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Inhaled Pollutants: The Molecular Scene behind Respiratory and Systemic Diseases Associated with Ultrafine Particulate Matter

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Air pollution of anthropogenic origin is largely from the combustion of biomass (e.g., wood), fossil fuels (e.g., cars and trucks), incinerators, landfills, agricultural activities and tobacco smoke. Air pollution is a complex mixture that varies in space and time, and contains hundreds of compounds including volatile organic compounds (e.g., benzene), metals, sulphur and nitrogen oxides, ozone and particulate matter (PM). PM0.1 (ultrafine particles (UFP)), those particles with a diameter less than 100 nm (includes nanoparticles (NP)) are considered especially dangerous to human health and may contribute significantly to the development of numerous respiratory and cardiovascular diseases such as chronic obstructive pulmonary disease (COPD) and atherosclerosis. Some of the pathogenic mechanisms through which PM0.1 may contribute to chronic disease is their ability to induce inflammation, oxidative stress and cell death by molecular mechanisms that include transcription factors such as nuclear factor κB (NF-κB) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Epigenetic mechanisms including non-coding RNA (ncRNA) may also contribute towards the development of chronic disease associated with exposure to PM0.1. This paper highlights emerging molecular concepts associated with inhalational exposure to PM0.1 and their ability to contribute to chronic respiratory and systemic disease.
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... A major difference between fine PM and ultrafine PM is aerosol particle size, with the latter being smaller than the former [18,27]. Ambient PM 2.5 aerosol particles are inhaled through the mouth and nose and travel down the trachea and bronchial tubes deep into the lungs [25,27,28]. Ultrafine PM can traverse lung tissue, enter the circulatory system, and can be deposited into heart tissue [27,29]. ...
... Ultrafine PM can traverse lung tissue, enter the circulatory system, and can be deposited into heart tissue [27,29]. Various authors have suggested that PM's adverse physiologic and health outcome effects are inversely related with aerosol particle size, with smaller aerosol particles producing greater physiologic and epidemiologic disruptions from normal functioning than larger aerosol particles [21,26,28,30,31]. Currently, ongoing population-based PM monitoring only occurs for PM 2.5 , and not for ultrafine PM [20]. ...
... Work on the adverse effects of ultrafine PM on a variety of physiologic measures and health outcomes has continued for three decades, but it is now becoming more relevant given the unequivocal evidence of the detrimental effects of ambient and modeled fine PM on many health outcomes [28]. Mechanistically, ultrafine PM's adverse effects should be even more severe than fine PM's adverse effects on the occurrence of respiratorycardiovascular chronic diseases [21,22,24,25,[27][28][29]92]. ...
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Optimal use of Hierarchical Bayesian Model (HBM)-assembled aerosol optical depth (AOD)-PM2.5 fused surfaces in epidemiologic studies requires homogeneous temporal and spatial fused surfaces. No analytical method is available to evaluate spatial heterogeneity. The temporal case-crossover design was modified to assess the spatial association between four experimental AOD-PM2.5 fused surfaces and four respiratory–cardiovascular hospital events in 12 km2 grids. The maximum number of adjacent lag grids with significant odds ratios (ORs) identified homogeneous spatial areas (HOSAs). The largest HOSA included five grids (lag grids 04; 720 km2) and the smallest HOSA contained two grids (lag grids 01; 288 km2). Emergency department asthma and inpatient asthma, myocardial infarction, and heart failure ORs were significantly higher in rural grids without air monitors than in urban grids with air monitors at lag grids 0, 1, and 01. Rural grids had higher AOD-PM2.5 concentration levels, population density, and poverty percentages than urban grids. Warm season ORs were significantly higher than cold season ORs for all health outcomes at lag grids 0, 1, 01, and 04. The possibility of elevated fine and ultrafine PM and other demographic and environmental risk factors synergistically contributing to elevated respiratory–cardiovascular chronic diseases in persons residing in rural areas was discussed.
... is a potent inducer of reactive oxygen species (ROS) and oxidative stress, which in turn induces a variety of inflammatory responses, including activation of nuclear factor κB (NF-κB), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), and c-Jun kinase (JNK) 73 ...
... We also sought to determine the signaling mechanisms by which PM2.5 induces myofibroblast differentiation. PM is recognized to trigger a variety of signaling pathways, including the activation of AhR and NF-κB 73,97,98 . Our data demonstrated that the PM2.5-induced increase in myofibroblast differentiation was dependent on NF-κB activation and not via activation of AhR. ...
