Diesel Exhaust Particles Exposure Research Articles

Shengmai Yin alleviated plaque vulnerability and ischemic myocardial damage in diesel exhaust particle-aggravated atherosclerosis with myocardial ischemia

Exposure to diesel exhaust particles (DEP) increases the risk of ischemic heart disease, especially heart attacks and ischemic/thrombotic strokes. Shengmai Yin (SMY) is a traditional Chinese medicine used to treat coronary heart disease. The aim of this study was to determine the protective role of SMY and the mechanism by which SMY affects DEP-induced cardiovascular injury. This study is expected to provide the basis for the development of an adaptive signature of SMY in the prevention of atherosclerotic cardiovascular disease and premature death from global air pollution exposure. We developed animal models of myocardial ischemia and atherosclerosis (AS) in response to DEP exposure. After SMY treatment, serum lipids returned to normal. Aortic plaque area and MMP9 expression were significantly reduced and collagen fiber expression increased after SMY treatment compared to DEP exposure alone. Thus, the risk of plaque formation and vulnerability is reduced. In addition, SMY improved left ventricular structure, morphology, function, blood flow, infarct area, myocardial damage, and ROS accumulation to varying degrees in ApoE-/- mice. These results indicate that the use of SMY is effective, to varying degrees, for the treatment of dyslipidemia, atherosclerosis, myocardial ischemia, and oxidative stress in ApoE-/- mice. SMY has a potential protective effect in DEP-aggravated AS in people with myocardial ischemia.

Exposure to urban air pollution particulate matter: neurobehavioral alteration and hippocampal inflammation.

Air pollution is associated with many neurodevelopmental and neurological disorders in human populations. Rodent models show similar neurotoxic effects of urban air pollution ultrafine particulate matter (UFPs < 100nm (PM0.1)), collected by different methods or from various sources. Exposure to ultrafine particulate matter (UFPs < 100nm (PM0.1)) can be adversely impacting the central nervous system (CNS) by the activation of proinflammatory pathways and reactive oxygen species associated with air pollution particulate matter. We investigated hippocampal inflammatory cytokines, neurobehavioral alteration, and neuronal morphology following exposure to diesel exhaust particles (DEPs) in mice. Male mice were DEPs exposed for 14weeks. Mice exposed to DEPs showed more disorders in spatial memory and learning and depressive-like responses than control mice. Expression of hippocampal pro-inflammatory cytokine was increased among DEPs exposure mice. The density of neurons in hippocampus CA1, CA3, and dentate gyrus (DG) regions decreased in DEPs mice. Overall, these findings show that prolonged exposure to DEPs in the world's major cities can alter neurobehavioral and impair cognition.

Inhaled diesel exhaust particles result in microbiome-related systemic inflammation and altered cardiovascular disease biomarkers in C57Bl/6 male mice

BackgroundThe gut microbiota plays a vital role in host homeostasis and is associated with inflammation and cardiovascular disease (CVD) risk. Exposure to particulate matter (PM) is a known mediator of inflammation and CVD and is reported to promote dysbiosis and decreased intestinal integrity. However, the role of inhaled traffic-generated PM on the gut microbiome and its corresponding systemic effects are not well-characterized. Thus, we investigated the hypothesis that exposure to inhaled diesel exhaust particles (DEP) alters the gut microbiome and promotes microbial-related inflammation and CVD biomarkers. 4–6-week-old male C57Bl/6 mice on either a low-fat (LF, 10% fat) or high-fat (HF, 45% fat) diet were exposed via oropharyngeal aspiration to 35 μg DEP suspended in 35 μl saline or saline only (CON) 2x/week for 30 days. To determine whether probiotics could prevent diet or DEP exposure mediated alterations in the gut microbiome or systemic outcomes, a subset of animals on the HF diet were treated orally with 0.3 g/day (~ 7.5 × 108 CFU/day) of Winclove Ecologic® Barrier probiotics throughout the study.ResultsOur results show that inhaled DEP exposure alters gut microbial profiles, including reducing Actinobacteria and expanding Verrucomicrobia and Proteobacteria. We observed increased circulating LPS, altered circulating cytokines (IL-1α, IL-3, IL-13, IL-15, G-CSF, LIF, MIP-2, and TNF-α), and CVD biomarkers (siCAM, PAI-1, sP-Selectin, thrombomodulin, and PECAM) in DEP-exposed and/or HF diet mice. Furthermore, probiotics attenuated the observed reduction of Actinobacteria and expansion of Proteobacteria in DEP-exposed and HF-diet mice. Probiotics mitigated circulating cytokines (IL-3, IL-13, G-CSF, RANTES, and TNF- α) and CVD biomarkers (siCAM, PAI-1, sP-Selectin, thrombomodulin, and PECAM) in respect to DEP-exposure and/or HF diet.ConclusionKey findings of this study are that inhaled DEP exposure alters small intestinal microbial profiles that play a role in systemic inflammation and early CVD biomarkers. Probiotic treatment in this study was fundamental in understanding the role of inhaled DEP on the microbiome and related systemic inflammatory and CVD biomarkers.

