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.
Highlights
Asthma affects 27 million Americans, the World Health Organization estimates that 235 million people have asthma worldwide, and the prevalence continues to rise
We hypothesized that intratracheal instillation of a water-soluble statin, pravastatin, would (1) produce quantifiable levels of pravastatin in blood plasma, lung tissue, and bronchoalveolar lavage fluid (BALF) using mass spectrometry; (2) achieve high drug concentrations locally in the lung with minimal systemic absorption; and (3) reduce eosinophilic inflammation, goblet cell hyperplasia, and airway hyperresponsiveness. In this proof-of-principle study, we report a novel method for quantifying pravastatin in plasma, homogenized lung tissue, and BALF specimens using ultra performance liquid chromatography – mass spectrometry (UPLC-MS), and show that i.t. pravastatin reduces aller
Our data demonstrate the ability to directly measure and detect pravastatin in lung tissues using mass spectrometry, and the ability of the drug to concentrate in the lung while achieving minimal systemic absorption
Summary
Asthma affects 27 million Americans, the World Health Organization estimates that 235 million people have asthma worldwide, and the prevalence continues to rise. We and others have previously shown that systemic treatment with statins in animal models of asthma (Zeki et al 2009) and chronic obstructive pulmonary disease (COPD) (Davis et al 2013) mitigates inflammation and early features of airway remodeling (Zeki et al 2010) In this current work, we explore whether delivering statins directly to the lungs by intratracheal (i.t.) instillation can mitigate experimental asthma. Statins exhibit pleiotropic properties that result in a wide range of cellular and physiological effects by both HMGCRdependent and -independent mechanisms (Wang et al 2008; Zeki et al 2011) They have garnered wide interest giving rise to studies investigating their therapeutic benefits in different diseases including lung diseases such as asthma, COPD, pulmonary hypertension, lung cancer, pneumonia, and bronchiectasis
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