Thesis
Particulate matter (PM) has long been appreciated as a biologically significant component of air pollution that has major impacts on public health. Exposure to PM less than 2.5 µm in diameter (PM2.5) is associated with mortality, and increased incidence of lung diseases. While the effect that PM2.5 exposure has on many cell types, such as epithelial cells, is relatively well studied, the effect it has on mesenchymal cells, such as fibroblasts, is less understood. This study seeks to determine the effect that PM2.5 exposure has on fibroblast-to-myofibroblast differentiation, which is a critical step in pulmonary fibrosis, a disease that has been shown to be exacerbated by PM2.5 exposure. We assessed the effect that PM2.5 exposure has on fibroblast biology and myofibroblast differentiation through four research aims. In Aim 1, we delineated the conditions and determinants by which ambient PM2.5 affected fibroblast-to-myofibroblast differentiation and found that, interestingly, repeated low concentration PM2.5 exposures promoted increases in αSMA and collagen, markers of myofibroblast differentiation. Furthermore, follow-up studies utilizing pharmacological inhibitors showed that NF-κB is critical for this effect. In Aim 2, we sought to investigate the effect that PM2.5 exposure has on bone morphogenic protein (BMP)2 expression and secretion in fibroblasts. BMP2 is a cytokine that can promote or inhibit myofibroblast differentiation and can be activated by NF-κB. We found that PM2.5 exposure promoted a dose-dependent increase in BMP2 transcript and secreted protein. The role of BMP2 on PM2.5-induced increase in myofibroblast differentiation was less clear; however, as treatment with exogenous BMP2 promoted myofibroblast differentiation, while blocking endogenous BMP2 with an siRNA or inhibitory protein (noggin), also promoted myofibroblast differentiation. This implies that a certain level of BMP2 signaling is critical for fibroblasts to maintain homeostasis, but that too much signaling has deleterious effects as well. In Aim 3, we examine the effect that PM2.5 exposure has on cytokine secretion and DNA methylation in lung fibroblasts. We analyze fibroblasts exposed to PM2.5 on a DNA methylation array, as well as supernatants collected from similarly exposed fibroblasts on a Luminex cytokine kit. We found that low concentrations of PM2.5 promoted methylation changes in genes enriched in cell cycle whereas high concentrations promoted methylation changes in a completely different set of genes, including those enriched in adhesion, neuronogeneis, and cell signaling. Additionally, IL-12 was found to be significantly upregulated following low concentration exposure to PM2.5 in our Luminex experiments. We sought to determine if PM2.5 exposure in vivo increases susceptibility to pulmonary fibrosis in Aim 4. The data in our prior Aims suggest that PM2.5 exposure promotes myofibroblast differentiation, an important process in fibrogenesis. Here, we exposed mice to PM2.5 and assess their susceptibility to bleomycin-induced fibrosis. Despite promising results in a pilot experiment, where we demonstrated a trend toward higher collagen content, as measured by hydroxyproline, in the lungs of male mice exposed to PM2.5 prior to bleomycin treatment, we were unable to replicate the results in a larger study with female mice. This implies that sex may have significant effects on susceptibility to PM2.5 exposure. PM2.5 exposure results in a myriad of changes in fibroblast biology, changes that can often promote fibrosis. The exact effects of PM2.5 on fibroblasts vary depending on the duration, frequency, and concentration of exposure, demonstrating the public health significance of even low levels of air pollution.
... Inflammation of the airways is a well-documented response to the inhalation of environmental pollutants and a cause of the progression of acute and chronic lung disorders [24]. During inflammation, pro-inflammatory cytokines (interleukins) and inflammatory cells accumulate and activate to induce the cytokine storm, a marker and driver of inflammation and inflammatory disease [25]. ...
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... Globally, around 9 million deaths occur every year from air pollution, and about 90% of these deaths befall in low-and middle-income countries [5]. Further, it was reported that 25% of air pollution-related deaths were respiratory in nature [6]. Air pollution is a mixture of particulate matter (PM) and gaseous components like ozone, volatile organic compounds (VOCs), carbon monoxide and nitrogen oxides. ...
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Chronic obstructive pulmonary disease (COPD) is a progressive lung disorder with substantial patient burden and leading cause of death globally. Cigarette smoke remains to be the most recognised causative factor behind COPD pathogenesis. Given the alarming increase in prevalence of COPD amongst non-smokers in recent past, a potential role of air pollution particularly particulate matter (PM) in COPD development has gained much attention of the scientists. Indeed, several epidemiological studies indicate strong correlation between airborne PM and COPD incidence/exacerbations. PM-induced oxidative stress seems to be the major player in orchestrating COPD inflammatory cycle but the exact molecular mechanism(s) behind such a process are still poorly understood. This may be due to the complexity of multiple molecular pathways involved. Oxidative stress-linked mitochondrial dysfunction and autophagy have also gained importance and have been the focus of recent studies regarding COPD pathogenesis. Accordingly, the present review is aimed at understanding the key molecular players behind PM-mediated COPD pathogenesis through analysis of various experimental studies supported by epidemiological data to identify relevant preventive/therapeutic targets in the area.
... Regarding the chemical composition of PM, metals in PM greatly contribute to the generation of reactive oxygen and nitrogen species (ROS and NOS). The latter are the main molecules that induce oxidative imbalance and subsequent damage to the lung [63][64][65], heart [66], and liver [67]. ...
Chapter
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... The inhalation of aerosols is often associated with increased morbidity and mortality. Long-term excessive exposure to aerosols leads to higher risks of lung cancer, chronic obstructive pulmonary diseases, ischemic heart disease, and strokes (Traboulsi et al. 2017). ...
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