Summary of Study ST000844

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.

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Study IDST000844
Study TitleStatin Immuno-Metabolomics in Asthma (part II)
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
LaboratoryNewman's Lab
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)wiff
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:SU000871
Subject Type:Animal
Subject Species:Macaca mulatta
Taxonomy ID:9544
Species Group:Mammal

Factors:

Subject type: Animal; Subject species: Macaca mulatta (Factor headings shown in green)

mb_sample_id local_sample_id Treatment Day
SA046850PLAZ-31Control Day 0
SA046851PLAZ-20Control Day 0
SA046852PLAZ-14Control Day 0
SA046853PLAZ-33Control Day 0
SA046854PLAZ-32Control Day 0
SA046855PLAZ-23Control Day 0
SA046856PLAZ-29Control Day 12
SA046857PLAZ-05Control Day 12
SA046858PLAZ-12Control Day 12
SA046859PLAZ-01Control Day 12
SA046860PLAZ-11Control Day 12
SA046861PLAZ-30Control Day 12
SA046862PLAZ-15Control Day 8
SA046863PLAZ-18Control Day 8
SA046864PLAZ-17Control Day 8
SA046865PLAZ-08Control Day 8
SA046866PLAZ-34Control Day 8
SA046867PLAZ-04Control Day 8
SA046868PLAZ-36Pravastatin Day 0
SA046869PLAZ-22Pravastatin Day 0
SA046870PLAZ-24Pravastatin Day 0
SA046871PLAZ-28Pravastatin Day 12
SA046872PLAZ-16Pravastatin Day 12
SA046873PLAZ-03Pravastatin Day 12
SA046874PLAZ-02Pravastatin Day 8
SA046875PLAZ-27Pravastatin Day 8
SA046876PLAZ-07 Rep Avg.Pravastatin Day 8
SA046877PLAZ-09Simvastatin Day 0
SA046878PLAZ-19Simvastatin Day 0
SA046879PLAZ-26Simvastatin Day 0
SA046880PLAZ-35Simvastatin Day 12
SA046881PLAZ-10Simvastatin Day 12
SA046882PLAZ-21Simvastatin Day 12
SA046883PLAZ-25Simvastatin Day 8
SA046884PLAZ-13Simvastatin Day 8
SA046885PLAZ-06 Rep Avg.Simvastatin Day 8
Showing results 1 to 36 of 36

Collection:

Collection ID:CO000865
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. Lung wash fluid was collected at day 0, 8 and 12 of each treatment.
Sample Type:Blood
Blood Serum Or Plasma:Plasma

Treatment:

Treatment ID:TR000885
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. Lung wash fluid was collected at day 0, 8 and 12 of each treatment.

Sample Preparation:

Sampleprep ID:SP000878
Sampleprep Summary:Oxylipins, endocannabinoids, bile acids and fatty acids were isolated from an aliquot of 20μl plasma in Eppendorf tubes. The tube was spiked was 5ul of OxyEndo Fusion, 10μl spike of Bile Acid SSTD Solutions, and 5μl of BHT/EDTA solution. A total of 100μl CUDA/PHAU in methanol was added to the tube, before it was capped, vortexed, and centrifuged (3 min, 10,000 RCF, room temp). It was then placed on wet ice for 5 min. Next it was spin filtered with Millapore spin filters (0.1 µm, Millipore, Billerica, MA) at 8 ºC, 4500 RPM for 3 min, 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 AN001366 AN001367
Analysis type MS MS
Chromatography type Reversed phase Reversed phase
Chromatography system Waters Acquity Waters Acquity
Column Waters Acquity BEH C18 (100 x 2mm,1.7um) Waters Acquity BEH C18 (100 x 2mm,1.7um)
MS Type ESI ESI
MS instrument type Triple quadrupole Triple quadrupole
MS instrument name ABI Sciex 6500 QTrap ABI Sciex 6500 QTrap
Ion Mode NEGATIVE POSITIVE
Units Concentration (nM) Concentration (nM)

Chromatography:

Chromatography ID:CH000953
Instrument Name:Waters Acquity
Column Name:Waters Acquity BEH C18 (100 x 2mm,1.7um)
Column Temperature:60 °C
Flow Gradient:See protocol/methods file
Flow Rate:0.25 mL/min
Internal Standard:See protocol/methods file
Retention Time:See protocol/methods file
Sample Injection:5 µL
Solvent A:100% water; 0.1% acetic acid
Solvent B:90% acetonitrile/ 10% isopropanol
Analytical Time:20 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:MS001258
Analysis ID:AN001366
Instrument Name:ABI Sciex 6500 QTrap
Instrument Type:Triple quadrupole
MS Type:ESI
Ion Mode:NEGATIVE
  
MS ID:MS001259
Analysis ID:AN001367
Instrument Name:ABI Sciex 6500 QTrap
Instrument Type:Triple quadrupole
MS Type:ESI
Ion Mode:POSITIVE
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