FGF9-induced proliferative response to eosinophilic inflammation in oesophagitis

Abstract

Background: Oesophagitis is characterised by basal cell hyperplasia and activated eosinophils, which release mediators including major basic protein (MBP). MBP and its mimetic polyarginine activate the calcium sensing receptor (CaSR) on oesophageal epithelium. Fibroblast growth factor 9 (FGF9) is implicated in epithelial homeostasis and proliferative response to injury, but has not been characterised in the oesophagus. Objective: To characterise FGF9 in oesophageal epithelium and oesophagitis, as the result of MBP activation of the CaSR. Methods: Human oesophageal epithelial cells (HET-1A) were used to compare affects of calcium, polyarginine and MBP-peptide on FGF9. HET-1A were transfected with interfering RNA (siRNA CaSR ). FGF9, FGF receptors 2 and 3, bone morphogenetic protein (BMP)-2, BMP-4 and noggin mRNA expression were detected by reverse transcriptase polymerase chain reaction. FGF9 was measured from HET-1A and from normal, gastro-oesophageal reflux and eosinophilic oesophagitis (EoE) patient biopsies using ELISA and immunohistochemistry. HET-1A proliferation was studied using bromodeoxyuridine and MTT. Results: FGF9 was secreted by HET-1A cells treated with polyarginine and MBP-peptide, but not calcium. This effect was abrogated by siRNA CaSR

Esophageal dilation in eosinophilic esophagitis

“…This was confirmed in our recent review of complications of EoE, where perforation associated with contrast extravasation into the chest could be found in only 14 patients (25). Four were related to endoscope passage sometimes with a rigid instrument, seven due to spontaneous (Boerhaave's) perforation, three in which the etiology could not be M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 16 determined and only one in a 17 year old girl was associated with esophageal dilation. As shown in Table 2, experienced gastroenterologists using a conservative approach to esophageal dilation report only three esophageal perforations.…”

“…Other profibrotic molecules, including CC chemokine ligand 18 (CCL-18) and fibroblast growth factor 9 (FGF-9) are increased in EoE patients and may have TGFB1 independent pathways to fibrosis. (15,16) Both TGFB1 and IL-13 also increase the levels of periostin, an extracellular matrix protein that promotes the migration and adherence of eosinophils to tissue sites (17).…”

Subepithelial collagen deposition, profibrogenic cytokine gene expression, and changes after prolonged fluticasone propionate treatment in adult eosinophilic esophagitis: A prospective study

“…11 EoE-associated fibrosis is related to the extent of esophageal eosinophil activation, as evidenced by eosinophil degranulation, which can be determined through immunohistochemical staining for MBP. 5 EoE biopsy specimens show that eosinophil-released MBP increases the expression of fibroblast growth factor 9 (FGF-9), 12 a cytokine implicated in the proliferative response to injury, 13 which in turn correlates with EoE-associated basal cell hyperplasia. In a murine model of EoE, subepithelial fibrosis was found to be directly caused by tissue eosinophilia induced by IL-5, 4 a T H 2-type cytokine the expression of which is also upregulated in human EoE.…”

Adult versus pediatric eosinophilic esophagitis: important differences and similarities for the clinician to understand

“…Eosinophil-released major basic protein increases gene expression of FGF-9, a cytokine implicated in the proliferative response after tissue damage [75]. Eosinophils also produce and secrete high amounts of CCL18, a type-2 chemokine implicated in fibrous remodeling of the lungs through fibroblast proliferation and collagen deposition, and the expression levels of which have been shown to be increased in EoE [56].…”