%0 Journal Article
%A Pérez Diego, Mario
%A Angelina Querencias, Alba
%A Pat, Yağız
%A Maldonado, Angel
%A Sevilla Ortega, Carmen
%A Martín De La Cruz, Leticia
%A Yazici, Duygu
%A Rückert,  Beate
%A Sokolowska, Milena
%A Martín-Fontecha Corrales, María Del Mar
%A Akdis , Mübeccel
%A Akdis, Cezmi A
%A Palomares Gracia, Óscar
%T Cannabinoid WIN55,212-2 restores bronchial epithelium by regulating oxidative stress and STAT6 phosphorylation
%D 2025
%U https://hdl.handle.net/20.500.14352/122508
%X Background: Viral infections and type 2 immune responses perpetuate airway epithelial barrier dysfunction and inflammation, leading to the development and progression of asthma. The synthetic cannabinoid WIN55,212-2 displays anti-inflammatory properties by acting on different immune system cells.Objective: We sought to investigate the capacity of WIN55,212-2 to restore bronchial epithelial barrier function in asthma in the context of viral infections or type 2-driven inflammation.Methods: Air-liquid interface cultures of human bronchial epithelial cells and human bronchial epithelial spheroids were generated to assess the capacity of WIN55,212-2 to restore airway epithelial barrier damage induced by human rhinovirus A16 (RV-A16) infection or type 2 inflammation. RT-PCR, cytokine quantification, permeability assays, metabolic studies, flow cytometry, and Western blot techniques were employed to assess the effects of WIN55,212-2 on the airway epithelium. The in vivo relevance of our findings was evaluated in a murine model of IL-13-induced airway inflammation.Results: Prophylactic and therapeutic administration of WIN55,212-2 accelerated the recovery from RV-A16-induced bronchial epithelial barrier damage. WIN55,212-2 inhibited the acquisition of IL-13-induced type 2 asthma features in air-liquid interface cultures, self-assembled bronchial epithelial spheroids, and in vivo asthma model of airway inflammation and epithelial dysfunction. Mechanistically, WIN55,212-2 impaired IL-13-induced oxidative stress in epithelial cells, restoring the activity of protein tyrosine phosphatases, which in turn inhibited pSTAT6-mediated signaling pathways and asthma features.Conclusions: The cannabinoid WIN55,212-2 displays airway epithelial barrier protective effects during RV-A16 infection or type 2 inflammation by mechanisms associated with the modulation of oxidative metabolism and pSTAT6-mediated signaling.
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