Ketamine Attenuates Airway Inflammation via Inducing Inflammatory Cells Apoptosis and Activating Nrf2 Pathway in a Mixed-Granulocytic Murine Asthma Model

Abstract

The use of ketamine, an anesthetic, as a treatment for asthma has been investigated in numerous studies. However, how ketamine affects asthma is unclear. The present study examined the effects of ketamine on a murine model of mixed-granulocytic asthma, and the role of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Methods: The murine model of mixed-granulocytic asthma was established using ovalbumin (OVA) for sensitization and the combination of OVA and lipopolysaccharides (LPS) for challenge. The main characteristics of asthma, oxidative stress biomarkers, and the expression of the Nrf2 pathway were examined. ML385 was administered to verify the role of the Nrf2 pathway. Results: Mice in the OVA +LPS group developed asthmatic characteristics, including airway hyperresponsiveness, mixedgranulocytic airway inflammation, mucus overproduction, as well as increased levels of oxidative stress and impaired apoptosis of inflammatory cells. Among the three concentrations, ketamine at 75mg/kg effectively attenuated these asthmatic symptoms, activated the Nrf2 pathway, decreased oxidative stress, and induced apoptosis of eosinophils and neutrophils in bronchoalveolar lavage fluid (BALF) with a reducing level of myeloid cell leukemia 1(Mcl-1). ML385 (an Nrf2 inhibitor) eliminated the protective effects of ketamine on the mixed-granulocytic asthma model. Conclusion:The study concluded that ketamine reduced oxidative stress and attenuated asthmatic symptoms (neutrophilic airway inflammation) by activating the Nrf2-Keap1 pathway, with 75 mg/kg ketamine showing the best results. Ketamine administration also increased neutrophil and eosinophil apoptosis in BALF, which may contribute to the resolution of inflammation. The use of ketamine as a treatment for asthma may therefore be beneficial.

Esculentoside A ameliorates DNCB‐induced atopic dermatitis by suppressing the ROS‐NLRP3 axis via activating the Nrf2 pathway

“…ML385 was purchased from MedChemExpress (HY‐100523) with a purity of 99.72% and dissolved in DMSO. The dose of ML385 used in the present study was based on the previous study 69 . Mice in the Control group were stimulated with the same amount of vehicle with acetone and olive oil and intraperitoneally treated with an equal amount of DMSO daily.…”

Ketamine, an Old–New Drug: Uses and Abuses

“…These effects could be explained by several mechanisms, which include inhibition of the NMDA receptor in the airways leading to relaxation of tracheal smooth muscle and bronchodilation, decrease of the nitric oxide levels mediating bronchospasm by inhibition of mRNA overexpression, and protein induction by nitric oxide synthetase. As an antinflammatory agent, ketamine decreases cytokine production, reduces the macrophages, and prevents catecholamine reuptake in the periphery,which increases the free norepinephrine levels and produces a more pronounced effect on the beta-2 receptors, leading to bronchodilatation [85][86][87][88]. Ketamine is considered the bronchodilator of choice in rescue therapy for refractory status asthmaticus in the intensive care unit (ICU).…”

Ketamine, an Old–New Drug: Uses and Abuses

“…These effects could be explained by several mechanisms, which include inhibition of the NMDA receptor in the airways leading to the relaxation of the tracheal smooth muscle and bronchodilation, a decrease in the nitric oxide levels mediating bronchospasm by inhibition of mRNA overexpression, and protein induction by nitric oxide synthetase. As an anti-inflammatory agent, ketamine decreases cytokine production, reduces macrophages, and prevents catecholamine reuptake in the periphery, which increases free norepinephrine levels and produces a more pronounced effect on beta-2 receptors, leading to bronchodilatation [ 97 , 98 , 99 , 100 ]. Ketamine can be used in cases of life-threatening status asthmaticus with doses of 0.1–0.2 mg/kg followed by an infusion of 0.15–2.5 mg/kg/h [ 56 , 101 ].…”