Antifibrotic Effects of the Thiazolidinediones in Eosinophilic Esophagitis Pathologic Remodeling: A Preclinical Evaluation.

INTRODUCTION: Eosinophilic esophagitis (EoE) is a T-helper 2 (Th2), eosinophilic disease associated with pathologic tissue remodeling that leads to end-organ dysfunction. During early-stage disease, inflammation and subepithelial fibrosis are coupled and reversible, but in late-stage or therapy-resistant disease, there can be uncoupling of these features with progressive esophageal rigidity and strictures contributing to clinical dysphagia and food impactions. No current pharmacotherapeutic interventions directly target esophageal fibrosis. Based on the ability of the thiazolidinediones (TZD) to regulate intestinal and hepatic fibrosis, we tested the antifibrotic effects of the TZDs, rosiglitazone and pioglitazone, in preclinical studies using primary human esophageal fibroblasts. METHODS: Primary fibroblasts isolated from normal or EoE esophagi were treated with transforming growth factor (TGF)-ß1 in the absence or presence of TZDs and, in some experiments, without or with budesonide and analyzed by quantitative real-time PCR and immunoblotting. Immunohistochemical analysis of human esophageal biopsies was performed. RESULTS: EoE esophageal biopsies and esophageal fibroblasts expressed higher levels of the TZD receptor, peroxisome proliferator-activated receptor-γ (PPAR-γ), than normal controls. PPAR-γ was inducible by the Th2 cytokine, interleukin 4 (IL-4). TZD significantly reduced TGF-ß1-induced myofibroblast and fibrotic gene and protein expression preferentially in EoE, but not normal esophageal fibroblasts. In esophageal fibroblasts, TGF-ß1 increased phosphorylated Smad2/3 and p38, but TZDs preferentially inhibited p38 phosphorylation, suggesting signaling pathway-specific effects. The TZDs were more potent than budesonide at decreasing collagen-1α1 expression. DISCUSSION: The TZDs preferentially exert antifibrotic effects in TGF-ß1-activated EoE fibroblasts and provide a preclinical foundation for further investigation of the potential of the TZDs in EoE pathologic remodeling.

Germination of pollen grains in the oesophagus of individuals with eosinophilic oesophagitis.

BACKGROUND: Eosinophilic oesophagitis (EoE) is characterized by oesophageal dysfunction and, histologically, by eosinophilic inflammation. There is no a clear aetiologic treatment. EoE exacerbations are often seasonal. We hypothesized that the inflammatory response of the oesophageal mucosa in patients with high levels of antibodies to pollen allergens and worsened seasonal EoE might be due to swallowing airborne pollen and the intrusion into the oesophageal mucosa of pollen allergens and pollen tubes, which encounter a pH and humidity resembling the stigma at pollination. OBJECTIVE: The aim of our study was to demonstrate the possible pathogenic role of environmental allergens in EoE through molecular and anatomopathological studies METHODS: One hundred and twenty-nine patients with EoE were tested for environmental and food allergens. Component resolved diagnosis (CRD), histological and botanical analysis was performed. Microscopic examination of oesophageal biopsies of 129 adults patients with EoE, 82 of them with seasonal exacerbation, and 100 controls, with gastroesophageal reflux without eosinophilic infiltrate, were made to verify the presence of callose (polysaccharide abundant in pollen tubes but absent in animal tissues) in the oesophagus. RESULTS: Component resolved diagnosis detected pollen allergens in 87.6% of patients with EoE. The predominant allergens were group 1 grass (55%), Art v 3 (11.3%) and lipid transfer proteins (LTPs) (19.4%) of common Mediterranean foods such as peach, hazelnuts, walnuts and wheat. Callose from pollen tubes was found in 65.6% of biopsies. CONCLUSION: Alteration of the mucosal barrier in EoE might cause the penetration of pollen grains into the oesophageal tissues. In EoE patients, anatomopathological studies searching for intrusion to plant foods and pollen, and specific-guided diet and immunotherapy after plant structures detection in biopsies, might be effective. CLINICAL RELEVANCE: It is possible to see the intrusion into animal tissues (oesophagus mucosa) of plant structures (pollen grains or pollen tubes) using an adecuate histologic botanical analysis. Molecular and anatomopathological studies can help to demonstrate a possible pathogenic role of environmental allergens in EoE.

Does Aeroallergen Sensitization Cause or Contribute to Eosinophilic Esophagitis?

Eosinophilic esophagitis is an atopic disease defined clinically by esophageal symptoms in combination with a dense esophageal eosinophilia. EoE is triggered and maintained by exposure to certain foods and it is known that dietary modification controls symptoms and achieves disease remission. Recently, aeroallergens have been implicated in the pathogenesis of EoE. To examine the role of aeroallergens in EoE, we reviewed the published literature. Sensitization and production of IgE antibodies to foods and aeroallergens in subjects with EoE has been demonstrated. However, the evidence suggests only a minor role for IgE-mediated immune reactions in EoE. There is some evidence to support an association of EoE diagnosis and flares with environmental allergen exposure, and animal studies support the notion that EoE may be induced by exposure to inhalant allergens. Some studies show that newly diagnosed cases of EoE follow a seasonal pollen distribution (summer and spring), but the weight of evidence does not support the seasonal occurrence of diagnosis or worsening of symptoms. Overall, we conclude that the current evidence does not support causality in inhalant allergen exposure and the genesis nor exacerbations of EoE in humans, although there is a possibility that inhalant allergen sensitization could play a modifying role in EoE in the context of cross-reacting food allergens.

