Controlled diesel exhaust and allergen coexposure modulates microRNA and gene expression in humans: Effects on inflammatory lung markers.
Air pollution's association with asthma may be due to its augmentation of allergenic effects, but the role of microRNA (miRNA) and gene expression in this synergy is unknown.



We sought to determine whether exposure to allergen, exposure to diesel exhaust (DE), or coexposures modulate miRNA, gene expression, or inflammatory pathways and whether these measurements are correlated.



Fifteen participants with atopy completed this controlled study of 2 hours of filtered air or DE (300 μg PM2.5/m3) exposure, followed by saline-controlled segmental bronchial allergen challenge. Gene and miRNA expression in bronchial brushings and lung inflammatory markers were measured 48 hours later, in study arms separated by approximately 4 weeks. Expression of miRNAs, messenger RNAs, and inflammatory markers and their interrelationships were determined using regression.



Robust linear models indicated that DE plus saline and DE plus allergen significantly modulated the highest number of miRNAs and messenger RNAs, respectively, relative to control (filtered air plus saline). In mixed models, allergen exposure modulated (q ≤ 0.2) miRNAs including miR-183-5p, miR-324-5p, and miR-132-3p and genes including NFKBIZ and CDKN1A, but DE did not significantly modify this allergenic effect. Repression of CDKN1A by allergen-induced miR-132-3p may contribute to shedding of bronchial epithelial cells.



Expression of specific miRNAs and genes associated with bronchial immune responses were significantly modulated by DE or allergen. However, DE did not augment the effect of allergen at 48 hours, suggesting that adjuvancy may be transient or require higher or prolonged exposure. In silico analysis suggested a possible mechanism contributing to epithelial wall damage following allergen exposure.
Chan-Yeung Centre for Occupational and Environmental Respiratory Disease (COERD), University of British Columbia, Vancouver, British Columbia, Canada; Department of Medicine, Division of Respiratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Christopher F
CF
Rider
Chan-Yeung Centre for Occupational and Environmental Respiratory Disease (COERD), University of British Columbia, Vancouver, British Columbia, Canada; Department of Medicine, Division of Respiratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Masatsugu
M
Yamamoto
Günther Analytics, Vancouver, British Columbia, Canada.
Oliver P
OP
Günther
Chan-Yeung Centre for Occupational and Environmental Respiratory Disease (COERD), University of British Columbia, Vancouver, British Columbia, Canada; Department of Medicine, Division of Respiratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Centre for Heart Lung Innovation, St Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada; Institute for HEART + LUNG Health, University of British Columbia, Vancouver, British Columbia, Canada.
Jeremy A
JA
Hirota
Centre for Heart Lung Innovation, St Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada; Institute for HEART + LUNG Health, University of British Columbia, Vancouver, British Columbia, Canada; Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada.
Amrit
A
Singh
Department of Medicine, Division of Respiratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Centre for Heart Lung Innovation, St Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada; Institute for HEART + LUNG Health, University of British Columbia, Vancouver, British Columbia, Canada; Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, British Columbia, Canada.
Scott J
SJ
Tebbutt
Chan-Yeung Centre for Occupational and Environmental Respiratory Disease (COERD), University of British Columbia, Vancouver, British Columbia, Canada; Department of Medicine, Division of Respiratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Centre for Heart Lung Innovation, St Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada; Institute for HEART + LUNG Health, University of British Columbia, Vancouver, British Columbia, Canada; School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: carlsten@mail.ubc.ca.
Chris
C
Carlsten
D048868:Adaptor Proteins, Signal Transducing; D000485:Allergens / Q000009:adverse effects / Q000276:immunology; D015415:Biomarkers / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004781:Environmental Exposure / Q000009:adverse effects; D004847:Epithelial Cells / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D006967:Hypersensitivity / Q000175:diagnosis / Q000276:immunology*; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D001335:Vehicle Emissions
D048868:Adaptor Proteins, Signal Transducing; D000485:Allergens; D015415:Biomarkers; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; C547077:MIRN132 microRNA, human; C533449:MIRN183 microRNA, human; C000599310:MIRN324 microRNA, human; D035683:MicroRNAs; C417234:NFKBIZ protein, human; D009687:Nuclear Proteins; D001335:Vehicle Emissions
Air pollution; allergy; controlled human exposure; inflammatory markers; multi-omics