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FGF9-induced proliferative response to eosinophilic inflammation in esophagitis
  1. Daniel J Mulder (3dm16{at}queensu.ca)
  1. Queen's University, Canada
    1. Ivan Pacheco (pacheci1{at}kgh.kari.net)
    1. Queen's University, Canada
      1. David J Hurlbut (hurlbutd{at}kgh.kari.net)
      1. Queen's University, Canada
        1. Nanette Mak (makn{at}queensu.ca)
        1. Queen's University, Canada
          1. Glenn T Furuta (furuta.glenn{at}tchden.org)
          1. University of Colorado Denver, United States
            1. R John MacLeod (rjm5{at}post.queensu.ca)
            1. Queen's University, Canada
              1. Christopher J Justinich (justinic{at}kgh.kari.net)
              1. Queen's University, Canada

                Abstract

                Background: Esophagitis is characterized 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 esophageal epithelium. Fibroblast growth factor 9 (FGF9) is implicated in epithelial homeostasis and proliferative response to injury, but has not been characterized in the esophagus.

                Objective: Characterize FGF9 in esophageal epithelium and esophagitis, as the result of MBP activation of the CaSR.

                Methods: Human esophageal epithelial cells (HET-1A) were used to compare effects of calcium, polyarginine and MBP-peptide on FGF9. HET-1A were transfected with interfering RNA (siRNACaSR). FGF9, FGF receptors 2 and 3, bone morphogenetic protein (BMP)-2, BMP-4 and noggin mRNA expression was detected by RT-PCR. FGF9 was measured from HET-1A and from normal, gastroesophageal reflux and eosinophilic esophagitis (EoE) patient biopsies using ELISA and immunohistochemistry. HET-1A proliferation was studied using BrdU and MTT.

                Results: FGF9 was secreted by HET-1A cells treated with polyarginine and MBP-peptide, but not calcium. This effect was abrogated by siRNACaSR. FGF9 receptor mRNA was present. HET-1A cells proliferated following rhFGF9, but not MBP-peptide treatment, and rhFGF9 altered transcription of downstream proliferation-related genes (noggin, BMP-2 and BMP-4). FGF9 was increased in biopsies from patients with eosinophilic esophagitis, which correlated with basal hyperplasia.

                Conclusion: Eosinophil released MBP acts on the CaSR to increase FGF9 in esophageal epithelial cells, leading to proliferation. Increased FGF9 is found in biopsies of EoE patients and may play a role in the pathogenesis of esophagitis.

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