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

Amir Zeki, Jennifer M. Bratt, Kevin Y. Chang, Lisa M. Franzi, Sean Ott, Mark Silveria, Oliver Fiehn, Jerold A Last, Nicholas Kenyon

Research output: Contribution to journalArticle

14 Citations (Scopus)

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 TNFa 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.

Original languageEnglish (US)
Article numbere12352
JournalPhysiological Reports
Volume3
Issue number5
DOIs
StatePublished - 2015

Fingerprint

Hydroxymethylglutaryl-CoA Reductase Inhibitors
Pravastatin
Bronchoalveolar Lavage Fluid
Asthma
Ovalbumin
Lung
Mass Spectrometry
Therapeutics
Anti-Inflammatory Agents
Air
Cytokines
Inflammation
Goblet Cells
Metaplasia
Mucus
Aerosols
Eosinophils
Liquid Chromatography
Hyperplasia
Hypersensitivity

Keywords

  • Airway hyperreactivity
  • Airway hypersensitivity
  • Airway inflammation
  • Asthma
  • Asthma treatment
  • Goblet cells
  • Inhaled statin
  • Intratracheal statin
  • Mass spectrometry
  • Pravastatin
  • Remodeling

ASJC Scopus subject areas

  • Physiology (medical)
  • Physiology

Cite this

Intratracheal instillation of pravastatin for the treatment of murine allergic asthma : A lung-targeted approach to deliver statins. / Zeki, Amir; Bratt, Jennifer M.; Chang, Kevin Y.; Franzi, Lisa M.; Ott, Sean; Silveria, Mark; Fiehn, Oliver; Last, Jerold A; Kenyon, Nicholas.

In: Physiological Reports, Vol. 3, No. 5, e12352, 2015.

Research output: Contribution to journalArticle

Zeki, Amir ; Bratt, Jennifer M. ; Chang, Kevin Y. ; Franzi, Lisa M. ; Ott, Sean ; Silveria, Mark ; Fiehn, Oliver ; Last, Jerold A ; Kenyon, Nicholas. / Intratracheal instillation of pravastatin for the treatment of murine allergic asthma : A lung-targeted approach to deliver statins. In: Physiological Reports. 2015 ; Vol. 3, No. 5.
@article{23ad0483e2524774abcf6cd447ffbf0b,
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 TNFa 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.",
keywords = "Airway hyperreactivity, Airway hypersensitivity, Airway inflammation, Asthma, Asthma treatment, Goblet cells, Inhaled statin, Intratracheal statin, Mass spectrometry, Pravastatin, Remodeling",
author = "Amir Zeki and Bratt, {Jennifer M.} and Chang, {Kevin Y.} and Franzi, {Lisa M.} and Sean Ott and Mark Silveria and Oliver Fiehn and Last, {Jerold A} and Nicholas Kenyon",
year = "2015",
doi = "10.14814/phy2.12352",
language = "English (US)",
volume = "3",
journal = "Physiological Reports",
issn = "2051-817X",
publisher = "John Wiley and Sons Inc.",
number = "5",

}

TY - JOUR

T1 - Intratracheal instillation of pravastatin for the treatment of murine allergic asthma

T2 - A lung-targeted approach to deliver statins

AU - Zeki, Amir

AU - Bratt, Jennifer M.

AU - Chang, Kevin Y.

AU - Franzi, Lisa M.

AU - Ott, Sean

AU - Silveria, Mark

AU - Fiehn, Oliver

AU - Last, Jerold A

AU - Kenyon, Nicholas

PY - 2015

Y1 - 2015

N2 - 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 TNFa 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.

AB - 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 TNFa 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.

KW - Airway hyperreactivity

KW - Airway hypersensitivity

KW - Airway inflammation

KW - Asthma

KW - Asthma treatment

KW - Goblet cells

KW - Inhaled statin

KW - Intratracheal statin

KW - Mass spectrometry

KW - Pravastatin

KW - Remodeling

UR - http://www.scopus.com/inward/record.url?scp=84974794126&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84974794126&partnerID=8YFLogxK

U2 - 10.14814/phy2.12352

DO - 10.14814/phy2.12352

M3 - Article

AN - SCOPUS:84974794126

VL - 3

JO - Physiological Reports

JF - Physiological Reports

SN - 2051-817X

IS - 5

M1 - e12352

ER -