Demographic, clinical and allergological characteristics of Eosinophilic Esophagitis in a Spanish central region

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic inflammatory emerging disease of the oesophagus with immunoallergic aetiology. The allergens involved have not been clearly defined and may depend on the exposure of the population to aeroallergens or food antigens. MATERIALS AND METHODS: Patients diagnosed with EoE between 2006 and 2011 were referred to our Allergy Section. Patch and skin prick tests (SPT) with aeroallergens and foods were performed, and total and specific IgE levels, eosinophil cationic protein levels and eosinophil count were determined. RESULTS: 43 patients were included. 36 (83.7%) were atopic. 29 patients presented choking, 19 dysphagia, 9 food impaction with urgent endoscopy, 4 chest pain, 1 isolated vomiting and 1 epigastric pain. 22 had two or more symptoms. The mean duration of symptoms was 3.73 years. Concomitant allergic diseases included rhinoconjunctivitis and/or asthma (31 patients), IgE food allergy (21 patients) and atopic dermatitis (3 patients).32 (74%) were sensitized to aeroallergens, of which 90% were sensitized to pollens; 23 (54%) showed positive tests to foods and 12 of them (52%) to lipid transfer proteins (LTP).Of the 29 pollen-allergic patients, 15 (52%) were sensitized to plant foods and 10 (34.4%) to LTP. CONCLUSIONS: Our findings support those reported in the literature: the disease is more common in men aged 30-40 years with at least a three-year history of symptoms of esophageal dysfunction, sensitized to pollens, the predominant aeroallergen in our area, but also to plant foods or panallergens. These results increase the evidence for an immunoallergic aetiology and can help us in the early diagnosis of EoE

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Significance of para-esophageal lymph nodes in food or aeroallergen-induced iNKT cell-mediated experimental eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is a recently recognized inflammatory disorder driven by food hypersensitivity; however, the specific foods and mechanisms involved are unclear. In patients with EoE, we have found that hypersensitivities to corn and peanuts are the most common. Accordingly, we sensitized and exposed mice either intranasally or intragastrically with corn or peanut extract or saline. Esophageal eosinophilia, the genes of eosinophil-directed cytokines, and allergen-induced antibodies were examined in mice challenged with corn or peanut extract or saline. A high number of esophageal lamina propria eosinophils as well as eosinophilic microabscesses, intraepithelial eosinophils, extracellular eosinophilic granules, thickened and disrupted epithelial mucosa, and mast cell hyperplasia were observed in the esophagus of peanut or corn allergen-challenged mice. Mechanistic analysis indicated that para-esophageal lymph nodes might be critical in the trafficking of eosinophils to the esophagus and in EoE association to airway eosinophilia. Furthermore, experimentation with gene-targeted mice revealed that peanut allergen-induced EoE was dependent on eotaxin and invariant natural killer T (iNKT) cells, as CD1d and eotaxin-1/2 gene-deficient mice were protected from disease induction. Thus we provide evidence that para-esophageal lymph nodes are involved in food- or aeroallergen-induced eosinophilia and patchy EoE pathogenesis, likely a mechanism dependent on eotaxins and iNKT cells.

[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.

Eosinophil infiltration of the oesophageal mucosa in patients with pollen allergy during the season.

BACKGROUND: The oesophagus is normally devoid of eosinophils. There are some disorders accompanying with eosinophil infiltration. Food allergy has been reported as a common reason, especially in children but some other studies have also indicated that aeroallergens might have a role in oesophageal eosinophil accumulation. OBJECTIVE: In this study we investigated whether there is any eosinophil recruitment in the oesophagus of pollen-allergic patients who had respiratory symptoms during the season. METHODS: Thirty-eight symptomatic patients (allergic rhinitis (AR) with or without asthma) who had sensitization to grass pollen were included in the study during the pollen season. Controls were composed of 25 healthy non-atopics and 24 patients diagnosed as having gastro-oesophageal reflux disease. Reflux was excluded in allergic and non-atopic groups, whereas the presence of allergy was eliminated in control groups. Gastrointestinal endoscopy was performed in all participants, and biopsy specimens were taken from both the proximal and the distal oesophagus to evaluate eosinophil accumulation. At the same time, blood eosinophil numbers were counted. Results Oesophageal eosinophil accumulation was found in 10 allergic patients (26%) and in five patients (21%) with gastro-oesophageal reflux disease but none of the healthy controls had eosinophils (0%) (P<0.05). Blood eosinophils were higher in these 10 patients than the rest of the 28 patients without infiltration. In this group, blood eosinophils were also correlated with the number of accumulated eosinophils in the oesophagus (P<0.001). There was more intense eosinophil infiltration at the distal part of the oesophagus in the reflux group when compared with the allergic group (mean 7.6+/-5.6 vs. 3.2+/-3.7). Nevertheless, eosinophils were found to be concentrated (mean 5.5+/-7.3) in the proximal oesophagus of allergic patients, although it was 1.7+/-1.5 in reflux patients (P>0.05). Conclusion Our results showed that eosinophil infiltration might be observed in oesophageal tissue of patients with respiratory tract allergy during the symptomatic period. This finding may possibly reflect the systemic and common mucosal aspects of allergic inflammation.