The Antidiabetic Agent Glibenclamide Protects Airway Hyperresponsiveness and Inflammation in Mice
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The Antidiabetic Agent Glibenclamide Protects Airway Hyperresponsiveness and Inflammation in Mice Wei Cui,1 Shufang Zhang,2 Zhijian Cai,3 Xinlei Hu,2 Ruifeng Zhang,4 Yong Wang,5 Na Li,1 Zhihua Chen,6 and Gensheng Zhang1,7
Abstract—Glibenclamide has a newly discovered role in inflammation regulation besides its antidiabetic effect. As an inhibitor of ATP-sensitive potassium (KATP) channel, glibenclamide antagonizes the relaxation of the tracheal smooth muscle. This indicates that glibenclamide might attenuate airway inflammation while aggravate airway hyperresponsiveness (AHR) in asthmatics. Clinically, many diabetics with asthma are prescribed with glibenclamide to control blood glucose. However, whether glibenclamide could exert any effects on asthmatic inflammation remains unknown. Using an ovalbumin (OVA)-induced mouse model of asthma, we evaluated the effects of glibenclamide on the AHR and inflammation. Interestingly, glibenclamide reduced all the cardinal features of asthma in OVAchallenged mice, including AHR, airway inflammation, and T-helper type 2 (Th2) cytokines. Glibenclamide also downregulated OVA-induced expressions of vascular cell adhesion molecule 1 (VCAM-1) and phosphorylated signal transducer and activator of transcription 6 (p-STAT6) in the lung. In addition, increased sulfonylurea receptor 1 (SUR1) expression in the lung was observed after the OVA challenge. These findings suggest that the classic sulfonylurea glibenclamide plays an important protective role in the development of asthma, which not only provides the evidence for the safety of prescribed glibenclamide in diabetics combined with asthma but also indicates a possible new therapeutic for asthma via targeting glibenclamide-related pathways. KEY WORDS: airway hyperresponsiveness; airway inflammation; asthma; glibenclamide; sulfonylurea receptor 1.
INTRODUCTION Sulfonylureas, like glibenclamide, have been used for type 2 diabetes for more than 50 years and are still the leading class of oral antihyperglycemic agents [1]. Recently, a wide range of anti-inflammatory effects of glibenclamide have been indicated [2–7]. Glibenclamide attenuates inflammation in targeted tissues via reducing vascular permeability, leukocyte recruitment, and proinflammatory cytokine production in the animal model of ischemia and reperfusion injury [2–5]. In an ex vivo model of human endotoxinemia, glibenclamide inhibits lipopolysaccharide-induced releases of interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) [6]. Glibenclamide, but not insulin or metformin, benefits mortality in human melioidosis, which correlates with its antiinflammatory effect on the immune system in a clinical study [7]. Inhibition of host inflammasome assembly [8], suppression of inflammatory mediators and leukocyte recruitment [3–5, 9], and regulation of oxidative stress and
Wei Cui and Shufang Zhang contributed equally to this work. 1
Department of Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China 2 Binjiang Br
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