Altered secretome by diesel exhaust particles and lipopolysaccharide in primary human nasal epithelium

Airway epithelial cells can actively participate in the defense against environmental pathogens to elicit local or systemic inflammation. Diesel exhaust particles (DEP), a main component of urban air pollution with particulate matter, are associated with the occurrence of acute and chronic upper airway inflammatory diseases. We sought to investigate the effect of DEP alone or in combination with lipopolysaccharide on the secretome in the primary human nasal epithelium (PHNE) and to find potential biomarkers to relate DEP exposure to upper airway inflammatory diseases. PHNE was cultured at an air-liquid interface to create a differentiated invivo-like model. Secreted proteins (secretome) on the bottom media of the PHNE were analyzed by mass spectrometry-based label-free quantitative proteomics and ELISA. Considerably more differentially expressed secreted proteins were identified in response to DEP plus lipopolysaccharide than to DEP alone. Some canonical pathways related to inflammation and cancer such as the p53, β-catenin, and extracellular signal-regulated kinase 1/2 pathways were involved. Among differentially expressed secreted proteins, leukemia inhibitory factor was also detected at a high level in the middle ear effusions of otitis media patients, and the leukemia inhibitory factor level was significantly correlated with daily mean mass concentrations of atmospheric particulate matter averaged over 8 days before sample collection. Apical stimulation with DEP and lipopolysaccharide can significantly alter the basal secretome in PHNE, and this alteration can be reflected by surrounding inflammation with effusion of fluids invivo such as middle ear effusions in otitis media patients.

Diesel Exhaust Particles Impair Therapeutic Effect of Human Wharton's Jelly-Derived Mesenchymal Stem Cells against Experimental Colitis through ROS/ERK/cFos Signaling Pathway.

Background and ObjectivesEpidemiological investigations have shown positive correlations between increased diesel exhaust particles (DEP) in ambient air and adverse health outcomes. DEP are the major constituent of particulate atmospheric pollution and have been shown to induce proinflammatory responses both in the lung and systemically. Here, we report the effects of DEP exposure on the properties of human Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs), including stemness, regeneration, and immunomodulation.Methods and ResultsNon-apoptotic concentrations of DEP (10 μg/ml) inhibited the migration and osteogenic differentiation capacity of WJ-MSCs. Gene expression profiling showed that DEP increased intracellular reactive oxygen species (ROS) and expression of pro-inflammatory and metabolic-process-related genes including cFos. Furthermore, WJ-MSCs cultured with DEP showed impaired suppression of T cell proliferation that was reversed by inhibition of ROS or knockdown of cFos. ERK inhibition assay revealed that DEP-induced ROS regulated cFos through activation of ERK but not NF-κB signaling. Overall, low concentrations of DEP (10 μg/ml) significantly suppressed the stemness and immunomodulatory properties of WJ-MSCs through ROS/ERK/cFos signaling pathways. Furthermore, WJ-MSCs cultured with DEP impaired the therapeutic effect of WJ-MSCs in experimental colitis mice, but was partly reversed by inhibition of ROS.ConclusionsTaken together, these results indicate that exposure to DEP enhances the expression of pro-inflammatory cytokines and immune responses through a mechanism involving the ROS/ERK/cFos pathway in WJ-MSCs, and that DEP-induced ROS damage impairs the therapeutic effect of WJ-MSCs in colitis. Our results suggest that modulation of ROS/ERK/cFos signaling pathways in WJ-MSCs might be a novel therapeutic strategy for DEP-induced diseases.

Role of diesel exhaust exposure in promoting Alzheimer’s disease susceptibility by impairing glymphatic drainage of amyloid beta (aβ) and other toxic metabolites from the brain

Chronic exposure to air pollution has been linked with increased rates of dementia and Alzheimer's disease. Exposure to diesel exhaust particles (DEP) is used as a model for studying the effects of air pollution in rodents and has been shown to induce spatial memory deficits in mice. Emerging evidence has indicated that the exchange of ISF and CSF through the glymphatic system, is critical for the removal of toxic metabolites such as amyloid beta (Aβ) from the brain. The following study seeks to evaluate whether DEP exposure decreases rates of Aβ clearance (as well as other toxic metabolites) from the brain.Mice will be exposed to DEP or vehicle control for 14 days. Changes in glymphatic clearance will be measured in anesthetized mice using in-vivo two-photon imaging with a cranial window implantation after the injection of a fluorescent tracer. As a direct measure of Aβ clearance we will inject Aβ into the prefrontal cortex of mice and measure the concentration of Aβ in the brain 0.5,1, and 4 hours later via ELISA.This ongoing work is expected to show that mice exposed to DEP will display impairments in lymphatic clearance. We will also test the hypothesis that old mice (20 month) will display increased susceptibility to the pathological effects of DEP due to exacerbation of impairments in the clearance of toxic metabolites (i.e. Aβ) from the brain. We hypothesize that decreased drainage of toxic metabolites through the glymphatic system promotes a highly inflammatory environment in the brain and is a critical mediator of age related increases in neuroinflammation and AD susceptibility.Accumulating evidence indicates modifiable risk factors as major contributors in the development and progression of sporadic AD. In particular, numerous studies have drawn correlation between rates of AD and exposure to air pollution. This study is based on the novel hypothesis that exposure to air pollution promotes AD susceptibility by impairing the clearance of Aβ and other toxic metabolites from the brain.

