressed predominantly in the basal layer of normal oesophageal epithelium. In oesophagitis, TLR2 expression increased throughout the epithelium, and the superficial expression was significantly more intensive compared to normal epithelium, p <0.01. Nuclear and cytoplasmic TLR4 was expressed throughout the thickness of squamous epithelium, with no change in oesophagitis. FXR was expressed in the nuclei of squamous cells, and the intensity of the expression increased significantly in oesophagitis (p <0.05). FXR expression correlated with basal TLR2. In situ hybridization confirmed the immunohistochemical expression patterns of TLR2 and TLR4. In GERD, TLR2, but not TLR4, expression was upregulated which indicates that innate immunity is activated according to a specific pattern in GERD. FXR expression was increased in GERD and might have a regulatory connection to TLR2.

Leptin Aggravates Reflux Esophagitis by Increasing Tissue Levels of Macrophage Migration Inhibitory Factor in Rats.

Leptin, produced primarily by the adipose tissue, acts as a pro-inflammatory modulator, thereby contributing to the development of obesity-related disease. Although high levels of leptin in the obese are closely related to gastroesophageal reflux disease, the mechanism by which leptin influences esophageal inflammation remains unknown. Macrophage migration inhibitory factor (MIF) is produced by immune cells, such as T lymphocytes and macrophages, and MIF is known to induce the production of tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß) and interleukin 6 (IL-6). We therefore investigated the mechanism whereby leptin aggravates reflux esophagitis, by focusing on esophageal tissue levels of MIF and CD3+ T lymphocytes, both of which are crucial for the reflux-induced epithelial damage. Esophageal inflammation was surgically induced in male Wistar rats by ligating the forestomach and narrowing the duodenum to facilitate gastroesophageal reflux, followed by administration of leptin or vehicle with an osmotic pump system for 1 week. We demonstrated that the administration of leptin exacerbated the reflux esophagitis with the apparent infiltration of CD3+ T lymphocytes and caused the significant increase in the esophageal tissue levels of MIF. Moreover, the leptin caused increases in the esophageal tissue levels of TNF-α, IL-1ß and IL-6, downstream targets of MIF. Importantly, the increases in these pro-inflammatory cytokines were accompanied by increased protein levels of phospho-STAT3 and phospho-AKT, pivotal molecules of leptin signaling pathways. In conclusion, through enhancing the MIF-induced inflammatory signaling, leptin could contribute to the development of gastroesophageal reflux disease.

A new paradigm for GERD pathogenesis. Not acid injury, but cytokine-mediated inflammation driven by HIF-2α: a potential role for targeting HIF-2α to prevent and treat reflux esophagitis.

Traditionally, reflux esophagitis was assumed to develop as a caustic, chemical injury inflicted by refluxed acid. Recently, however, studies in rats and humans suggest that reflux esophagitis develops as a cytokine-mediated inflammatory injury, with hypoxia inducible factor (HIF)-2α playing a major role. In response to the reflux of acid and bile, HIF-2α in esophageal epithelial cells becomes stabilized, thereby increasing production of pro-inflammatory cytokines that attract T lymphocytes and other inflammatory cells to damage the esophagus. Recent studies have identified small molecule inhibitors of HIF-2α that demonstrate exquisite isoform selectivity, and clinical trials for treatment of HIF-2α-driven kidney cancers are ongoing. It is conceivable that a HIF-2α-directed therapy might be a novel approach to prevention and treatment of reflux esophagitis.

Decreased n-6/n-3 polyunsaturated fatty acid ratio reduces chronic reflux esophagitis in rats.

AIM: To investigate the effect of dietary ratio of n-6/n-3 PUFAs on chronic reflux esophagitis (RE) and lipid peroxidation. METHOD: Rat RE model were established and then fed on a diet contained different n-6/n-3 PUFA ratios (1:1.5, 5:1, 10:1) or received pure n-6 PUFA diet for 14 days. Esophageal pathological changes were evaluated using macroscopic examination and hematoxyline-eosin staining. IL-1ß, IL-8, and TNFα mRNA and protein levels of were determined using RT-PCR and Western blotting, respectively. Malondialdehyde (MDA) and superoxide dismutase (SOD) levels were determined using ELISA. RESULTS: The severity of esophagitis was lowest in the PUFA(1:1.5) group (P<0.05). IL-1ß, IL-8, and TNFα mRNA and protein and MDA levels were significantly increased in model groups with the increasing n-6/n-3 PUFA ratios. SOD levels were significantly decreased in all RE PUFA groups (P<0.05). CONCLUSION: Esophageal injury and lipid peroxidation appeared to be ameliorated by increased n-3 PUFAs intake.

