Cholinergic anti‐inflammatory pathway confers airway protection against oxidative damage and attenuates inflammation in an allergic asthma model

• Published in: Journal of cellular physiology 2020-02, Vol.235 (2), p.1838-1849
• Main Authors: Antunes, Géssica Luana, Silveira, Josiane Silva, Kaiber, Daniela Benvenutti, Luft, Carolina, da Costa, Mariana Severo, Marques, Eduardo Peil, Ferreira, Fernanda Silva, Breda, Ricardo Vaz, Wyse, Angela T. S., Stein, Renato Tetelbom, Pitrez, Paulo Márcio, Cunha, Aline Andrea
• Format: Article
• Language: English
• Subjects: Activation; airway inflammation; Antioxidants; Asthma; Catalase; cholinergic anti‐inflammatory pathway; Cholinergics; Cytokines; Eosinophils; Helper cells; Inflammation; Leukocytes (eosinophilic); Lymphocytes T; Neostigmine; Oxidation; Oxidative stress; Pharmacology; Reactive oxygen species; Respiratory tract; Respiratory tract diseases; Tumor necrosis factor
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.29101

Asthma is characterized by the influx of inflammatory cells, especially of eosinophils as well as reactive oxygen species (ROS) production, driven by the release of the T helper 2 (Th2)‐cell‐associated cytokines. The cholinergic anti‐inflammatory pathway (CAP) inhibit cytokines production and controls inflammation. Thus, we investigated the effects of pharmacological activation of CAP by neostigmine on oxidative stress and airway inflammation in an allergic asthma model. After the OVA challenge, mice were treated with neostigmine. We showed that CAP activation by neostigmine reduced the levels of pro‐inflammatory cytokines (IL‐4, IL‐5, IL‐13, IL‐1β, and TNF‐α), which resulted in a decrease of eosinophils influx. Furthermore, neostigmine also conferred airway protection against oxidative stress, attenuating ROS production through the increase of antioxidant defense, evidenced by the catalase (CAT) activity. We propose, for the first time, that pharmacological activation of the CAP can lead to new possibilities in the therapeutic management of allergic asthma. The clinical symptoms of allergic asthma are a consequence of chronic inflammation of the airway. Our results showed that pharmacological activation of the cholinergic anti‐inflammatory pathway by neostigmine was able to reduce the levels of IL‐4, IL‐5, IL‐13, IL‐1β, and TNF‐α, which resulted in a decrease of eosinophils influx and reduced the secretion of cytotoxic mediator EPO. Besides, treatment with neostigmine also conferred airway protection against oxidative damage, attenuating ROS production through an increase of antioxidant defense, evidenced by the CAT activity. Our findings showed that the protective effect found occurs by NFκB inhibition and increased Akt‐pAkt during α7 nicotinic ACh receptor signaling and lead to improves parameters of lung function. These findings provide a mechanism that can lead to new strategies, which inhibits the release of pro‐inflammatory cytokines and provides airway protection against oxidative damage in allergic asthma.