Abstract
Since airway hyperresponsiveness (AHR) and allergic inflammatory changes are regarded as the primary manifestations of asthma, the main goals of asthma treatment are to decrease inflammation and maximize bronchodilation. These goals can be achieved with aerosol therapy. Intravenous administration of the anesthetic, ketamine, has been shown to trigger bronchial smooth muscle relaxation. Furthermore, increasing evidence suggests that the anti-inflammatory properties of ketamine may protect against lung injury. However, ketamine inhalation might yield the same or better results at higher airway and lower ketamine plasma concentrations for the treatment of asthma. Here, we studied the effect of ketamine inhalation on bronchial hyperresponsiveness and airway inflammation in a Brown-Norway rat model of ovalbumin(OVA)-induced allergic asthma. Animals were actively sensitized by subcutaneous injection of OVA and challenged by repeated intermittent (thrice weekly) exposure to aerosolized OVA for two weeks. Before challenge, the sensitizened rats received inhalation of aerosol of phosphate-buffered saline (PBS) or aerosol of ketamine or injection of ketamine respectivity. Airway reactivity to acetylcholine (Ach) was measured in vivo, and various inflammatory markers, including Th2 cytokines in bronchoalveolar lavage fluid (BALF), as well as induciable nitric oxide synthase (iNOS) and nitric oxide (NO) in lungs were examined. Our results revealed that delivery of aerosolized ketamine using an ultrasonic nebulizer markedly suppressed allergen-mediated airway hyperreactivity, airway inflammation and airway inflammatory cell infiltration into the BALF, and significantly decreased the levels of interleukin-4 (IL-4) in the BALF and expression of iNOS and the concentration of NO in the inflamed airways from OVA-treated rats. These findings collectively indicate that nebulized ketamine attenuated many of the central components of inflammatory changes and AHR in OVA-provoked experimental asthma, potentially providing a new therapeutic approach against asthma.
Highlights
Asthma is characterized by acute and chronic airway inflammation, in which the severity of airway hyperreactivity (AHR) is correlated with the degree of inflammation [1]
We examined the effect of nebulized ketamine inhalation on allergeninduced AHR and inflammatory changes in OVA-sensitized Brown-Norway rats, a model in which chronic OVA challenge is used to stimulate airway inflammation and AHR [17]
In groups receiving 12.5, 25 and 50 mg/ml ketamine by inhalation and 50 and 100 μg/kg ketamine by i.p. injection, the doses required to increase the Re by 100% (PC100) were 31.09 ± 1.51 μg/kg (P < 0.001), 20.44 ± 1.28 μg/kg (P = 0.019), 25.57 ± 1.38 μg/kg (P < 0.001), 24.02 ± 1.32 μg/kg (P < 0.001) and 20.39 ± 1.29 μg/kg (P = 0.022) respectively
Summary
Asthma is characterized by acute and chronic airway inflammation, in which the severity of airway hyperreactivity (AHR) is correlated with the degree of inflammation [1]. Inhaled drugs play an important role in asthma management, as many of the beta-adrenergic and anti-cholinergic bronchodilators, corticosteroids, and nonsteroidal anti-inflammatory agents currently used in the treatment of acute asthma are administered as inhaled gases or aerosols [3]. Steroids and beta-agonists form the mainstay of asthma therapy, the symptoms in some asthmatics are poorly controlled with these drugs, and their therapeutic benefits may be outweighed to some degree by their undesirable side effects [4]. Researchers continue to seek and evaluate additional drugs capable of modulating inflammatory responses and AHR in the treatment of asthma
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