Simvastatin delivery via inhalation attenuates airway inflammation in a murine model of asthma
Highlights
► Simvastatin via inhalation delivery attenuates airway inflammation. ► Simvastatin via inhalation delivery showed a higher drug concentration in local lung tissue. ► Simvastatin is suitable for inhalation delivery. ► Simvastatin via inhalation delivery probably overcome the side effect liabilities and efficacy of oral simvastatin.
Introduction
Statins, which are inhibitors of 3-hydroxy-3-methyl-3-glutaryl coenzyme A reductase, not only reduce cholesterol but also have several other pharmacological actions that might be beneficial in airway inflammatory diseases, including anti-oxidant, anti-inflammatory, and immunomodulatory effects. Many of these pleiotropic effects of statins are mediated by the inhibition of the isoprenylation of small GTP-binding signaling molecules, such as Rho, Ras, and Rac [1]. McKay and colleagues showed for the first time that simvastatin treatment, either orally or by intraperitoneal injection (i.p.), effectively suppresses acute eosinophilic airway inflammation and Th2 cytokine secretion in a mouse asthmatic model [2]. Both oral and i.p simvastatin treatment reduced the ovalbumin-specific IgE levels; the number of total inflammatory cells, macrophages, neutrophils, and eosinophils in the bronchoalveolar lavage fluid; the expression of CD40, CD40 L and VCAM-1; the mRNA and protein levels of interleukin (IL)-4, IL-13 and tumor necrosis factor (TNF)-α; the number of goblet cells; and the activity of matrix metalloproteinases (MMPs); and induced the activity of small G proteins, MAP kinases and NF-kappaB activities in bronchoalveolar lavage cells and lung tissues in ovalbumin-induced allergic asthma in mice [3]. Cotreatment with mevalonate and simvastatin reversed the anti-inflammatory effects observed with simvastatin alone. The mevalonate pathway appears to modulate allergic airway inflammation, whereas the beneficial effects of simvastatin on lung compliance and airway hyperreactivity may be independent of the mevalonate pathway [4]. In the clinic, the published data are controversial. Oral statin treatment is associated with reduced hospitalization from asthma attacks in patients with asthma [5] and the prevention of chronic rhinosinusitis and pulmonary exacerbation of obstructive airway diseases [6], suggesting possible applications of statins in patients with asthma and other airway inflammatory diseases. Furthermore, oral statin treatment enhances the anti-inflammatory effect of an inhaled corticosteroid in asthmatic patients, which was mediated by the reduction of sputum macrophage counts and the alteration of the activity of indoleamine 2, 3-dioxygenase (IDO), a tryptophan-degrading enzyme, in macrophages [7], [8]. In asthma, there are theoretical reasons as to how statins might exert their therapeutic effects. In human tissue, statin actions include reducing both the proliferation and activation of T cells and the migration of leucocytes [9]; inhibiting the adhesion of eosinophils [10], the degranulation of mast cells [11], and the proliferation, synthesis and secretion of extracellular matrix proteins by the human airway smooth muscle cells [12], [13]; and enhancing inflammatory cell apoptosis [14]. However, there are three clinical studies of statins in asthma that have not demonstrated important differences between statin treatment and placebo for the spirometry or airway hyperresponsiveness (AHR) symptoms [15], [16], although the sputum leukotriene B4 and macrophages decreased significantly with statin treatment [17]. The administered dose in the three clinical studies was 40 mg oral atorvastatin or simvastatin daily, so we cannot exclude the possibility that the lack of clinical effects may have been because the dose of simvastatin was too low. Prospective, controlled trials are needed to establish if statins have a beneficial effect in patients with asthma and chronic obstructive pulmonary disease, especially those with systemic complications and comorbidities. The dose response for the pleiotropic effects of statins has not yet been established and may differ from the cholesterol-lowering effects. High oral doses of statins may have adverse effects, particularly on skeletal muscles [17], so it would be important for statins to be delivered by the inhaled route [18]. Inhaled aerosol drug delivery provides a unique opportunity for the topical treatment of the lungs. Ideally, this allows for high pulmonary concentrations of medication to be attained without high systemic levels, providing efficient and effective therapies that spare patients from the unwanted side effects. The object of this study was to determine if simvastatin delivered as an aerosol to the local airway of a murine model of asthma could reduce airway inflammation and AHR while maintaining a low systemic drug delivery by evaluating the concentrations in the blood and lung tissue after the aerosol and oral administration of simvastatin.
Section snippets
Animals
Inbred, female, specific pathogen-free BALB/c mice (weighing 20 ± 2 g, 6 weeks old) were purchased from the Shanghai Slac Laboratory Animal Co. Ltd. (Certificate No. SCXK 2007–0005, Shanghai, China). The animals were housed in a room maintained at 23 ± 2 °C with 50 ± 10% humidity and a 12-h light/12-h dark cycle (lights on from 8:00 a.m. to 8:00 p.m.). The animals were allowed free access to tap water and regular rodent chow. Rodent chow was withheld for 8 h before the experiments. All the animal care and
The effects of the different delivery routes of simvastatin on airway inflammatory cells
The total number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) of the vehicle-ovalbumin-treated mice was 6.8-fold greater than that in control mice. Simvastatin delivered by different routes (5 mg/mL i.h. for 10 min, 2 mg/kg i.t., 40 mg/kg i.g., and 40 mg/kg i.p.), the reference drug Y-27632 (10 mg/kg i.n.) and dexamethasone (1 mg/kg i.p.) all significantly inhibited the accumulation of the inflammatory cells in the airways. The eosinophils in the BALF in the vehicle-OVA-treated mice
Discussion
This study describes the pharmacology of simvastatin, which has a biological and pharmacokinetic profile ideal for delivery as an inhaled drug. Simvastatin is a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and has been widely prescribed to treat hyperlipidemia. Statins have several other pharmacological actions that might be beneficial in airway inflammation disease, including anti-inflammatory, anti-oxidant, and immunomodulatory effects. Many of these
Conflict of interest
The authors declare that there are no conflicts of interest.
Acknowledgments
This work was supported by grants from the National Scientific Foundation of China (No. 81172880 and 30973542).
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These authors contributed equally to this work.