Summary of study ST000847

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR000600. The data can be accessed directly via it's Project DOI: 10.21228/M83X2W This work is supported by NIH grant, U2C- DK119886.

See: https://www.metabolomicsworkbench.org/about/howtocite.php

This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST000847
Study TitleStatin Immuno-Metabolomics in Asthma (part V)
Study TypePlacebo-controled trial
Study SummaryInnovative and novel therapies are urgently needed for the treatment of patients with severe asthma, especially those who are refractory to standard-of-care bronchodilators and inhaled corticosteroids. The Zeki lab is investigating the role of the mevalonate (MA) pathway, in the pathogenesis of airway inflammation and remodeling. Although statins all inhibit HMGCR in the same manner in terms of enzyme binding site, the statins’ varied physiochemical properties with respect to their polarity (i.e. lipophilicity) result in very different immune and lipid effects. The major significance of this work is to advance a new class of inhaler therapies for asthma; the statins which work by an entirely different mechanism than current ICS/LABA mainstays. Evidence suggests that statins may have an additive benefit to corticosteroids in asthma, thereby confirming a unique mechanism, namely via MVA pathway inhibition. This becomes particularly important in the severe asthma population which is highly corticosteroid-resistant, is poorly controlled with high exacerbation rates and hospitalizations, and has the highest healthcare costs of all asthma phenotypes. In essence, the potential public health impact of even an incremental improvement in asthma symptom control cannot be underestimated. Even the prevention of 1 asthma attack preserves lung function and reduces the adverse personal and financial impact. This study aimed to determine if statin polarity affects airway drug concentration and systemic drug absorption and to determine the effect of inhaled statins on naïve airway immune cell populations and alveolar-capillary membrane and epithelial barrier integrity in healthy rhesus monkeys. In this particular component of the study, we investigated the metabolic effects resulting from the use of statins in these healthy rhesus monkeys. Specifically, the Newman lab analyzed for lipid mediator (oxylipin, endocannabinoid, fatty acid, and nitro lipid) in lung and trachea tissue, plasma, and BAL and bile acid changes in the lung and trachea tissue and plasma.
Institute
University of California, Davis
DepartmentUSDA Western Human Nutrition Research Center
Last NameNewman
First NameJohn
Address430 West Health Sciences Dr. Davis, Ca, 95616
EmailJohn.Newman@ars.usda.gov
Phone(530) 752-1009
Submit Date2017-08-09
Raw Data AvailableYes
Raw Data File Type(s).mzXML
Analysis Type DetailLC-MS
Release Date2017-10-11
Release Version1
John Newman John Newman
https://dx.doi.org/10.21228/M83X2W
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Project:

Project ID:PR000600
Project DOI:doi: 10.21228/M83X2W
Project Title:Statin Immuno-Metabolomics in Asthma
Project Type:Placebo-controled trial
Project Summary:Innovative and novel therapies are urgently needed for the treatment of patients with severe asthma, especially those who are refractory to standard-of-care bronchodilators and inhaled corticosteroids. The Zeki lab is investigating the role of the mevalonate (MA) pathway, in the pathogenesis of airway inflammation and remodeling. Although statins all inhibit HMGCR in the same manner in terms of enzyme binding site, the statins’ varied physiochemical properties with respect to their polarity (i.e. lipophilicity) result in very different immune and lipid effects. The major significance of this work is to advance a new class of inhaler therapies for asthma; the statins which work by an entirely different mechanism than current ICS/LABA mainstays. Evidence suggests that statins may have an additive benefit to corticosteroids in asthma, thereby confirming a unique mechanism, namely via MVA pathway inhibition. This becomes particularly important in the severe asthma population which is highly corticosteroid-resistant, is poorly controlled with high exacerbation rates and hospitalizations, and has the highest healthcare costs of all asthma phenotypes. In essence, the potential public health impact of even an incremental improvement in asthma symptom control cannot be underestimated. Even the prevention of 1 asthma attack preserves lung function and reduces the adverse personal and financial impact. This study aimed to determine if statin polarity affects airway drug concentration and systemic drug absorption and to determine the effect of inhaled statins on naïve airway immune cell populations and alveolar-capillary membrane and epithelial barrier integrity in healthy rhesus monkeys. In this particular component of the study, we investigated the metabolic effects resulting from the use of statins in these healthy rhesus monkeys. Specifically, the Newman lab analyzed for lipid mediator (oxylipin, endocannabinoid, fatty acid, and nitro lipid) in lung and trachea tissue, plasma, and BAL and bile acid changes in the lung and trachea tissue and plasma.
Institute:University of California, Davis
Department:Internal Medicine
Last Name:Zeki
First Name:Amir
Address:2825 J St. Suite 400 Sacramento, CA 95816
Email:aazeki@ucdavis.edu
Phone:(916) 734-8230

Subject:

Subject ID:SU000874
Subject Type:Animal
Subject Species:Rhesus Macaque
Taxonomy ID:9544
Species Group:Mammal

