title: A novel murine model of esophageal nonerosive reflux disease: from inflammation to impairment in mucosal integrity.
abstract: Nonerosive reflux disease (NERD) is a highly prevalent phenotype of the gastroesophageal reflux disease. In this study, we developed a novel murine model of NERD in mice with microscopic inflammation and impairment in the epithelial esophageal barrier. Female Swiss mice were subjected to the following surgical procedure: the transitional region between the forestomach and the glandular portion of the stomach was ligated, and a nontoxic ring was placed around the duodenum near the pylorus. The control group underwent sham surgery. The animals were euthanized at 1, 3, 7, and 14 days after surgery. Survival and body weight were monitored daily. Esophageal wet weight, macroscopic lesion, histopathological alterations, myeloperoxidase (MPO) activity, cytokine levels, transepithelial electrical resistance (TEER), and mucosal permeability were evaluated. The survival rate was 78% at 14 days, with mild loss in body weight. Surgery did not induce erosive esophagitis but instead induced microscopic inflammation and increased esophageal wet weight, IL-6, keratinocyte-derived cytokine (KC) levels, and MPO activity with maximal peak between 3 and 7 days and resolution at 14 days postsurgery. Epithelial esophageal barrier was evaluated in operated mice at 7 and 14 days postsurgery; a decrease in TEER and increase in the esophageal epithelial permeability were observed compared with the sham-operated group. In addition, the inhibition of acid secretion with omeprazole significantly prevented the esophageal inflammation and impairment of barrier function at 7 days postsurgery. Thus we established a novel experimental model of NERD in mice, which can contribute to understanding the pathophysiological events associated with NERD.NEW & NOTEWORTHYIn this study, we standardized an experimental model of nonerosive reflux disease (NERD) in mice. This model involves an acute inflammatory response followed by impaired esophageal mucosal integrity, even in the absence of inflammation. Thus this model can serve for evaluation of pathophysiological aspects of NERD and open new perspectives for therapeutic strategies for patients with this disorder.
authors.affiliation: Laboratory of Physiopharmacology Study of Gastrointestinal Tract, Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors.forename: Renan O
authors.initials: RO
authors.lastname: Silva
authors.affiliation: Laboratory of Physiopharmacology Study of Gastrointestinal Tract, Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors.forename: Francisco Fábio B
authors.initials: FFB
authors.lastname: Oliveira
authors.affiliation: Laboratory of Physiopharmacology Study of Gastrointestinal Tract, Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors.forename: Rudy D
authors.initials: RD
authors.lastname: Bingana
authors.affiliation: Laboratory of Physiopharmacology Study of Gastrointestinal Tract, Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors.forename: Mailton O
authors.initials: MO
authors.lastname: Arruda
authors.affiliation: Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Philip
authors.initials: P
authors.lastname: Woodland
authors.affiliation: Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Chung
authors.initials: C
authors.lastname: Lee
authors.affiliation: Department of Clinical Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil; and souzamar@ufc.br.
authors.forename: Miguel A N
authors.initials: MAN
authors.lastname: Souza
authors.affiliation: Laboratory of Physiopharmacology Study of Gastrointestinal Tract, Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Ceará, Brazil.|Department of Morphology, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors.forename: Pedro M G
authors.initials: PMG
authors.lastname: Soares
authors.affiliation: Laboratory of Physiopharmacology Study of Gastrointestinal Tract, Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors.forename: Armênio A
authors.initials: AA
authors.lastname: Santos
authors.affiliation: Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sifrim
authors.affiliation: Laboratory of Physiopharmacology Study of Gastrointestinal Tract, Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Ceará, Brazil; souzamar@ufc.br.|Department of Clinical Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil; and.
authors.forename: Marcellus H L P
authors.initials: MHLP
authors.lastname: Souza
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004386:Duodenum / Q000601:surgery; D017097:Electric Impedance; D000071041:Esophageal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D004942:Esophagitis, Peptic / Q000209:etiology / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D005764:Gastroesophageal Reflux / Q000209:etiology / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D008026:Ligation; D051379:Mice; D009929:Organ Size; D010539:Permeability; D009195:Peroxidase / Q000378:metabolism; D010641:Phenotype; D054328:Proton Pump Inhibitors / Q000494:pharmacology; D013270:Stomach / Q000601:surgery; D013997:Time Factors
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D054328:Proton Pump Inhibitors; D009195:Peroxidase
keywords: esophageal mucosa; inflammation; mucosal integrity; nonerosive reflux disease