Impact of the inflammatory microenvironment on T-cell phenotype in the progression from reflux oesophagitis to Barrett oesophagus and oesophageal adenocarcinoma.

The incidence of oesophageal adenocarcinoma (OAC), arising from reflux-induced Barrett oesophagus (BO), is increasing dramatically. T-cells have recently been implicated in the initiation of oesophagitis; however, their role in the progression from oesophagitis to BO and OAC has not been fully elucidated. Previous studies have examined the secreted cytokines from oesophageal tissue during disease progression but this study is the first to examine the activation phenotype and the inflammatory profile of CD4(+) and CD8(+) T-cells in human oesophagitis, BO and OAC tissue. Results demonstrated significantly higher levels of IL-4 producing CD4(+) T-cells and secreted levels of IL-6, confirming a Th2 phenotype in BO. In OAC tissue, both pro- and anti-inflammatory cytokines were secreted, with significantly higher levels of IL-6, IL-1ß, TNF-α, IFN-γ, IL-2 and IL-10 compared with normal oesophageal tissue. In addition, CD4(+) T-cells infiltrating OAC tissue displayed a decreased activation profile, with significantly lower CD45RO and CD69 expression compared with normal tissue. Data from this study suggest that factors in the tissue microenvironment may alter T-cell phenotype and function early during oesophageal disease progression and may represent targets for immune intervention.

Epithelial-derived nuclear IL-33 aggravates inflammation in the pathogenesis of reflux esophagitis.

BACKGROUND: IL-33 is a new tissue-derived cytokine constitutively expressed in epithelial cells and plays a role in sensing damage caused by inflammatory diseases. The function of IL-33 in the esophageal mucosa has not been previously described. Accordingly, we examined the expression of IL-33 and its role in the pathogenesis of reflux esophagitis (RE). METHODS: IL-33 in the esophageal mucosa of RE patients and in an in vitro stratified normal esophageal squamous epithelial model was examined at the messenger RNA and protein levels. The correlation of the level of IL-33 and IL-8 or IL-6 was examined. Cell layers were stimulated with bile acids and cytokines. IL-33 was knocked down by small interfering RNA (siRNA). Pharmacological inhibitors and signal transducer and activator of transcription 1 (STAT1) siRNA were used. RESULTS: IL-33 was significantly upregulated in RE patients, and was located in the nuclei of basal and suprabasal layers. Upregulated IL-33 messenger RNA expression was correlated with IL-8 and IL-6 expression. In vitro, IL-33 was upregulated in the nuclei of basal and suprabasal layers by interferon-γ (IFNγ), and the upregulation was aggravated by the combination of deoxycholic acid (DCA) and IFNγ. IL-33 knockdown dampened IFNγ- and DCA-induced IL-8 and IL-6 production. IFNγ-induced IL-33 was inhibited by a Janus kinase inhibitor, a p38 mitogen-activated protein kinase inhibitor, and STAT1 siRNA. CONCLUSIONS: Nuclear IL-33 is upregulated in erosive mucosa of RE patients and is correlated with IL-8 and IL-6 levels. The normal esophageal epithelial model enables us to show for the first time that epithelial-cell-derived nuclear but not exogenous IL-33 is located upstream of the production of inflammatory cytokines and can aggravate the inflammation.

Clinical features distinguish eosinophilic and reflux-induced esophagitis.

BACKGROUND AND OBJECTIVES: Diagnosing eosinophilic esophagitis (EoE) depends on intraepithelial eosinophil count of ≥15 eosinophils per high-power field (HPF); however, differentiating EoE from gastroesophageal reflux disease (GERD) continues to be a challenge because no true "criterion standard" criteria exist. Identifying clinical and endoscopic characteristics that distinguish EoE could provide a more comprehensive diagnostic strategy than the present criteria. The aim of the study was to determine symptoms and signs that can be used to distinguish EoE from reflux esophagitis. METHODS: Adult and pediatric patients with EoE were identified by present diagnostic guidelines including an esophageal biopsy finding of ≥15 eosinophils/HPF. Patients with GERD were age-matched one to one with patients with EoE. Clinical, endoscopic, and histologic information at the time of diagnosis was obtained from the medical record and compared between pairs by McNemar test. A conditional logistic regression model was created using 6 distinguishing disease characteristics. This model was used to create a nomogram to differentiate EoE from reflux-induced esophagitis. RESULTS: Patients with EoE were 75% men and 68% had a history of atopy. Many aspects of EoE were statistically distinct from GERD when controlling for age. Male sex, dysphagia, history of food impaction, absence of pain/heartburn, linear furrowing, and white papules were the distinguishing variables used to create the logistic regression model and scoring system based on odds ratios. The area under the curve of the receiver-operator characteristic curve for this model was 0.858. CONCLUSIONS: EoE can be distinguished from GERD using a scoring system of clinical and endoscopic features. Prospective studies will be needed to validate this model.

