The bugs in our lungs, called microbes, include those that are pathogenic (cause disease) and those that are simply colonizing (living in lung but not causing disease). By definition, the bugs living in our lungs originated elsewhere, and that source may well be the air in our primary living space (our homes). We propose to test this idea by testing the air in home environments of those with common airway diseases (like chronic obstructive pulmonary disease [COPD]) to see what bugs exist therein, and to also test the lungs, nasal passages and stool samples of those living in those homes, to see what bugs are similar between the microenvironments. Then, we will see if those bugs that are common to the microenvironments are those that seem to be most related to clinical features like lung function, lung inflammation, and “genomic” changes in the lung (this means changes in the way our genes are chemically modified and produce the proteins they are programmed to produce). If there is such a relationship, we will use these results to design interventions, such as the use of air purifiers, that may alter the relationship between the outside (air) and inner (lung) environment and then thereafter test these interventions to see if they can beneficially alter clinically meaningful parameters.
Chronic exposure to diesel exhaust (DE) is associated with a wide range of adverse health outcomes: e.g. cognitive impairment, vascular diseases, and increased morbidity and mortality associated respiratory illness, and DE has been classified as carcinogenic to humans (Group 1) by the International Agency for Research on Cancer (IARC). Both chronic and acute exposures to DE have been associated with respiratory illnesses; chronic DE exposure is associated with lung fibrosis and acute exposure to DE is associated with increased asthma exacerbations reflected in reduced lung function, and increased wheezing. Prominent pathophysiological and molecular mechanisms linking DE exposure to negative health outcomes include increased inflammation, oxidative stress and airway resistance. However, these molecular signatures are not specific to DE exposure, have poorly- defined dose-response relationships, and are derived from body fluids and tests that are inconvenient, expensive, and time-consuming to access and analyze. Therefore, the broad goal of this project is to elucidate a more robust signature of exposure to DE that can offer both mechanistic insight as well as temporal and, importantly, dose-response resolution. Such signature specificity and resolution will be crucial in informing both provincial and national policy and decision-makers as they work towards reasonable limits to occupational DE exposure and devise practical monitoring program.
Inflammation is the body’s response to harmful things, such as pathogens or irritating chemicals, which can cause symptoms. Exposure to allergens to which an individual is sensitive also causes inflammation, which can be seen and measured in the skin during a skin prick test in which a small amount of allergen is placed on the skin and the skin pierced. Specific allergens also cause inflammation in the lungs when inhaled them by individuals who are sensitive to these allergens and have asthma, resulting in symptoms such as wheezing, chest tightness, coughing and increased sticky secretions of mucus. Lung inflammation is enhanced by exposure to air pollutants, such as wood smoke or diesel exhaust. Many asthmatics take inhaled corticosteroids to reduce the inflammation in the lungs and thereby decrease asthma symptoms. We are interested in studying the effects of an inhaled corticosteroid on lung inflammation after exposure to diesel exhaust. This research study will test whether diesel exhaust reduces the effectiveness of inhaled corticosteroids.
The use of diesel engines is increasing because they are more fuel-efficient than gasoline engines, however, diesel engines produce different emissions than gasoline engines. Diesel exhaust is emitted from the tailpipe of both “on- road” diesel engine vehicles (diesel cars, buses and trucks) and “non-road” diesel engines (locomotives, marine vessels and some construction equipment). Diesel exhaust consists of both gaseous and particulate air pollutants. Since people with asthma and allergic diseases appear to be sensitive to air pollution, we wanted to know how diesel exhaust (DE) affected their respiratory and immune systems. Below we present our research findings in this study.
Jiang R, Jones MJ, Sava F, Kobor MS, Carlsten C. Short-term diesel exhaust inhalation in a controlled human crossover study is associated with changes in DNA methylation of circulating mononuclear cells in asthmatics. Part Fibre Toxicol. 2014;11(1):1-12. doi:10.1186/s12989-014-0071-3
Carlsten C, MacNutt MJ, Zhang Z, Sava F, Pui M. Anti-oxidant N-acetylcysteine diminishes diesel exhaust-induced increased airway responsiveness in person with airway hyper-reactivity. Toxicol Sci. 2014;139(2):479-487. doi:10.1093/toxsci/kfu040
Yamamoto, M., Singh, A., Sava, F., Pui, M., Tebbutt, S. J., & Carlsten, C. (2013). MicroRNA expression in response to controlled exposure to diesel exhaust: attenuation by the antioxidant N-acetylcysteine in a randomized crossover study. Environmental health perspectives. 2013; 121(6), 670. doi:10.1289/ehp.1205963
Air pollution collectively describes the presence of a complex mixture of particulate matter (PM), organic compounds (e.g. polycyclic aromatic hydrocarbons and endotoxins), gases (e.g. carbon monoxide, sulfur oxides, ground-level ozone, nitrogen oxides) and metals present in indoor and outdoor air, which can cause harm or discomfort to humans or other living organisms. Although the effects of prolonged exposure to traffic-related air pollution (TrAP), specifically, are well characterized with respect to respiratory and cardiovascular outcomes, comparatively little is known about the impact of particulate matter on affective and cognitive processes, neurodegenerative effects and microcirculation. Research using animal models, along with epidemiology, has greatly enhanced our understanding of DE-related cognitive and learning outcomes, and has implicated several important potential mechanisms. However, such models are inherently limited given interspecies differences (animal models), some degree of unavoidable residual confounding (epidemiology), and a bias towards subacute or chronic effects (epidemiology). By largely overcoming these limitations, our in vivo human model, using freshly-generated exhaust that is diluted and aged to reflect real-world conditions, allows us to augment existing knowledge in a manner applicable both to current research on environmental effects on cognition, as well as current public health concerns of great relevance to Canadians. This study has finished participant enrolment and data analysis is now underway.
