The long-term inhibition of Orai-STIM coupling alleviates airways remodeling changes in experimental conditions

[Speaker] Martina Sutovska:1
[Co-author] Michaela Kocmalova:1, Ivana Kazimierova:1, Marta Joskova:1, Marian Adamkov:2, Sona Franova:1
1:Department of Pharmacology and BioMed (Martin's Biomedical Center), Jessenius Faculty of Medicine, Comenius University, Mala Hora, 11161 4D, 036 01 Martin, Slovakia, 2:Institute of Histology and Embryology, Jessenius Faculty of Medicine, Comenius University, Mala Hora 4, 03601, Martin, Slovakia

Background: Airway remodeling (AR) in asthma includes complex of morphological changes, i.e. epithelial alterations, subepithelial fibrosis, goblet cells enlargement, increased smooth muscle mass and neovascularization. These changes contribute to thickening of airway walls and, consequently, lead to poor clinical outcomes among asthmatic patients. AR is mediated by various mediators, cytokines and growth factors that are released from epithelial, immune and airway smooth muscle (ASM) cells and that act though Ca2+ - dependent pathways. There is an increased evidence that Orai-STIM coupling represents one of the most important extracellular Ca2+ sources involved in AR.
Methods: This study was focused on Orai-STIM pathway involvement in mechanisms of AR and evaluated effect of long-term Orai-STIM pathway inhibition on AR in experimental conditions. 28 days-long sensitization by ovalbumin was used to induce AR changes in guinea pigs airways. In experimental group, sensitization procedure was followed by long-term administration (14 days-long) of 3-fluoropyridine-4-carboxylic acid (FPCA, inhibitor of Orai-STIM coupling) or by control drugs in control groups (positive control drugs budesonide and salmeterol, negative control saline). AR and anti-remodeling effect were evaluated using histological (Gomori staining method) and immunohistochemical methods (using anti-alpha smooth muscle actin (SMA) and anti-mucin 5AC antibodies). The molecular changes responsible for the anti-remodeling effect mediation were evaluated by BioPlex assay and ELISA.
Results: Histological and immunohistochemical analysis confirmed development of the main histomorphological features of AR as the result of repetitive exposure to ovalbumin, i.e. increase in collagen III and SMA wall layer and goblet cells hyperplasia. Histomorphological evaluation pointed on anti-remodeling effect of Orai-STIM long-term inhibition (Fig. 1). Furthermore, AR was shown to be mediated by various cytokines and growth factors (IL-4, IL-5, IL-13, TNF-alpha, INF-gamma, GM-CSF, VEGF, TGF-beta and EGF) and Orai-STIM coupling inhibitor possessed anti-remodeling effect through suppression of IL-4, IL-13, TNF-alpha, INF-gamma and TGF-beta functions.
Conclusion: Reversal of remodeling is of paramount therapeutic importance. Targeting Orai-STIM seems to be a new and promising approach to manage chronic airway diseases. By modulating activities of airway epithelial, ASM and inflammatory cells at the same time, Orai-STIM inhibitors would be particularly effective in damping down both immune and remodeling components.

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