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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Inflammation Pharmacology
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1393702
This article is part of the Research Topic Women in Inflammation Pharmacology: 2023 View all 3 articles

Establishment of a human nasal epithelium model of histamineinduced inflammation to assess the activity of fexofenadine as an inverse agonist and its link to clinical benefit

Provisionally accepted
Anne Barbot Anne Barbot 1*Michele Lheritier-Barrand Michele Lheritier-Barrand 1Margarita Murrieta-Aguttes Margarita Murrieta-Aguttes 1Maud Leonetti Maud Leonetti 2Jimmy Vernaz Jimmy Vernaz 3Song Huang Song Huang 3Samuel Constant Samuel Constant 3Bernadett Boda Bernadett Boda 3
  • 1 Sanofi, CHC Scientific Innovation, Neuilly, France
  • 2 Sanofi R&D, Vitry-sur-Seine, France
  • 3 Epithelix, Plan-les-Ouates, Switzerland

The final, formatted version of the article will be published soon.

    Background: Fexofenadine (FEX) is an antihistamine that acts as an inverse agonist against histamine (HIS) receptor 1 (H1R), which mediates the allergic reaction. Inverse agonists may be more potent than neutral antagonists, as they bind the same receptor as the agonist (HIS) but stabilise the inactive form and induce an opposite pharmacological response, suppressing the basal activity of H1R and preventing HIS from binding. This study aims to establish and validate a model of HISinduced inflammation based on fully reconstituted human nasal epithelial tissue, to assess the activity of FEX as an inverse agonist in this model and explore its link to clinical benefit. Methods: The model was developed using nasal MucilAir™ (Epithelix) in vitro epithelium challenged by HIS. Two conditions were assessed in a side-by-side comparison: tissue was exposed to HIS+FEX with/without FEX pre-treatment (1-hour prior to HIS challenge). Tissue functionality, cytotoxicity, H1R gene expression and inflammatory cytokines were assessed.Results: HIS at 100 µM induced significant 3.1-fold and 2.2-fold increases for inflammatory biomarkers interleukin(IL)-8 and IL-6 respectively (p<0.0001), and rapid upregulation of H1R mRNA. Inflammatory biomarkers were inhibited by FEX and H1R expression was significantly reduced (p<0.0001). FEX alone decreased H1R expression at all doses tested. With one-hour FEX pre-treatment, there was significantly higher downregulation of IL-8 (p<0.05) and further downregulation of H1R expression and IL-6 versus without FEX pre-treatment; the effects of FEX were improved from 22-40%.Conclusions: A model of HIS-induced airway inflammation was established based on IL-8, IL-6 and H1R gene expression, and was validated with FEX. FEX works as an inverse agonist, with higher effect when used before+during versus just during HIS challenge. Taking FEX before+during allergen exposure, or when symptoms first occur, may reduce basal activity and H1R gene Internal expression, providing stronger protection against the worsening of symptoms upon allergen exposure.

    Keywords: Inflammation, allergy, Nasal epithelium, antihistamine, fexofenadine, biomarkers, inverse agonist

    Received: 29 Feb 2024; Accepted: 29 Apr 2024.

    Copyright: © 2024 Barbot, Lheritier-Barrand, Murrieta-Aguttes, Leonetti, Vernaz, Huang, Constant and Boda. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Anne Barbot, Sanofi, CHC Scientific Innovation, Neuilly, France

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.