title: Intratracheal instillation of pravastatin for the treatment of murine allergic asthma: a lung-targeted approach to deliver statins.
abstract: Systemic treatment with statins mitigates allergic airway inflammation, TH2 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.
authors.affiliation: University of California, Davis, California Department of Internal Medicine, University of California, Davis, California Division of Pulmonary, Critical Care and Sleep Medicine, University of California, Davis, California Center for Comparative Respiratory Biology and Medicine (CCRBM) University of California, Davis, California aazeki@ucdavis.edu.
authors.forename: Amir A
authors.initials: AA
authors.lastname: Zeki
authors.affiliation: University of California, Davis, California Department of Internal Medicine, University of California, Davis, California Division of Pulmonary, Critical Care and Sleep Medicine, University of California, Davis, California Center for Comparative Respiratory Biology and Medicine (CCRBM) University of California, Davis, California.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Bratt
authors.affiliation: University of California, Davis, California.
authors.forename: Kevin Y
authors.initials: KY
authors.lastname: Chang
authors.affiliation: University of California, Davis, California Department of Internal Medicine, University of California, Davis, California Division of Pulmonary, Critical Care and Sleep Medicine, University of California, Davis, California Center for Comparative Respiratory Biology and Medicine (CCRBM) University of California, Davis, California.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Franzi
authors.affiliation: University of California, Davis, California Department of Internal Medicine, University of California, Davis, California Division of Pulmonary, Critical Care and Sleep Medicine, University of California, Davis, California Center for Comparative Respiratory Biology and Medicine (CCRBM) University of California, Davis, California.
authors.forename: Sean
authors.initials: S
authors.lastname: Ott
authors.affiliation: U.C. Davis, West Coast Metabolomics Center (WCMC) University of California, Davis, California.
authors.forename: Mark
authors.initials: M
authors.lastname: Silveria
authors.affiliation: U.C. Davis, West Coast Metabolomics Center (WCMC) University of California, Davis, California King Abdulaziz University, Biochemistry Department, Jeddah, Saudi Arabia.
authors.forename: Oliver
authors.initials: O
authors.lastname: Fiehn
authors.affiliation: University of California, Davis, California Department of Internal Medicine, University of California, Davis, California Division of Pulmonary, Critical Care and Sleep Medicine, University of California, Davis, California Center for Comparative Respiratory Biology and Medicine (CCRBM) University of California, Davis, California.
authors.forename: Jerold A
authors.initials: JA
authors.lastname: Last
authors.affiliation: University of California, Davis, California Department of Internal Medicine, University of California, Davis, California Division of Pulmonary, Critical Care and Sleep Medicine, University of California, Davis, California Center for Comparative Respiratory Biology and Medicine (CCRBM) University of California, Davis, California.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Kenyon
keywords: Airway hyperreactivity; airway hypersensitivity; airway inflammation; asthma; asthma treatment; goblet cells; inhaled statin; intratracheal statin; mass spectrometry; pravastatin; remodeling