No abstract

The role of the anti-inflammatory cytokine interleukin-10 (IL-10) was investigated in the mouse model of liver injury induced by carbon tetrachloride (CCl 4 ). To address the role of endogenous IL-10 production, acute hepatitis was induced by CCl 4 in C57Bl/6 IL-10 gene knock out (KO) and wild-type (WT) mice. After CCl 4 challenge, serum and liver levels of tumor necrosis factor-alpha (TNF-␣) and serum levels of transforming growth factor-beta 1 (TGF-␤1) increased and were significantly higher in IL-10 KO mice, whereas IL-6 serum levels were only slightly increased compared with WT mice. At histological examination, the livers disclosed a significantly more prominent neutrophilic infiltration in IL-10 KO mice 12 and 24 hours after CCl 4 injection. In contrast, hepatocyte necrosis, evaluated by histological examination and serum alanine aminotransferase levels, was only marginally affected. The proliferative response of hepatocytes, assessed by the proliferating cell nuclear-antigen labeling index, was significantly increased in IL-10 KO mice, compared with WT mice 48 hours after CCl 4 injection. Finally, repeated CCl 4 injections led to more liver fibrosis in IL-10 KO mice after 7 weeks. In conclusion, endogenous IL-10 marginally affects the hepatocyte necrosis although it controls the acute inflammatory burst induced by CCl 4 . During liver repair, it limits the proliferative response of hepatocytes and the development of fibrosis. (HEPATOLOGY 1998;28:1607-1615.)

Background A novel transoral incisionless fundoplication (TIF) procedure using the EsophyX system with SerosaFuse fasteners was designed to reconstruct a full-thickness valve at the gastroesophageal junction through tailored delivery of multiple fasteners during a single-device insertion. The safety and efficacy of TIF for treating gastroesophageal reflux disease (GERD) were evaluated in a prospective multicenter trial. Methods Patients (n = 86) with chronic GERD treated with proton pump inhibitors (PPIs) were enrolled. Exclusion criteria included an irreducible hiatal hernia [ 2 cm. Results The TIF procedure (n = 84) reduced all hiatal hernias (n = 49) and constructed valves measuring 4 cm (2-6 cm) and 230°(160°-300°). Serious adverse events consisted of two esophageal perforations upon device insertion and one case of postoperative intraluminal bleeding. Other adverse events were mild and transient. At 12 months, aggregate (n = 79) and stratified Hill grade I tight (n = 21) results showed 73% and 86% of patients with C50% improvement in GERD health-related quality of life (HRQL) scores, 85% discontinuation of daily PPI use, and 81% complete cessation of PPIs; 37% and 48% normalization of esophageal acid exposure; 60% and 89% hiatal hernia reduction; and 62% and 80% esophagitis reduction, respectively. More than 50% of patients with Hill grade I tight valves had a normalized cardia circumference. Resting pressure of the lower esophageal sphincter (LES) was improved significantly (p \ 0.001), by 53%. EsophyX-TIF cured GERD in 56% of patients based on their symptom reduction and PPI discontinuation. Conclusion The 12-month results showed that EsophyX-TIF was safe and effective in improving quality of life and for reducing symptoms, PPI use, hiatal hernia, and G.

BACKGROUND & AIMS: Swallowed topical-acting corticosteroids are recommended as first-line therapy for eosinophilic esophagitis (EoE). Asthma medications not optimized for esophageal delivery are sometimes effective, although given offlabel. We performed a randomized, placebo-controlled trial to assess the effectiveness and tolerability of a budesonide orodispersible tablet (BOT), which allows the drug to be delivered to the esophagus in adults with active EoE. METHODS: We performed a double-blind, parallel study of 88 adults with active EoE in Europe. Patients were randomly assigned to groups that received BOT (1 mg twice daily; n ¼ 59) or placebo (n ¼ 29) for 6 weeks. The primary end point was complete remission, based on clinical and histologic factors, including dysphagia and odynophagia severity 2 on a scale of 0-10 on each of the 7 days before the end of the double-blind phase and a peak eosinophil count <5 eosinophils/high power field. Patients who did not achieve complete remission at the end of the 6-week double-blind phase were offered 6 weeks of open-label Gastroenterology 2019;157:74-86 CLINICAL AT treatment with BOT (1 mg twice daily). RESULTS: At 6 weeks, 58% of patients given BOT were in complete remission compared with no patients given placebo (P < .0001). The secondary end point of histologic remission was achieved by 93% of patients given BOT vs no patients given placebo (P < .0001). After 12 weeks, 85% of patients had achieved remission. Six-week and 12-week BOT administration were safe and well tolerated; 5% of patients who received BOT developed symptomatic, mild candida, which was easily treated with an oral antifungal agent. CONCLUSIONS: In a randomized trial of adults with active EoE, we found that budesonide oral tablets were significantly more effective than placebo in inducing clinical and histologic remission. Eudra-CT number 2014-001485-99; ClinicalTrials.gov ID NCT02434029.

Experimental T‐cell‐mediated hepatitis induced by concanavalin A (Con A) involves the production of proinflammatory cytokines. Because interleukin (IL)‐10 is a potent anti‐inflammatory cytokine derived from macrophages and T cells and is produced within the liver, we investigated the role of IL‐10 in modulating the hepatotoxicity and the secretion of cytokines following in vivo injection of Con A. IL‐10 is produced early in the serum after Con A challenge. Neutralization of endogenous IL‐10 by monoclonal antibodies (mAbs) increases the secretion of tumor necrosis factor α (TNF‐α) (+111%), interferon gamma (IFN‐γ) (+92%), and IL‐12 (+730%) 8 hours after Con A injection, and increases the hepatotoxicity, assessed by serum alanine transaminase (ALT) (+174%) measurement and by histology, 24 hours after induction of hepatitis. Conversely, preadministration of recombinant IL‐10 reduces the production of these proinflammatory cytokines (‐47%, ‐80%, and ‐47% for TNF‐α, IL‐12, and IFN‐γ, respectively), and decreases neutrophil infiltration and ALT serum concentration (‐74%) 8 hours after Con A challenge. We conclude that IL‐10, either endogenously produced or exogenously added, has a hepatoprotective role in Con A‐induced hepatitis, through its suppressive property on proinflammatory cytokine production, and that it might be of therapeutic relevance in human liver diseases involving activated T cells.