16 research outputs found
Challenges in IBD Research: Update on Progress and Prioritization of the CCFAĘĽs Research Agenda
Clinical Implications of Pediatric Colonic Eosinophilia
Objective: Pediatric colonic eosinophilia represents a confounding finding with a wide differential. It is often difficult to determine which children may progress to inflammatory bowel disease (IBD), which have an eosinophilic colitis (EC), and which may have no underlying pathology. There is little guidance for the practitioner on the approach to these patients. To define the clinical presentations of colonic eosinophilia and identify factors which may aid in diagnosis we reviewed patients with colonic eosinophilia and the clinicopathologic factors associated with their diagnoses.
Mehtods: An 8-year retrospective chart review of children whose histopathology identified colonic eosinophilia (N = 72) compared to controls with normal biopsies (N = 35).
Results: Patients with colonic eosinophilia had increased eosinophils/high-power field compared to controls (P 1 colonoscopy and 68% of these had change from initial diagnoses.
Conclusions: There are 3 main phenotypes of children with colonic eosinophilia. Signs of chronic systemic inflammation raise suspicion for IBD. Peripheral eosinophilia and male sex are associated with EC. A significant percent of children with colonic eosinophilia do not have colonic disease. Eosinophils/high-power field is not reliable to differentiate etiologies. Repeat colonoscopies may be required to reach final diagnoses
Hypoxia-inducible factor-1 alpha–dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa
Recent studies have demonstrated dramatic shifts in metabolic
supply-and-demand ratios during inflammation, a process resulting in localized tissue hypoxia within inflammatory lesions (“inflammatory hypoxia”). As part of the adaptive immune response,
T cells are recruited to sites of inflammatory hypoxia. Given the
profound effects of hypoxia on gene regulation, we hypothesized
that T-cell differentiation is controlled by hypoxia. To pursue this
hypothesis, we analyzed the transcriptional consequences of ambient hypoxia (1% oxygen) on a broad panel of T-cell differentiation
factors. Surprisingly, these studies revealed selective, robust induction of FoxP3, a key transcriptional regulator for regulatory T cells
(Tregs). Studies of promoter binding or loss- and gain-of-function
implicated hypoxia-inducible factor (HIF)-1α in inducing FoxP3. Similarly, hypoxia enhanced Treg abundance in vitro and in vivo. Finally, Treg-intrinsic HIF-1α was required for optimal Treg function
and Hif1a–deficient Tregs failed to control T-cell–mediated colitis.
These studies demonstrate that hypoxia is an intrinsic molecular
cue that promotes FoxP3 expression, in turn eliciting potent antiinflammatory mechanisms to limit tissue damage in conditions of
reduced oxygen availability
Targeted Inhibition of Heat Shock Protein 90 Suppresses Tumor Necrosis Factor–α and Ameliorates Murine Intestinal Inflammation
Strategies to Cure Experimental Autoimmune Colitis Using Antigen-Specific Foxp3+ Regulatory T Cells
Epithelial-specific A2B adenosine receptor signaling protects the colonic epithelial barrier during acute colitis
Central to inflammatory bowel disease (IBD) pathogenesis is loss of mucosal barrier function. Emerging evidence
implicates extracellular adenosine signaling in attenuating mucosal inflammation. We hypothesized that adenosinemediated protection from intestinal barrier dysfunction involves tissue-specific signaling through the A2B adenosine
receptor (Adora2b) at the intestinal mucosal surface. To address this hypothesis, we combined pharmacologic studies
and studies in mice with global or tissue-specific deletion of the Adora2b receptor. Adora2b / mice experienced a
significantly heightened severity of colitis, associated with a more acute onset of disease and loss of intestinal epithelial
barrier function. Comparison of mice with Adora2b deletion on vascular endothelial cells (Adora2bfl/flVeCadCre Ăľ ) or
intestinal epithelia (Adora2bfl/flVillinCre Ăľ ) revealed a selective role for epithelial Adora2b signaling in attenuating colonic
inflammation. In vitro studies with Adora2b knockdown in intestinal epithelial cultures or pharmacologic studies
highlighted Adora2b-driven phosphorylation of vasodilator-stimulated phosphoprotein (VASP) as a specific barrier
repair response. Similarly, in vivo studies in genetic mouse models or treatment studies with an Adora2b agonist
(BAY 60-6583) recapitulate these findings. Taken together, our results suggest that intestinal epithelial Adora2b signaling
provides protection during intestinal inflammation via enhancing mucosal barrier responses
Alpha-1-antitrypsin Therapy Ameliorates Acute Colitis and Chronic Murine Ileitis
Background: Fecal alpha-1-antitrypsin (AAT) clearance has been a marker of clinical disease severity in inflammatory bowel diseases (IBDs) for many
years. Although AAT deficiency is more often associated with lung and liver pathologies, AAT-deficient patients with concomitant IBD have been
shown to develop more aggressive disease and rapid progression to surgery. Although recent studies have highlighted the pleiotropic anti-inflammatory
functions of AAT, including reducing proinflammatory cytokine production and suppressing immune cell activation, its potential therapeutic role in IBD
has not been described.
Methods: The therapeutic potential of human AAT administration was assessed in murine models of IBD including new-onset and established
chemically induced colitis and spontaneous chronic murine ileitis. Histological assessment of inflammation, cytokine secretion profiling, and flow
cytometric evaluation of inflammatory infiltrate were performed in each model. The effect of AAT on intestinal barrier function was also examined both
in vitro and in vivo.
Results: AAT attenuated inflammation in small and large intestinal IBD models through reduced secretion of proinflammatory cytokines, inflammatory
cell infiltration, and reduced tissue injury. AAT also increased intestinal restitution after chemically induced colitis. AAT significantly decreased
intestinal permeability in vitro and in vivo as part of a protective mechanism for both acute and chronic models of IBD.
Conclusions: Our findings describe a beneficial role for AAT in IBD models through suppression of cytokine production and enhanced intestinal
barrier function. This raises the possibility that AAT supplementation, which has a long history of proven safety, may have a therapeutic effect in
human IBD