[Influence of SGHWJN particles on mediators of inflammation in esophageal tissues of rat with reflux esophagitis].

OBJECTIVE: To study the influence of SGHWJN particles on inflammation and the mediators of inflammation in esophageal tissues of rat with reflux esophagitis. METHOD: Fifty SD rats were randomly divided into 5 groups, namely, a control group, a sham-operated group, a model group, a SGHWJN particles group and a PPI group. Reflux esophagitis was induced by adopting partial pyloric ligation plus cardiomyotomy. One week later, the rats were orally administered twice daily for 28 days. Pathological changes of esophagus mucous membrane were evaluated by using HE staining and Harry S. Cooper's method in every groups. MDA and SOD contents in esophageal tissues were measured by colorimetric method. Expression of TNF-alpha in esophageal tissues were examined by real-time fluorescent quantitative reverse transcriptase polymerase chain reaction (RT-FQ-PCR) with SYBR Green. RESULT: Model group, esophageal inflammation scores, expression of TNF-alpha in esophageal tissues and MDA contents compared with the normal group and sham operation group were significantly higher (P < 0.05). SOD contents in the esophageal tissues of the model group was significantly lower than that of control group and sham-operated group (P < 0.05). SGHWJN particles group and PPI group of esophageal tissue inflammation scores, expression of TNF-a in esophageal tissues and MDA levels than those in model group decreased significantly (P < 0.05). SOD content was significantly higher than that of model group (P < 0.05), SGHWJN particles group and PPI group showed no statistically significant difference between the above-mentioned indicators. The above-mentioned indicators showed no statistically significant difference between the normal group and sham-operated group. MDA content and expression of TNF-alpha in esophageal tissue was positively correlated with inflammatory scores of model group (r = 0.813). Model group esophageal tissue SOD content and inflammation scores were negatively correlated (r = -0.847). Esophageal tissue SOD levels were negatively correlated with MDA levels (r = -0.863). CONCLUSION: SGHWJN particles can effectively inhibit inflammation in rat with reflux esophagitis through regulating TNF-alpha, SOD and MDA.

IL-17A and IL-17F gene expression is strongly induced in the mucosa of H. pylori-infected subjects from Kenya and Germany.

Helicobacter pylori infection is the major cause of gastritis. Immunologically, H. pylori gastritis is associated with an infiltration of immune cells into gastric mucosa and the upregulation of various cytokines. Here, we analysed the gene expression of IL-1- and IL-17-related cytokines in regard to H. pylori infection in 85 German and 51 Kenyan patients with reflux-related or dyspeptic symptoms, respectively. Degree of gastritis and density of colonization were assessed histologically in accordance with the updated Sydney classification. Gene expression levels of cytokines IL-1ß, IL-8, IL-18, IL-33, IL-17A, IL-17F and IL-23 as well as IL-23R were analysed by real-time RT-PCR. In both populations, H. pylori-infected individuals had significant higher inflammatory scores for activity and chronicity than H. pylori-negative subjects (P values between 0.006 and <0.0001). IL-8 mRNA was induced up to 6-fold in H. pylori-infected patients (P < 0.05), while the expression levels of IL-1ß, IL-18, IL-23, IL-33 and IL-23R did not differ with respect to the H. pylori status in both groups. Most strikingly, a significant induction of both IL-17A and IL-17F was noted in H. pylori-infected individuals of both ethnic groups. Almost all IL-17F-positive samples revealed co-expression of IL-17A (40/42, 95.2%). Analysing IL-17A and IL-17F transcript levels of these 40 'double-positive' samples, a highly significant positive correlation between both genes was identified (P < 0.001). Taken together, H. pylori infection leads to a strong upregulation of both IL-17A and IL-17F in the gastric mucosa suggesting a regulatory link between both genes.

