British journal of pharmacology · 2025
Protectin D1 and maresin 1 attenuate airway hyperreactivity induced by IL-13 in human isolated small bronchi.
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Abma Willem, Dahlén Sven-Erik, Wheelock Craig E, Adner Mikael, Al-Amerie Mamdoh, Sachs Erik, Vali Jalali Kasra, De Maria Leonardo, Olsson Henric, Säfholm Jesper
Аннотация
BACKGROUND AND PURPOSE: Interleukin (IL)-13 is implicated in airway hyperreactivity (AHR), a key feature of asthma. We explored the potential anti-AHR activity of selected specialised pro-resolving mediators (SPMs) in IL-13-induced AHR models, using human bronchial smooth muscle cells (BSMCs) and human isolated bronchi.
EXPERIMENTAL APPROACH: Calcium flux responses induced by histamine or LTD4 were assessed in BSMCs preconditioned with IL-13 and SPMs for 24 h. Human bronchi were isolated from lung tissue and preconditioned for 48 h in the presence or absence of IL-13 and SPMs. Concentration-response relationships for histamine and LTD4 were established using myography to determine efficacy (Emax) and potency (pEC50) following interventions.
KEY RESULTS: In BSMCs, exposure to IL-13 increased calcium flux (Emax) triggered by histamine and LTD4. Protectin D1 (PD1) and maresin 1 (MaR1) reversed this effect, but not lipoxin A4, resolvin D2, and maresin-conjugate in tissue repair 3 (MCTR3). In bronchi, IL-13 exposure amplified contractions to histamine and LTD4, and this enhancement was reversed by PD1 and MaR1. In contrast, PD1 and MaR1 added acutely during myography had no effect on agonist-induced contractility. PD1 attenuated IL-13-induced enhancement of airway contractions triggered by mast cell activation. CysLT1 antagonism did not influence the anti-hyperreactive effect of SPMs. Chemo-informatics revealed structural similarities between PD1 and MaR1 that may explain the anti-hyperreactive action of these two SPMs.
CONCLUSION AND IMPLICATIONS: This new anti-hyperreactive action of PD1 and MaR1 encourages further research into their potential as therapies for the treatment of airway hyperreactivity.
EXPERIMENTAL APPROACH: Calcium flux responses induced by histamine or LTD4 were assessed in BSMCs preconditioned with IL-13 and SPMs for 24 h. Human bronchi were isolated from lung tissue and preconditioned for 48 h in the presence or absence of IL-13 and SPMs. Concentration-response relationships for histamine and LTD4 were established using myography to determine efficacy (Emax) and potency (pEC50) following interventions.
KEY RESULTS: In BSMCs, exposure to IL-13 increased calcium flux (Emax) triggered by histamine and LTD4. Protectin D1 (PD1) and maresin 1 (MaR1) reversed this effect, but not lipoxin A4, resolvin D2, and maresin-conjugate in tissue repair 3 (MCTR3). In bronchi, IL-13 exposure amplified contractions to histamine and LTD4, and this enhancement was reversed by PD1 and MaR1. In contrast, PD1 and MaR1 added acutely during myography had no effect on agonist-induced contractility. PD1 attenuated IL-13-induced enhancement of airway contractions triggered by mast cell activation. CysLT1 antagonism did not influence the anti-hyperreactive effect of SPMs. Chemo-informatics revealed structural similarities between PD1 and MaR1 that may explain the anti-hyperreactive action of these two SPMs.
CONCLUSION AND IMPLICATIONS: This new anti-hyperreactive action of PD1 and MaR1 encourages further research into their potential as therapies for the treatment of airway hyperreactivity.