AUTHOR=Cerqua Ida , Granato Elisabetta , Corvino Angela , Severino Beatrice , D’Avino Danilo , Simonelli Martina , Perissutti Elisa , Scognamiglio Antonia , Mirra Davida , D’Agostino Bruno , Caliendo Giuseppe , Rossi Antonietta , Cirino Giuseppe , Motta Chiara Maria , Roviezzo Fiorentina 

TITLE=Prednisone-hydrogen sulfide releasing hybrid shows improved therapeutic profile in asthma

JOURNAL=Frontiers in Pharmacology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1266934

DOI=10.3389/fphar.2023.1266934

ISSN=1663-9812

ABSTRACT=<p><bold>Introduction:</bold> Hydrogen sulfide (H<sub>2</sub>S) is emerging as an important potential therapeutic option for respiratory inflammatory diseases. In this study, we investigated the effectiveness of a novel corticosteroid derivative, that is chemically linked to an H<sub>2</sub>S donor, in managing asthma features.</p><p><bold>Methods:</bold> The effects of prednisone (PS), H<sub>2</sub>S donor (4-hydroxybenzamide; TBZ), and their combination (PS-TBZ) have been evaluated <italic>in vitro</italic> and <italic>in vivo</italic>. The <italic>in vitro</italic> experiments were conducted using lipopolysaccharidestimulated J774 macrophages, while the <italic>in vivo</italic> experiments utilizing an experimental asthma model.</p><p><bold>Results:</bold> In the <italic>in vitro</italic> study we found that PS-TBZ exhibited an increased effect compared to the individual parent compounds in modulating the production of inflammatory mediators. TBZ also significantly reduced bronchial contractility and enhanced bronchial relaxation. In the <italic>in vivo</italic> experiments, where we administered PS, TBZ, or PS-TBZ to ovalbumin-sensitized BALB/c mice, we confirmed that PS-TBZ had a significantly better action in controlling airway hyperreactivity as compared to TBZ or PS alone. Moreover, PS-TBZ was more effective in restoring salbutamol-induced relaxation. The immunohistochemistry analysis demonstrated a significant reduction in the production of α-SMA and procollagen III, indicating the efficacy of PS-TBZ in controlling airway remodeling. Moreover, PS-TBZ also promoted epithelial repair, recovery of the bronchial and parenchyma structure and inhibited mucin production.</p><p><bold>Discussion:</bold> In conclusion, PS-TBZ offers an important opportunity to optimize the beneficial impact of corticosteroids on asthma features.</p>