4 research outputs found
CCR3 Blockade Attenuates Eosinophilic Ileitis and Associated Remodeling
Intestinal remodeling and stricture formation is a complication of inflammatory bowel disease (IBD) that often requires surgical intervention. Although eosinophils are associated with mucosal remodeling in other
organs and are increased in IBD tissues, their role in
IBD-associated remodeling is unclear. Histological and
molecular features of ileitis and remodeling were assessed using immunohistochemical, histomorphometric, flow cytometric, and molecular analysis (real-time
RT-PCR) techniques in a murine model of chronic eosinophilic ileitis. Collagen protein was assessed by Sircol
assay. Using a spontaneous eosinophilic Crohn鈥檚-like
mouse model SAMP1/SkuSlc, we demonstrate an association between ileitis progression and remodeling over
the course of 40 weeks. Mucosal and submucosal eosinophilia increased over the time course and correlated
with increased histological inflammatory indices. Ileitis
and remodeling increased over the 40 weeks, as did
expression of fibronectin. CCR3-specific antibody-mediated reduction of eosinophils resulted in significant decrease in goblet cell hyperplasia, muscularis propria
hypertrophy, villus blunting, and expression of inflammatory and remodeling genes, including fibronectin.
Cellularity of local mesenteric lymph nodes, including
T- and B-lymphocytes, was also significantly reduced.
Thus, eosinophils participate in intestinal remodeling, supporting eosinophils as a novel therapeutic
target
Local hypersensitivity reaction in transgenic mice with squamous epithelial IL-5 overexpression provides a novel model of eosinophilic oesophagitis
Objective: Eosinophilic oesophagitis (EoE) is a chronic
inflammatory condition of the oesophagus with limited
treatment options. No previous transgenic model has
specifically targeted the oesophageal mucosa to induce
oesophageal eosinophilia.
Design: We developed a mouse model that closely
resembles EoE by utilising oxazolone haptenation in mice
with transgenic overexpression of an eosinophil poietic
and survival factor (interleukin (IL)-5) in resident
squamous oesophageal epithelia.
Results: Overexpression of IL-5 in the healthy
oesophagus was achieved in transgenic mice (L2-IL5)
using the squamous epithelial promoter Epstein鈥揃arr
virus ED-L2. Oxazolone-challenged L2-IL5 mice
developed dose-dependent pan-oesophageal
eosinophilia, including eosinophil microabscess formation
and degranulation as well as basal cell hyperplasia.
Moreover, oesophagi expressed increased IL-13 and the
eosinophil agonist chemokine eotaxin-1. Treatment of
these mice with corticosteroids significantly reduced
eosinophilia and epithelial inflammation.
Conclusions: L2-IL5 mice provide a novel experimental
model that can potentially be used in preclinical testing
of EoE-related therapeutics and mechanistic studies
identifying pathogenetic features associated with
mucosal eosinophilia