Comparative analysis of FcεRI expression patterns in patients with eosinophilic and reflux esophagitis.

BACKGROUND AND OBJECTIVE: Eosinophilic esophagitis (EoE) is an allergic disease of the esophagus. The IgE receptors on immune cells that infiltrate the esophagus are poorly defined. The high-affinity receptor for IgE, FcεRI, may play a role in EoE. The objective of the present study is to identify and compare the IgE receptors in the esophageal epithelium of patients with EoE, reflux esophagitis (RE), and normal controls. PATIENTS AND METHODS: A retrospective case-control study of 62 patients (19 EoE, 22 RE, 21 normal controls) was conducted. Biopsies were immunostained for FcεRI, CD23, galectin-3, c-kit, CD1a, and langerin. RESULTS: FcεRI was the only IgE receptor present in the esophageal epithelium of patients with EoE. The FcεRI-positive cell count varied by diagnosis (proximal biopsies EoE 32.6 ± 19.0 cells/high-power field, RE 26.7 ± 16.6, controls 15.6 ± 8.3, ANOVA P = 0.005; distal biopsies EoE 24.2 ± 16.2, RE 35.7 ± 27.6, controls 15.3 ± 8.4, P = 0.006). In the proximal esophagus, the FcεRI count was higher in EoE than in controls (P = 0.006); in the distal esophagus, the FcεRI count was higher in RE than in controls (P = 0.004). EoE and RE had similar FcεRI-positive cell counts. A subset of FcεRI-positive cells was similar in morphology and distribution to Langerhans cells (CD1a and langerin positive). CONCLUSIONS: The presence of FcεRI-positive cells in high numbers in the esophageal epithelium implies this receptor must be critical in the IgE-mediated activation of immune cells in the esophagus. Langerhans cells in the esophageal epithelium appear to express FcεRI. The role of Langerhans cells in the pathophysiology of EoE needs to be elucidated.

Interleukin-1beta and -10 polymorphisms influence erosive reflux esophagitis and gastritis in Taiwanese patients.

BACKGROUND AND AIMS: Helicobacter pylori (H. pylori) infection induces cytokine production and is associated with gastrointestinal diseases. This study examined the relationship of gene polymorphisms, including interleukin (IL)-1beta, -10, -8, and tumor necrosis factor-alpha (TNF-alpha), H. pylori infection, and susceptibility to gastrointestinal disorders in Taiwanese patients. METHODS: IL-1beta-511/-31/+3953, -10-1082/-819/-592, -8-251, and TNF-alpha-308 polymorphisms were assessed in 628 gastrointestinal disease patients, and 176 healthy controls were analyzed using the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: IL-1beta-511 T/T and -31 C/C genotypes, and IL-1beta-511 T and -31 C alleles were associated with an increased risk of reflux esophagitis (P = 0.034, odds ratio [OR] = 1.384, 95% confidence interval [CI]: 1.023-1.871; P = 0.031, OR = 1.388, 95% CI: 1.028-1.873; P = 0.044, OR = 1.342, 95% CI: 1.008-1.786; and P = 0.040, OR = 1.349, 95% CI: 1.014-1.796, respectively). No relationship was found between H. pylori infection and the risk of reflux esophagitis. IL-10-819 C/T and -10-592 A/C genotypes and IL-10-1082/-819/-592 ATA/ACC and ATA/GCC haplotypes were associated with an increased risk of gastritis (P = 0.021, OR = 1.721, 95% CI: 1.084-2.733; P = 0.016, OR = 1.766, 95% CI: 1.112-2.805; P = 0.039, OR = 1.662, 95% CI: 1.024-2.697; and P = 0.035, OR = 1.600, 95% CI: 1.024-2.499, respectively). CONCLUSION: Among Taiwanese patients, IL-1beta and -10 polymorphisms were associated with an increased risk of erosive reflux esophagitis and gastritis, respectively.

A novel external esophageal perfusion model for reflux-associated respiratory symptoms.