Factors:

Subject type: Animal; Subject species: Rhesus Macaque (Factor headings shown in green)

mb_sample_id local_sample_id Tissue Treatment
SA046940Zeki L 48Left Lung Control
SA046941Zeki L 74Left Lung Control
SA046942Zeki L 28 Repl Avg.Left Lung Control
SA046943Zeki L 68Left Lung Simvastatin
SA046944Zeki L 40Left Lung Simvastatin
SA046945Zeki L 95Left Lung Simvastatin
SA046946Zeki R 74Right Lung Control
SA046947Zeki R 28 Repl Avg.Right Lung Control
SA046948Zeki R 48Right Lung Control
SA046949Zeki R 95Right Lung Simvastatin
SA046950Zeki R 68Right Lung Simvastatin
SA046951Zeki R 40Right Lung Simvastatin
SA046952Zeki T 28 Repl Avg.Trachea Control
SA046953Zeki T 74Trachea Control
SA046954Zeki T 48Trachea Control
SA046955Zeki T 95Trachea Simvastatin
SA046956Zeki T 68Trachea Simvastatin
SA046957Zeki T 40Trachea Simvastatin
Showing results 1 to 18 of 18

Collection:

Collection ID:CO000868
Collection Summary:Monkeys were treated with placebo or Provastatin for 12 days. Further, after the wash out period animals were treated with Simvastatin for 12 days. Plasma was collected at day 0, 8 and 12 of each treatment.
Sample Type:Tissue
Tissue Cell Identification:Trachea and lung tissue

Treatment:

Treatment ID:TR000888
Treatment Summary:Monkeys were treated (by inhalation) with placebo or Provastatin for 12 days. Further, after the wash out period animals were treated with Simvastatin for 12 days. Plasma was collected at day 0, 8 and 12 of each treatment.

Sample Preparation:

Sampleprep ID:SP000881
Sampleprep Summary:Oxylipins, endocannabinoids, bile acids and fatty acids were isolated using a Waters Ostro Sample Preparation Plate (Milford, MA). Lung and trachea samples were aliquoted (~40-60mg) into 2mL polypropylene tubes and spiked with a 5 µL anti-oxidant solution (0.2 mg/ml solution BHT/EDTA in 1:1 MeOH:water) and 10 μL 1000nM analytical deuterated surrogates. A total of 50 µL of methanol, 550µL isopropanol w/ 10mM ammonium formate & 1% formic acid and 100 uL water were added and the tube was placed in a Geno/Grinder for 30 sec before being centrifuged at 10,000g for 5 min at room temp. The supernate was then transferred into the plate wells and samples were eluted into glass inserts containing 10 μL 20% glycerol by applying a vacuum at 15 Hg for 10 min. Eluent was dried by speed vacuum for 35 min at the medium BP setting, before switching to an aqueous setting for an additional 35 min. Once dry, samples were re-constituted with the internal standard 1-cyclohexyl ureido, 3-dodecanoic acid (CUDA) and 1-Phenyl 3-Hexadecanoic Acid Urea (PHAU) at 100 nM (50:50 MeOH:CAN), vortexed 1 min, transferred to a spin filter (0.1 µm, Millipore, Billerica, MA), centrifuged for 3 min at 6ºC at <4500g (rcf), before being transferred to 2 mL LC-MS amber vials. Extracts were stored at -20ºC until analysis by UPLC-MS/MS. The internal standard was used to quantify the recovery of surrogate standards.

Combined analysis:

Analysis ID AN001371
Analysis type MS
Chromatography type Reversed phase
Chromatography system Waters Acquity
Column Aquity C18 BEH 1.7μm 100mm x 2.1mm column
MS Type ESI
MS instrument type Triple quadrupole
MS instrument name ABI Sciex 6500 QTrap
Ion Mode NEGATIVE
Units Concentration (nM)

Chromatography:

Chromatography ID:CH000956
Instrument Name:Waters Acquity
Column Name:Aquity C18 BEH 1.7μm 100mm x 2.1mm column
Column Temperature:60 °C
Flow Gradient:See protocol/methods file
Flow Rate:0.4 mL/min
Internal Standard:See protocol/methods file
Retention Time:See protocol/methods file
Sample Injection:5 µL
Solvent A:0.1% Formic Acid
Solvent B:0.1% Formic Acid in Acetonitrile
Analytical Time:16 min
Weak Wash Solvent Name:20% methanol, 10% isopropanol
Weak Wash Volume:600 µL
Strong Wash Solvent Name:50:50 Acetonitrile:Methanol
Strong Wash Volume:600 µL
Chromatography Type:Reversed phase

MS:

MS ID:MS001263
Analysis ID:AN001371
Instrument Name:ABI Sciex 6500 QTrap
Instrument Type:Triple quadrupole
MS Type:ESI
Ion Mode:NEGATIVE
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