DIGR: Diesel Exhaust Induces Glucocorticoid Resistance

Sponsor

University of British Columbia (Other)

Overall Status

Recruiting

CT.gov ID

NCT03615742

Collaborator

Canadian Institutes of Health Research (CIHR) (Other), AllerGen NCE Inc. (Industry)

Enrollment

Location

Arms

Anticipated Duration (Months)

0.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The investigators are studying the effects of exposure to diesel exhaust on lung inflammation in the presence and absence of an inhaled corticosteroid. Although data is mixed, studies show that asthmatics have increased lung inflammation and worse symptoms during periods of higher air pollution despite taking their anti-inflammatory corticosteroid medication. One possible reason is that air pollution exposure may decrease the ability of corticosteroids to combat inflammation.

To test this volunteers will inhale either a placebo or a corticosteroid, before sitting in an exposure booth for 2 hours breathing either filtered air or diluted diesel exhaust. Samples will be collected before and after exposure to analyze the effects of budesonide and diesel exhaust exposure.

Condition or Disease	Intervention/Treatment	Phase
Exposure to Pollution Glucocorticoid Resistance	Other: Placebo Drug: Budesonide Other: Filtered Air Other: Diesel Exhaust	Phase 4

Detailed Description

Purpose Inhalation of air pollutants leads to both airway inflammation, with increased cytokine expression and inflammatory cell recruitment to the airways, and to airway hyperresponsiveness, which together contribute to airway resistance and breathing difficulties. Correlational data indicate that exposure to air pollution increases inhaled corticosteroids (ICS) use in asthmatics, suggesting that steroidal anti-inflammatory medications are suboptimally effective under these conditions. However, a major issue is that no study has yet been performed specifically to determine the effects of controlled diesel exhaust (DE) exposure on responses to ICS. Furthermore, investigators need better insight into mechanisms, including the effects of epigenetic modifications and polymorphisms in oxidative stress response genes, which remain under explored. Investigators anticipate that an improved understanding of air pollution-induced ICS hyporesponsiveness (reduced effectiveness) could underpin preventative guidelines, guide ICS usage in response to environmental exposures, and inform rational pharmaceutical development. Ultimately this could lead to fewer exacerbations in asthmatic and other susceptible populations.

Hypothesis:

Acute exposure to DE reduces ICS-inducible gene expression in vivo in asthmatics, in part through effects on epigenetic processes.

Justification:

Air pollution exposure correlates with increased use of ICS inhalers in asthmatics, suggesting that ICS offer less control during periods of higher air pollution. As genes induced by ICS are critical in reducing inflammatory messenger ribonucleic acid (mRNA) and protein expression, the investigators have chosen to focus on the effects of DE on ICS-inducible gene expression as our primary endpoint.

Research Method:

To test this the effects of air pollution exposure on a corticosteroid, volunteers will inhale either a placebo (inhaler containing no medication) or budesonide (1.6mg), before sitting in our exposure booth for 2 hours breathing either filtered air (as a control) or diluted diesel exhaust (standardized to 300µg/m³ of particulate matter with a diameter of 2.5 micrometers or less).

Volunteers will visit our lab four different times to be exposed to: 1) placebo & filtered air, 2) placebo & diesel exhaust, 3) corticosteroid and filtered air, and 4) corticosteroid and diesel exhaust. Investigators can then compare responses to each of these combinations of exposures.

Investigators will take blood samples before and after volunteers complete each of these exposures to track how they affect the body. Six hours after placebo or budesonide inhalation a research bronchoscopy will be performed during which a very thin flexible tube will be inserted through the mouth and down into lungs to collect samples from each volunteer.