BACKGROUND AND OBJECTIVE: Gastroesophageal reflux disease (GERD) has been linked to a number of extra-esophageal symptoms and disorders, primarily in the respiratory tract. Current animal models of reflux esophagitis are adapted to diseases of the digestive system, rather than to reflux-associated respiratory symptoms. The aim of this study was to evaluate a novel external esophageal perfusion model to induce esophageal, tracheal and pneumonic histological injury similar to that associated with GERD. METHODS: Twenty guinea pigs were randomized to the acid-treated or PBS-treated group. Esophageal catheters were used to perfuse the esophageal lumen of guinea pigs with hydrochloric acid containing 1 g/l pepsin or PBS for 14 days. The total cell number and cell differential counts in bronchoalveolar lavage fluid (BALF) were determined 24 h after the last perfusion. Histological changes in the esophageal, tracheal and pneumonic tissues were observed by hematoxylin-eosin staining. RESULTS: The numbers of lymphocytes, eosinophils and total inflammatory cells in the BALF were significantly higher in acid-perfused than PBS-perfused animals. Histological evidence suggested esophageal and pneumonic inflammations were prominent in acid-treated animals. CONCLUSION: Repetitive, acid-perfused, esophageal events copied the animal models of reflux esophagitis, and elicited inflammatory responses in the airways and lungs of guinea pigs.

The role of acid and bile reflux in oesophagitis and Barrett's metaplasia.

The precise mechanisms whereby gastro-oesophageal reflux disease causes reflux oesophagitis and Barrett's oesophagus are not clear, even though these diseases have been known to be linked for many years. Recent studies indicate a role for the reflux-induced inflammatory response of oesophageal squamous epithelial cells and the immune cells in the pathogenesis of reflux oesophagitis. Although reflux oesophagitis commonly heals with oesophageal squamous cell regeneration, in some individuals the oesophagus heals through the process of metaplasia, a condition termed Barrett's oesophagus. Recent studies indicate that individual differences in the reflux-mediated response of oesophageal squamous epithelial cells in the type of immune response and/or in signalling pathways that regulate cell proliferation or cell phenotype may determine whether the oesophagus heals with the regeneration of squamous cells or through Barrett's metaplasia.

Combinational effect of low-dose oral corticosteroid and mizoribine for ulcerative colitis in a patient with systemic sclerosis.

The combinational effect of oral corticosteroid and mizoribine for ulcerative colitis is presented in a patient with systemic sclerosis (SSc). A 64-year-old woman came to our clinic complaining of a 30-year history of Raynaud's phenomenon. She had past history of ulcerative colitis with the continued medication of mesalazine without success. She was presented with sclerodactyly and finger joint swelling. She also showed epigastric discomfort. Laboratory study showed positive anti-nuclear antibody and positive anti-centromere antibody. Histological examination showed mild perivascular mononuclear cell infiltrates in the whole dermis and increased deposition of collagen fibers in the middle and lower dermis. Chest X-ray film showed mild bibasilar pulmonary fibrosis. An upper gastrointestinal series study showed reflux esophagitis and atrophic gastritis. These findings led to the diagnosis of systemic sclerosis (limited type) complicated with ulcerative colitis. Treatment with oral corticosteroid (5 mg/day) and mizoribine (150 mg/day) in the morning was started. She showed remarkable improvement for sclerodactyly and lower intestinal bleeding stopped after 6 months. She is under the same treatment without exaggeration and adverse effect of the drug until now.

Characteristic pathological findings and effects of ecabet sodium in rat reflux esophagitis.

AIM: To explore the pathological findings in the entire esophagus in rats with reflux esophagitis, and the effects of ecabet sodium (ES). METHODS: A rat model of chronic acid reflux esophagitis was used. In the treatment group, ES was administered after surgery (n = 16). No drug was administered postoperatively to the esophagitis group (n = 9). Sham-operated rats were used as a control group (n = 5). Rats were sacrificed on day 7 after the operation. The epithelial thickness and leukocyte infiltration were examined in the upper, middle and lower areas of the esophagus. The survival rate, incidence of esophageal ulcer, and mean surface area and number of esophageal ulcers were determined in the esophagitis and ES groups. Esophageal histology was assessed in all three groups. RESULTS: Leukocyte infiltration in the esophagitis group was 26.3 +/- 22.0 in the middle esophagus and 8.2 +/- 4.9 in the upper esophagus, which was significantly greater than that in the controls (1.3 +/- 1.1 and 1.4 +/- 1.0, respectively) (P < 0.05). The thickness of the epithelium in the esophagitis group was 210.8 +/- 47.7 microm in the lower esophagus and 204.2 +/- 60.1 microm in the middle esophagus, which was significantly greater than that in the controls (26.0 +/- 5.5 and 21.0 +/- 6.5 microm, respectively) (P < 0.05). The mean number of ulcers per animal in the ES group in the entire esophagus was 5.4 +/- 2.5, which was significantly less than that in the esophagitis group (9.0 +/- 3.5) (P < 0.05). The epithelial thickness in the ES group was 97.5 +/- 32.2 microm in the lower esophagus, which was decreased compared with that in the esophagitis group (210.8 +/- 47.7 microm) (P < 0.05). CONCLUSION: Mucosal inflammation extended to the upper esophagus close to the hypopharynx. Our study suggested that ES may have a useful defensive role in reflux esophagitis.

