Intratracheal instillation of pravastatin for the treatment of murine allergic asthma: a lung‐targeted approach to deliver statins

Physiological Reports

Amir A. Zeki¹  Jennifer M. Bratt¹  Kevin Y. Chang¹  Lisa M. Franzi¹  Sean Ott¹  Mark Silveria²  Oliver Fiehn²  Jerold A. Last¹ 

[1] University of California, Davis, California;U.C. Davis, West Coast Metabolomics Center (WCMC), University of California, Davis, California

关键词: Airway hyperreactivity;    airway hypersensitivity;    airway inflammation;    asthma;    asthma treatment;    goblet cells;    inhaled statin;    intratracheal statin;    mass spectrometry;    pravastatin;    remodeling;   

DOI  :  10.14814/phy2.12352

来源: Wiley

【 摘 要 】

Abstract

Systemic treatment with statins mitigates allergic airway inflammation, T_H2 cytokine production, epithelial mucus production, and airway hyperreactivity (AHR) in murine models of asthma. We hypothesized that pravastatin delivered intratracheally would be quantifiable in lung tissues using mass spectrometry, achieve high drug concentrations in the lung with minimal systemic absorption, and mitigate airway inflammation and structural changes induced by ovalbumin. Male BALB/c mice were sensitized to ovalbumin (OVA) over 4 weeks, then exposed to 1% OVA aerosol or filtered air (FA) over 2 weeks. Mice received intratracheal instillations of pravastatin before and after each OVA exposure (30 mg/kg). Ultra performance liquid chromatography – mass spectrometry was used to quantify plasma, lung, and bronchoalveolar lavage fluid (BALF) pravastatin concentration. Pravastatin was quantifiable in mouse plasma, lung tissue, and BALF (BALF > lung > plasma for OVA and FA groups). At these concentrations pravastatin inhibited airway goblet cell hyperplasia/metaplasia, and reduced BALF levels of cytokines TNFα and KC, but did not reduce BALF total leukocyte or eosinophil cell counts. While pravastatin did not mitigate AHR, it did inhibit airway hypersensitivity (AHS). In this proof-of-principle study, using novel mass spectrometry methods we show that pravastatin is quantifiable in tissues, achieves high levels in mouse lungs with minimal systemic absorption, and mitigates some pathological features of allergic asthma. Inhaled pravastatin may be beneficial for the treatment of asthma by having direct airway effects independent of a potent anti-inflammatory effect. Statins with greater lipophilicity may achieve better anti-inflammatory effects warranting further research.

【 授权许可】

CC BY   
© 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.