Inhaled pan-phosphodiesterase inhibitors ameliorate ovalbumin-induced airway inflammation and remodeling in murine model of allergic asthma.

Autor: Wójcik-Pszczoła K; Jagiellonian University Medical College, Faculty of Pharmacy, Department of Pharmaceutical Biochemistry, Medyczna 9, 30-688 Kraków, Poland. Electronic address: katarzynaanna.wojcik@uj.edu.pl., Pociecha K; Jagiellonian University Medical College, Faculty of Pharmacy, Department of Pharmacokinetics and Physical Pharmacy, Medyczna 9, 30-688 Kraków, Poland., Chłoń-Rzepa G; Jagiellonian University Medical College, Faculty of Pharmacy, Department of Medicinal Chemistry, Medyczna 9, 30-688 Kraków, Poland., Zadrożna M; Jagiellonian University Medical College, Faculty of Pharmacy, Department of Cytobiology, Medyczna 9, 30-688 Kraków, Poland., Nowak B; Jagiellonian University Medical College, Faculty of Pharmacy, Department of Cytobiology, Medyczna 9, 30-688 Kraków, Poland., Plutecka H; Jagiellonian University Medical College, Faculty of Medicine, Department of Internal Medicine, Skawińska 8, 31-066 Kraków, Poland., Koczurkiewicz-Adamczyk P; Jagiellonian University Medical College, Faculty of Pharmacy, Department of Pharmaceutical Biochemistry, Medyczna 9, 30-688 Kraków, Poland., Przejczowska-Pomierny K; Jagiellonian University Medical College, Faculty of Pharmacy, Department of Pharmacokinetics and Physical Pharmacy, Medyczna 9, 30-688 Kraków, Poland., Pękala E; Jagiellonian University Medical College, Faculty of Pharmacy, Department of Pharmaceutical Biochemistry, Medyczna 9, 30-688 Kraków, Poland., Gosens R; University of Groningen, Department of Molecular Pharmacology, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands., Wyska E; Jagiellonian University Medical College, Faculty of Pharmacy, Department of Pharmacokinetics and Physical Pharmacy, Medyczna 9, 30-688 Kraków, Poland.
Jazyk: angličtina
Zdroj: International immunopharmacology [Int Immunopharmacol] 2023 Jun; Vol. 119, pp. 110264. Date of Electronic Publication: 2023 May 07.
DOI: 10.1016/j.intimp.2023.110264
Abstrakt: Asthma is a heterogeneous, chronic respiratory disease characterized by airway inflammation and remodeling. Phosphodiesterase (PDE) inhibitors represent one of the intensively studied groups of potential anti-asthmatic agents due to their affecting both airway inflammation and remodeling. However, the effect of inhaled pan-PDE inhibitors on allergen induced asthma has not been reported to date. In this study we investigated the impact of two, representative strong pan-PDE inhibitors from the group of 7,8-disubstituted derivatives of 1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione: compound 38 and 145, on airway inflammation and remodeling in murine model of ovalbumin (OVA)-challenged allergic asthma. Female Balb/c mice were sensitized and challenged with OVA, 38 and 145 were administrated by inhalation, before each OVA challenge. The inhaled pan-PDE inhibitors markedly reduced the OVA-induced airway inflammatory cell infiltration, eosinophil recruitment, Th2 cytokine level in bronchoalveolar lavage fluid, as well as both, total and OVA-specific IgE levels in plasma. In addition, inhaled 38 and 145 decreased many typical features of airway remodeling, including goblet cell metaplasia, mucus hypersecretion, collagen overproduction and deposition, as well as Tgfb1, VEGF, and α-SMA expression in airways of allergen challenged mice. We also demonstrated that both 38 and 145 alleviate airway inflammation and remodelling by inhibition of the TGF-β/Smad signaling pathway activated in OVA-challenged mice. Taken together, these results suggest that the investigated pan-PDE inhibitors administered by inhalation are dual acting agents targeting both airway inflammation and remodeling in OVA-challenged allergic asthma and may represent promising, anti-asthmatic drug candidates.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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