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.

Study ID	ST000847
Study Title	Statin Immuno-Metabolomics in Asthma (part V)
Study Type	Placebo-controled trial
Study 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	USDA Western Human Nutrition Research Center
Last Name	Newman
First Name	John
Address	430 West Health Sciences Dr. Davis, Ca, 95616
Email	John.Newman@ars.usda.gov
Phone	(530) 752-1009
Submit Date	2017-08-09
Raw Data Available	Yes
Raw Data File Type(s)	wiff
Analysis Type Detail	LC-MS
Release Date	2017-10-11
Release Version	1

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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:	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	Tissue	Treatment
SA046940	Zeki L 48	Left Lung	Control
SA046941	Zeki L 74	Left Lung	Control
SA046942	Zeki L 28 Repl Avg.	Left Lung	Control
SA046943	Zeki L 68	Left Lung	Simvastatin
SA046944	Zeki L 40	Left Lung	Simvastatin
SA046945	Zeki L 95	Left Lung	Simvastatin
SA046946	Zeki R 74	Right Lung	Control
SA046947	Zeki R 28 Repl Avg.	Right Lung	Control
SA046948	Zeki R 48	Right Lung	Control
SA046949	Zeki R 95	Right Lung	Simvastatin
SA046950	Zeki R 68	Right Lung	Simvastatin
SA046951	Zeki R 40	Right Lung	Simvastatin
SA046952	Zeki T 28 Repl Avg.	Trachea	Control
SA046953	Zeki T 74	Trachea	Control
SA046954	Zeki T 48	Trachea	Control
SA046955	Zeki T 95	Trachea	Simvastatin
SA046956	Zeki T 68	Trachea	Simvastatin
SA046957	Zeki T 40	Trachea	Simvastatin

Showing results 1 to 18 of 18

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.

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 (100 x 2.1mm,1.7um)
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 (100 x 2.1mm,1.7um)
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:	100% water; 0.1% formic acid
Solvent B:	100% acetonitrile; 0.1% formic acid
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