Targeting AMCase reduces esophageal eosinophilic inflammation and remodeling in a mouse model of egg induced eosinophilic esophagitis.
Studies of AMCase inhibition in mouse models of lung eosinophilic inflammation have produced conflicting results with some studies demonstrating inhibition of eosinophilic inflammation and others not. No studies have investigated the role of AMCase inhibition in eosinophilic esophagitis (EoE). We have used a mouse model of egg (OVA) induced EoE to determine whether pharmacologic inhibition of AMCase with allosamidin reduced eosinophilic inflammation and remodeling in the esophagus in EoE. Administration of intra-esophageal OVA for 6weeks to BALB/c mice induced increased levels of esophageal eosinophils, mast cells, and features of esophageal remodeling (fibrosis, basal zone hyperplasia, deposition of the extracellular matrix protein fibronectin). Administration of intraperitoneal (ip) allosamidin to BALB/c mice significantly inhibited AMCase enzymatic activity in the esophagus. Pharmacologic inhibition of AMCase with ip allosamidin inhibited both OVA induced increases in esophageal eosinophilic inflammation and OVA induced esophageal remodeling (fibrosis, epithelial basal zone hyperplasia, extracellular matrix deposition of fibronectin). This inhibition of eosinophilic inflammation in the esophagus by ip allosamidin was associated with reduced eotaxin-1 expression in the esophagus. Oral allosamidin inhibited eosinophilic inflammation in the epithelium but did not inhibit esophageal remodeling. These studies suggest that pharmacologic inhibition of AMCase results in inhibition of eosinophilic inflammation and remodeling in the esophagus in a mouse model of egg induced EoE partially through effects in the esophagus on reducing chemokines (i.e. eotaxin-1) implicated in the pathogenesis of EoE.
Department of Medicine, University of California, San Diego, La Jolla, CA, USA. Electronic address: angelajyc858@gmail.com.
Jae Youn
JY
Cho
Department of Medicine, University of California, San Diego, La Jolla, CA, USA. Electronic address: prosenthal@ucsd.edu.
Peter
P
Rosenthal
Department of Medicine, University of California, San Diego, La Jolla, CA, USA. Electronic address: mamiller@ucsd.edu.
Marina
M
Miller
Department of Medicine, University of California, San Diego, La Jolla, CA, USA. Electronic address: alexakp@gmail.com.
Alexa
A
Pham
Department of Medicine, University of California, San Diego, La Jolla, CA, USA; Department of Pediatrics, University of California San Diego, San Diego, CA, USA. Electronic address: saceves@ucsd.edu.
Seema
S
Aceves
Faculty of Agriculture, The University of Tokyo, Tokyo, Japan. Electronic address: asakuda@mail.ecc.u-tokyo.ac.jp.
Shohei
S
Sakuda
Department of Medicine, University of California, San Diego, La Jolla, CA, USA. Electronic address: dbroide@ucsd.edu.
David H
DH
Broide
D000117:Acetylglucosamine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000485:Allergens / Q000276:immunology; D000818:Animals; D002478:Cells, Cultured; D054413:Chemokine CCL11 / Q000235:genetics / Q000378:metabolism; D002688:Chitinases / Q000378:metabolism*; D004195:Disease Models, Animal; D004531:Eggs / Q000009:adverse effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D057765:Eosinophilic Esophagitis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D004947:Esophagus / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D005260:Female; D005355:Fibrosis; D006801:Humans; D006965:Hyperplasia; D006969:Hypersensitivity, Immediate / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism; D008807:Mice, Inbred BALB C; D058990:Molecular Targeted Therapy; D010047:Ovalbumin / Q000009:adverse effects / Q000276:immunology; D014312:Trisaccharides / Q000008:administration & dosage*
D000485:Allergens; D054413:Chemokine CCL11; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D014312:Trisaccharides; C054851:allosamidin; D010047:Ovalbumin; C499255:AMCase, mouse; D002688:Chitinases; D000117:Acetylglucosamine
Allosamidin; Eosinophil; Eosinophilic esophagitis; Eotaxin-1; IL-13