Cliff R, Curran J, Hirota JA, Brauer M, Feldman H, Carlsten C. Effect of diesel exhaust inhalation on blood markers of inflammation and neurotoxicity: A controlled, blinded crossover study. Inhal Toxicol. 2016;28(3):145-153. doi:10.3109/08958378.2016.1145770
Curran J, Cliff R, Sinnen N, Koehle M, Carlsten C. Acute diesel exhaust exposure and postural stability: A controlled crossover experiment. J Occup Med Toxicol. 2018;13(1):2. doi:10.1186/s12995-017-0182-5
The detrimental effects of air pollution on cardiovascular and respiratory health are described in a large body of scientific literature. Olympic Games in cities known for high levels of air pollution such as Beijing 2008 and Athens 2000 raised concerns regarding athlete’s health and athletic performance. Ironically, especially athletes, who tend to follow a health-conscious lifestyle, are at risk of cardiorespiratory symptoms and illnesses triggered by air pollution. Physical activity leads to the release of epinephrine. Epinephrine induces a widening of the airways to facilitate the increased minute ventilations required to sustain the physical demands placed by the training loads. The inhalation of increased volumes of polluted air through widened airways, ultimately leads to an impairment in healthy lung function and athletic performance. function and athletic performance.The acute treatment of choice for these asthma-like symptoms is the inhalation of beta-2-agonists (IBA), which mimic epinephrine. While IBAs induce a further widening of the airways and relieve respiratory distress in the short-term, IBA use may increase the chance of pollutants reaching deeper areas in the bronchial tree, where they can cause structural (airway remodeling) and functional (decreased abilities to generate air flow) damage in the long term. The purpose of this proposed study is to investigate short- and long-term effects of IBA-use in the treatment of respiratory symptoms triggered by air pollution exposure in elite athletes.
Asthma is a disease associated with considerable health consequences whose prevalence has increased sharply over the past 40 years on a global level. Asthma is characterized by chronic inflammation and airway hyper-responsiveness to both irritant and allergenic exposures. While viral and allergenic exposures have been the primary focus of research of asthma exacerbation, the evidence linking combustion-derived particulate matter (PM) to asthma symptoms and exacerbations is considerable. Diesel exhaust (DE) is a key source of ambient PM less than 2.5 microns in diameter (PM2.5), which penetrates deeply into the lung and has been strongly associated with acute worsening of asthmatic lung function. Air pollution is a multi-inhalant mixture, but related research typically focuses on single exposures in each experiment. While binary “stimulus-response” types of questions are important initial steps to elucidating the mechanisms of asthma, our goal is to mimic the real-world milieu of inhaled toxicants by combining an allergen challenge with DE exposure. Therefore, our goal is to document, in humans and in-vivo, DE’s ability to augment allergen-induced immune responses (eg: oxidative stress, eosinophilia, IgE and Th2 cytokines in the lung).
Phthalates are found in high concentrations as softeners in PVC as well as in other plastics and a range of consumer products. They leak into the environment, and are ubiquitous environmental contaminants found in air, dust and food. Exposure of the general population is confirmed by the presence of phthalate metabolites in nearly all analysed urine samples. Consumer products, food and indoor environment are the main sources of phthalates, with inhalation, ingestion, dermal and mucous contact as the major exposure routes. Epidemiological studies suggest that phthalate exposure is associated with worsening or development of airway diseases, and both phthalate levels in house dust and urinary levels ofphthalates have been associated with various respiratory outcomes. This study will be the first to investigate airway effects due to inhalation of a known concentration of a single phthalate. We have chosen DBP as a model phthalate since some of the highest indoor air levels have been reported for this phthalate, and it appears to have a higher inflammatory potential in comparison to other phthalates in vitro. Allergen-sensitized (atopic) asthmatics and non-asthmatic individuals will be recruited, since the previous studies showed stronger effects in susceptible individuals.
COPD is a disease characterized by increasing airflow obstruction caused by chronic inflammation in the lung. Although smoking remains an important risk factor for COPD, accumulating evidence has identified nonsmoking risk factors that also contribute to COPD development and progression. Therefore, the rationale of this study is to further investigate the proposal that a component of ambient air pollution such as Diesel Exhaust (DE), is one such risk factor for COPD. The acute effects of DE will be examined in a cohort of patients that currently have or are at risk of developing COPD, as well as in healthy controls. The purpose of the COPA study is to provide biological plausibility and deepen mechanistic understanding of the emerging epidemiology suggesting a strong role for air pollution in COPD. The novelty of COPA is that those with COPD have never before been a specific focus of a controlled human exposure to particulate air pollution and COPA also enjoys the advantage of including healthy and at risk participants so that we may understand the very early stages of COPD development, oriented toward a framework of protection and prevention.