Barbot Anne, Lheritier-Barrand Michele, Murrieta-Aguttes Margarita, Leonetti Maud, Vernaz Jimmy, Huang Song, Constant Samuel, Boda Bernadett
Sanofi, CHC Scientific Innovation, Neuilly, France.
Sanofi R&D, Vitry-sur-Seine, France.
Front Pharmacol. 2024 Jun 12;15:1393702. doi: 10.3389/fphar.2024.1393702. eCollection 2024.
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 stabilize 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 HIS-induced 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.
The model was developed using nasal MucilAir™ (Epithelix) epithelium challenged by HIS. Two conditions were assessed in a side-by-side comparison: tissue was exposed to HIS + FEX with or without FEX pre-treatment (one-hour prior to HIS challenge). Tissue functionality, cytotoxicity, H1R gene expression, and inflammatory cytokines were assessed.
HIS at 100 µM induced significant 3.1-fold and 2.2-fold increases for inflammatory biomarkers interleukin (IL)-8 and IL-6, respectively ( < 0.0001), as well as rapid upregulation of H1R mRNA. Inflammatory biomarkers were inhibited by FEX and H1R expression was significantly reduced ( < 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 ( < 0.05) and further downregulation of H1R expression and IL-6 without FEX pre-treatment; the effects of FEX were improved from 22% to 40%.
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 a higher effect when used before+during only during the HIS challenge. Taking FEX before+during allergen exposure, or when symptoms first occur, may reduce basal activity and H1R gene expression, providing stronger protection against the worsening of symptoms upon allergen exposure.
非索非那定（FEX）是一种抗组胺药，作为组胺（HIS）受体1（H1R）的反向激动剂发挥作用，该受体介导过敏反应。反向激动剂可能比中性拮抗剂更有效，因为它们与激动剂（HIS）结合相同的受体，但稳定非活性形式并诱导相反的药理反应，抑制H1R的基础活性并阻止HIS结合。本研究旨在建立并验证基于完全重构的人鼻上皮组织的HIS诱导炎症模型，以评估FEX作为该模型中反向激动剂的活性，并探索其与临床益处的联系。
使用经HIS刺激的鼻MucilAir™（Epithelix）上皮建立模型。在并排比较中评估两种情况：组织在有或没有FEX预处理（在HIS刺激前一小时）的情况下暴露于HIS + FEX。评估组织功能、细胞毒性、H1R基因表达和炎性细胞因子。
100 μM的HIS分别使炎性生物标志物白细胞介素（IL）-8和IL-6显著增加3.1倍和2.2倍（<0.0001），以及H1R mRNA的快速上调。炎性生物标志物受到FEX的抑制，H1R表达显著降低（<0.0001）。单独使用FEX在所有测试剂量下均降低H1R表达。经过一小时的FEX预处理，IL-8的下调显著更高（<0.05），并且在没有FEX预处理的情况下H1R表达和IL-6进一步下调；FEX的效果从22%提高到40%。
基于IL-8、IL-6和H1R基因表达建立了HIS诱导的气道炎症模型，并用FEX进行了验证。FEX作为反向激动剂起作用，仅在HIS刺激期间之前和期间使用时效果更高。在变应原暴露之前和期间或症状首次出现时服用FEX，可能会降低基础活性和H1R基因表达，为防止变应原暴露后症状恶化提供更强的保护。
