Vasoactive intestinal peptide (VIP) appears to play an important role in the pathology of eosinophilic esophagitis (EoE) by recruiting mast cells and eosinophils that contribute to EoE’s hallmark symptoms of dysphagia and esophageal dysmotility, investigators reported in the February issue of.
Blocking one of three VIP receptors – chemoattractant receptor-homologous molecule expressed on Th2 (CRTH2) – could reduce eosinophil infiltration and mast cell numbers in the esophagus, wrote, a postodoctoral fellow at Tulane University in New Orleans, and his colleagues.
“We suggest that inhibiting the VIP–CRTH2 axis may ameliorate the dysphagia, stricture, and motility dysfunction of chronic EoE,” they wrote in a research letter to Cellular and Molecular Gastroenterology and Hepatology.
Several cytokines and chemokines, notably interleukin-5 and eotaxin-3, have been fingered as suspects in eosinophil infiltration, but whether chemokines other than eotaxin play a role has not been well documented, the investigators noted.
They hypothesized that VIP may be a chemoattractant that draws eosinophils into perineural areas of the muscular mucosa of the esophagus.
To test this idea, they looked at VIP-expression in samples from patients both with and without EoE and found that VIP expression was low among controls (without EoE); they also found that eosinophils were seen to accumulate near VIP-expressing nerve cells in biopsy samples from patients with EoE.
When they performed in vitro studies of VIP binding and immunologic functions, they found that eosinophils primarily express the CRTH2 receptor rather than the vasoactive intestinal peptide receptor 1 (VPAC-1) or VPAC-2.
They also demonstrated that VIP’s effects on eosinophil motility was similar to that of eotaxin and that, when they pretreated eosinophils with a CRTH2 inhibitor, esoinophil motility was hampered.
The investigators next looked at biopsy specimens from patients with EoE and found that eosinophils that express CRTH2 accumulated in the epithelial mucosa.
To see whether (as they and other researchers had suspected) VIP and its interaction with the CRTH2 receptor might play a role in mast cell recruitment, they performed immunofluorescence analyses and confirmed the presence of the CRTH2 receptor on tryptase-positive mast cells in the esophageal mucosa of patients with EoE.
“These findings suggest that, similar to eosinophils, mast cells accumulate via interaction of the CRTH2 receptor with neutrally derived VIP,” they wrote.
Finally, to see whether a reduction in peak eosinophil levels in patients with EoE with a CRTH2 antagonist – as seen in prior studies – could also ameliorate the negative effects of mast cells on esophageal function, they looked at the effects of CRTH2 inhibition in a mouse model of human EoE.
They found that, in the mice treated with a CRTH2 blocker, each segment of the esophagus had significant reductions in both eosinophil infiltration and mast cell numbers (P less than .05 for each).
The work was supported in part by grants from the National Institutes of Health and the Tulane Edward G. Schlieder Educational Foundation. Senior author Anil Mishra, PhD, disclosed serving as a consultant for Axcan Pharma, Aptalis, Elite Biosciences, Calypso Biotech SA, and Enumeral Biomedical. The remaining authors disclosed no conflicts of interest.