Melatonin protects against experimental reflux esophagitis.

Reflux esophagitis (RE), a major gastrointestinal disorder results from excess exposure of the esophageal mucosa to acidic gastric juice or bile-containing duodenal contents refluxed via an incompetent lower esophageal sphincter. Recent studies implicated oxygen derived free radicals in RE induced esophageal mucosal damage resulting in mucosal inflammation. Thus, control over free radical generation and modulation of inflammatory responses might offer better therapeutic effects to counteract the severity of RE. In this context we investigated the effect of melatonin against experimental RE in rats. Melatonin pretreatment significantly reduced the haemorrhagic lesions and decreased esophageal lipid peroxidation aggravated by RE. Moreover, the depleted levels of superoxide dismutase and glutathione observed in RE were replenished by melatonin signifying its free radical scavenging properties and antioxidant effects resulting in the improvement of esophageal defense mechanism. Further melatonin repressed the upregulated levels of expression of proinflammatory cytokines like, TNF-alpha, IL-1beta and IL-6 in RE. However, increased levels of the anti-inflammatory cytokine IL-10 remained unaltered after melatonin administration signifying its immunomodulatory effect through suppression of Th1-mediated immune responses. The involvement of receptor dependent actions of melatonin against RE were also investigated with MT2 receptor antagonist, luzindole (LUZ). LUZ failed to antagonize melatonin's protective effects against RE indicating that melatonin mediated these beneficial effects in a receptor-independent fashion. Thus, esophageal mucosal protection elicited by melatonin against experimental RE is not only dependent on its free radical scavenging activity but also mediated in part through its effect on the associated inflammatory events in a receptor-independent manner.

Direct evidence of mast cell participation in acute acid-induced esophageal inflammation in mice.

OBJECTIVES: Mast cells have been implicated in the pathogenesis of esophagitis resulting from gastroesophageal acid reflux, but their precise role has been difficult to define. We proposed to directly examine the contribution of mast cells to neutrophil infiltration in a mouse model of acid-induced esophageal injury. MATERIALS AND METHODS: Normal and mast cell-deficient (Kit) mice underwent either a surgical procedure to induce acute acid reflux injury of the esophagus or sham surgery. Neutrophil infiltration in the esophagus was determined by morphometrical quantification. To further delineate the involvement of mast cells, acid-induced esophageal injury was elicited in mast cell-deficient mice that had undergone mast cell reconstitution by bone marrow transplantation. RESULTS: Normal mice exhibited significant neutrophil infiltration into the esophagus as a result of acid-induced injury. The neutrophil accumulation was significantly diminished in mast cell-deficient mice. However, the neutrophil infiltration that resulted from acid-induced injury in mast cell-reconstituted Kit mice was similar to that seen in normal mice. CONCLUSIONS: Our findings provide direct evidence that mast cells participate in the recruitment of neutrophils during acid-induced esophageal injury in mice.

Protective effects of Helicobacter pylori against gastroesophageal reflux disease may be due to a neuroimmunological anti-inflammatory mechanism.

There is some evidence that Helicobacter pylori infection has a protective effect against gastroesophageal reflux disease (GORD) and its complications such as Barrett's oesophagus and oesophageal adenocarcinoma. In this paper, we propose that a neuroimmunological mechanism is responsible for the protective effect of H. pylori on GORD. H. pylori infection of the gastric mucosa induces a T helper1-like immune response and production of pro-inflammatory cytokines. These cytokines can inhibit local sympathetic tone, whereas they increase systemic sympathetic tone. Increased sympathetic tone can induce an anti-inflammatory milieu, which in turn can inhibit inflammation in the oesophagus and lower oesophageal sphincter (LOS). Furthermore, H. pylori infection may stimulate the cholinergic anti-inflammatory pathway. It has been suggested that reflux-induced oesophageal inflammation plays an important role in the pathogenesis of reflux oesophagitis. Reduction of oesophageal inflammation by increased systemic sympathetic tone and vagal activity may lead to a decrease in reflux-induced oesophageal injury and LOS dysfunction in GORD.