Simvastatin delivery via inhalation attenuates airway inflammation in a murine model of asthma

Xu, Long; Dong, Xing-wei; Shen, Liangliang; Li, Fenfen; Jiang, Jun; Cao, Rui; Yao, Hongyi; Shen, Huijuan; Sun, Yuanming; Xie, Qiang-min

doi:10.1016/j.intimp.2012.01.012

Cited by 62 publications

(54 citation statements)

References 39 publications

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“…Simvastatin inhibits RANTES secretion through inactivation of AKT and STAT3 in lung epithelial cells STAT3 can be phosphorylated by several kinases in cytoplasm [17,18]. Therefore, we investigated which kinase phosphorylates STAT3 in poly I:C-stimulated epithelial cells.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, the nasal mucosa presents an ideal site for bioadhesive drug delivery systems, and drugs administered via this route generally work quickly [17]. Recently, XU et al [18] reported that simvastatin administered by inhalation and intratracheal injection had a more potent effect than that of intraperitoneal injection and gavage. Their results also showed that inhalation delivery routes led to a higher drug concentration in local lung tissue and a lower drug concentration in the plasma than that obtained by gavage.…”

Section: Pulmonary Infections Cs Lee Et Almentioning

confidence: 99%

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Simvastatin suppresses RANTES-mediated neutrophilia in polyinosinic–polycytidylic acid-induced pneumonia

Lee

et al. 2012

Eur Respir J

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Recently, statins have been shown to have anti-inflammatory effects on lung inflammatory diseases. However, the mechanisms of action of simvastatin in viral pneumonia have yet to be elucidated, although viral infection remains a considerable health threat. In this study, we hypothesised that simvastatin inhibits polyinosinic-polycytidylic acid (poly I:C)-induced airway inflammation, such as RANTES (regulated on activation, normal T-cell expressed and secreted) expression and inflammatory cell recruitment.In bronchial cells, the effect of simvastatin on poly I:C-induced RANTES expression and signal transducer and activator of transcription (STAT)3-mediated signal transduction was determined using an ELISA and short hairpin (sh)RNA system. In a poly I:C-induced pneumonia mouse model, immunological changes in the lungs after simvastatin inhalation, such as inflammatory cell recruitment and cytokine/chemokine release, were examined.In poly I:C-stimulated bronchial cells, RANTES secretion was increased by STAT3 activation, and simvastatin suppressed poly I:C-induced STAT3 activation, resulting in inhibition of RANTES expression. In BALB/c mice stimulated with inhaled poly I:C, RANTES expression and neutrophil infiltration into the airway were elevated. However, simvastatin treatment attenuated STAT3 activation, RANTES release and subsequent neutrophilia in the lungs.These findings suggest that simvastatin inhibits airway inflammation, but there are other mechanisms that need to be fully elucidated.

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Section: Resultsmentioning

confidence: 99%

Section: Pulmonary Infections Cs Lee Et Almentioning

confidence: 99%

Simvastatin suppresses RANTES-mediated neutrophilia in polyinosinic–polycytidylic acid-induced pneumonia

Lee

et al. 2012

Eur Respir J

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“…Five-micrometer-thick paraffin sections were stained with H&E, periodic acid-Schiff (PAS), Masson's trichrome, or picrosirius red. A five-point scoring system was used, as described previously, to determine peribronchial cell counts and extent of inflammatory cell infiltration, extent of mucus-secreting goblet cells, and subepithelial fibrosis (20). The analyses were performed in a blind fashion, and the slides were presented in a random order for each examination.…”

Section: Lung Histopathology and Immunostainingmentioning

confidence: 99%

The Nitrated Fatty Acid 10-Nitro-Oleate Attenuates Allergic Airway Disease

Reddy

Lakshmi

Dornadula

et al. 2013

The Journal of Immunology

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Asthma is a serious, growing problem worldwide. Inhaled steroids, the current standard therapy, are not always effective in this chronic inflammatory disease and can cause adverse effects. We tested the hypothesis that nitrated fatty acids (NFAs) may provide an effective alternative treatment. NFAs are endogenously produced by nonenzymatic reaction of NO with unsaturated fatty acids and exert anti-inflammatory actions both by activating the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR)γ and via PPAR-independent mechanisms, but whether they might ameliorate allergic airway disease was previously untested. We found that pulmonary delivery of the NFA 10-nitro-oleic acid (OA-NO2) reduced the severity of murine allergic airway disease, as assessed by various pathological and molecular markers. Fluticasone, an inhaled steroid commonly used to treat asthma, produced similar effects on most end points, but only OA-NO2 induced robust apoptosis of neutrophils and their phagocytosis by alveolar macrophages. This suggests that OA-NO2 may be particularly effective in neutrophil-rich, steroid-resistant severe asthma. In primary human bronchial epithelial cells, OA-NO2 blocked phosphorylation and degradation of IκB and enhanced inhibitory binding of PPARγ to NF-κB. Our results indicate that the NFA OA-NO2 is efficacious in preclinical models of allergic airway disease and may have potential for treating asthma patients.

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“…Metered dose inhalers (MDI) are still the main type of device for pulmonary drug delivery used worldwide. However, dry powder inhalers (DPI) are gaining more visibility by presenting interesting advantages, such as a low cost and an ease of handling, increasing treatment compliance (15,(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

Development of Novel Chitosan Microcapsules for Pulmonary Delivery of Dapsone: Characterization, Aerosol Performance, and In Vivo Toxicity Evaluation

et al. 2015

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ABSTRACT. Pneumocystis carinii pneumonia (PCP) is a major opportunistic infection that affects patients with human immunodeficiency virus. Although orally administered dapsone leads to high hepatic metabolism, decreasing the therapeutic index and causing severe side effects, this drug is an effective alternative for the treatment of PCP. In this context, microencapsulation for pulmonary administration can offer an alternative to increase the bioavailability of dapsone, reducing its adverse effects. The aim of this work was to develop novel dapsone-loaded chitosan microcapsules intended for deep-lung aerosolized drug delivery. The geometric particle size (D 4,3 ) was approximately 7 μm, the calculated aerodynamic diameter (d aero ) was approximately 4.5 μm, and the mass median aerodynamic diameter from an Andersen cascade impactor was 4.7 μm. The in vitro dissolution profile showed an efficient dapsone encapsulation, demonstrating the sustained release of the drug. The in vitro deposition (measured by the Andersen cascade impactor) showed an adequate distribution and a high fine particles fraction (FPF= 50%). Scanning electron microscopy of the pulmonary tissues demonstrated an adequate deposition of these particles in the deepest part of the lung. An in vivo toxicity experiment showed the low toxicity of the drug-loaded microcapsules, indicating a protective effect of the microencapsulation process when the particles are microencapsulated. In conclusion, the pulmonary administration of the novel dapsone-loaded microcapsules could be a promising alternative for PCP treatment.

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Simvastatin delivery via inhalation attenuates airway inflammation in a murine model of asthma

Cited by 62 publications

References 39 publications

Simvastatin suppresses RANTES-mediated neutrophilia in polyinosinic–polycytidylic acid-induced pneumonia

Simvastatin suppresses RANTES-mediated neutrophilia in polyinosinic–polycytidylic acid-induced pneumonia

The Nitrated Fatty Acid 10-Nitro-Oleate Attenuates Allergic Airway Disease

Development of Novel Chitosan Microcapsules for Pulmonary Delivery of Dapsone: Characterization, Aerosol Performance, and In Vivo Toxicity Evaluation

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