Bronchoalveolar lavage, bronchial washes, bronchial brushes and tissue biopsies will be obtained for analysis of gene expression and epigenetic endpoints. Nasal lavage samples will also be collected to examine responses in the upper airways and blood and urine will be studied to examine systemic responses. Spirometry will be used to assess effects on airway function.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Intervention Model Description:

Volunteers will visit our lab four different times to be exposed to: 1) placebo & filtered air, 2) placebo & diesel exhaust, 3) budesonide and filtered air, and 4) budesonide and diesel exhaustVolunteers will visit our lab four different times to be exposed to: 1) placebo & filtered air, 2) placebo & diesel exhaust, 3) budesonide and filtered air, and 4) budesonide and diesel exhaust

Masking:

Triple (Participant, Investigator, Outcomes Assessor)

Masking Description:

Blinding of exposures will be performed by the air pollution exposure laboratory (APEL) engineer, who will not interact with volunteers. Visually indistinguishable placebo and budesonide inhalers will be coded by research pharmacy staff. All assays will be performed by personnel who do not know the exposure conditions of individual samples.

Primary Purpose:

Prevention

Official Title:

Diesel Exhaust Induces Glucocorticoid Resistance

Actual Study Start Date :

Dec 1, 2018

Anticipated Primary Completion Date :

Dec 31, 2022

Anticipated Study Completion Date :

Dec 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo and Filtered Air Volunteers will use an inhaler that does not contain any medication, before sitting in a booth and being exposed to high-efficiency particulate air (HEPA) filtered air for 2 hours.	Other: Placebo Inhalation of air through a Turbuhaler that contains no medication, as a control. Other: Filtered Air Exposure to HEPA filtered air, as a control.
Active Comparator: Budesonide and Filtered Air Volunteers will inhale 1.6mg of budesonide before sitting in a booth and being exposed to HEPA filtered air for 2 hours.	Drug: Budesonide 1.6mg of budesonide from a Turbuhaler. Other Names: Pulmicort Other: Filtered Air Exposure to HEPA filtered air, as a control.
Active Comparator: Placebo and Diesel Exhaust Volunteers will use an inhaler that does not contain any medication, before sitting in a booth and being exposed to 300µg/m³ concentration of diesel exhaust for 2 hours.	Other: Placebo Inhalation of air through a Turbuhaler that contains no medication, as a control. Other: Diesel Exhaust Diesel exhaust standardized to 300µg/m³ of particulate matter with a diameter of 2.5 micrometers or less (PM2.5). Other Names: Traffic Related Air Pollution
Experimental: Budesonide and Diesel Exhaust Volunteers will inhale 1.6mg of budesonide before sitting in a booth and being exposed to 300µg/m³ concentration of diesel exhaust for 2 hours.	Drug: Budesonide 1.6mg of budesonide from a Turbuhaler. Other Names: Pulmicort Other: Diesel Exhaust Diesel exhaust standardized to 300µg/m³ of particulate matter with a diameter of 2.5 micrometers or less (PM2.5). Other Names: Traffic Related Air Pollution

Outcome Measures

Primary Outcome Measures

Change in DNA methylation, mRNA and protein expression attributable to diesel exhaust and inhaled corticosteroid [Baseline versus 6 hours]
EPIC arrays and RNA Seq will be used to determine effect of exposure(s)

Secondary Outcome Measures

Modification by variants in genes governing inflammation and responses to oxidative stress after DE exposure and ICS. [Baseline versus 6 hours]
genotypes will be assessed by polymerase chain reaction assay (PCR) and a gene score created for statistical interaction analysis

Eligibility Criteria

Criteria

Ages Eligible for Study:

19 Years to 49 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Aged 19-49
Have physician-diagnosed asthma confirmed by the study physician examination, spirometry, methacholine challenge provocative concentration causing a 20% fall (PC20) of <16 mg/mL, and questionnaires during a screening visit

Exclusion Criteria:

Smoking of any kind (0.5 pack-years ever, or any current) or use of vape/vaporizing devices
Regular anti-histamine, NSAID, corticosteroid or other controller medication use
Pregnancy or breastfeeding
Methacholine PC20 >16
Relevant cardiac condition or arrhythmia
Body mass index of >35
Currently participating in another study that may interfere with this study
Use of either inhaled or oral corticosteroids in preceding 6 months
Substantial comorbidities on study physician's examination or other concerns
Surgery scheduled before anticipated study completion