The biomechanistic aspects of renal cortical injury induced by diesel exhaust particles in rats and the renoprotective contribution of quercetin pretreatment: Histological and biochemical study.

Although several studies have reported a toxic effect of diesel exhaust particles (DEP) exposure on the kidney tissues, the involvement of autophagy/NF-kB signaling as encountered mechanisms and the protective effects of a natural flavonoid, quercetin on DEP remains unclear. Thirty-two albino rats were divided as control, quercetin-treated (60 mg/kg, oral), DEP-exposed (0.5mg/kg, intra-tracheal), and quercetin/DEP-exposed groups. Specimens of the renal cortex were subjected to histo-biochemical study and immunohistochemical analysis using anti-NF-kB, and anti-LC3β antibodies followed by morphometric and statistical analyses. The expression level of autophagy genes was quantitatively evaluated using RT-PCR, as well. The DEP-exposed rats showed an elevation in the renal tissue levels of MDA and a decrease in the catalase and superoxide dismutase (p < .05). Histologically, there were cytoplasmic vacuolar changes in the lining cells of the renal tubules, glomerular atrophy, and vascular congestion. In addition, renal inflammation was evident as confirmed by the increased NF-kB immunoexpression. Moreover, the gene expression of Becn1, ATG5, and LC3β increased (p <. 0) due to DEP exposure. Conversely, quercetin pretreatment improved these renal histo-biochemical alterations (p < .05) and regulated autophagy/NF-kB pathways. Overall, the study proved the renal toxicity mediated by DEP exposure via precipitating renal inflammation, autophagy activation, and oxidative stress. Quercetin pretreatment could antagonize such machinery to protect the kidney against DEP.

A unique population of neutrophils generated by air pollutant–induced lung damage exacerbates airway inflammation

Diesel exhaust particles (DEPs) are the main component of traffic-related air pollution and have been implicated in the pathogenesis and exacerbation of asthma. However, the mechanism by which DEP exposure aggravates asthma symptoms remains unclear. This study aimed to identify a key cellular player of air pollutant-induced asthma exacerbation and development. We examined the distribution of innate immune cells in the murine models of asthma induced by house dust mite and DEP. Changes in immune cell profiles caused by DEP exposure were confirmed by flow cytometry and RNA-Seq analysis. The roles of sialic acid-binding, Ig-like lectin F (SiglecF)-positive neutrophils were further evaluated by adoptive transfer experiment and invitro functional studies. DEP exposure induced a unique population of lung granulocytes that coexpressed Ly6G and SiglecF. These cells differed phenotypically, morphologically, functionally, and transcriptionally from other SiglecF-expressing cells in the lungs. Our findings with murine models suggest that intratracheal challenge with DEPs induces the local release of adenosine triphosphate, which is a damage-associated molecular pattern signal. Adenosine triphosphate promotes the expression of SiglecF on neutrophils, and these SiglecF+ neutrophils worsen type 2 and 3 airway inflammation by producing high levels of cysteinyl leukotrienes and neutrophil extracellular traps. We also found Siglec8- (which corresponds to murine SiglecF) expressing neutrophils, and we found it in patients with asthma-chronic obstructive pulmonary disease overlap. The SiglecF+ neutrophil is a novel and critical player in airway inflammation and targeting this population could reverse or ameliorate asthma.

Effects of diesel exhaust particles and urban particles on brain endothelial cells.

Exposure to diesel exhaust particles (DEPs) and urban particles (UPs) increases the incidence of degenerative brain diseases as well as respiratory diseases. However, there is limited evidence on the mechanism of neurotoxicity on exposure to these particles. In the present study, the damage to blood-brain barrier (BBB) function by DEP or UP exposure was evaluated in bEnd.3 cells, which are derived from the brain tissue of Balb/c mice. It was demonstrated that DEP and UP exposure may induce oxidative stress via increasing reactive oxygen species (ROS) and decreasing total antioxidant capacity (TAC) level in bEnd.3 cells. In addition, cells exposed to DEP and UP demonstrated a resistance value of about 50% each compared to the value noted prior to exposure; additionally, Claudin-5 and ZO-1 expression levels were significantly decreased compared to the corresponding levels in the control. It was inferred that DEP or UP exposure diminishes the expression of tight junction proteins in endothelial cells through ROS generation, thereby enhancing endothelial membrane permeability. This study showed that DEPs or UPs induced cell permeability and oxidative stress by increasing ROS generation in bEnd.3 cells. This suggests the possibility that exposure to DEPs or UPs may compromise the integrity of the BBB and induce adverse effects in the CNS.

Air pollution-induced tanning of human skin.

Melanism is more frequent in animals living in polluted areas on urban-industrial sites. Given that an increasing number of people are exposed to elevated air pollution levels, it is possible that environmental pollutants affect melanogenesis in human skin. Epidemiological studies have shown that exposure to traffic-related air pollutants such as diesel exhaust particles (DEP) is associated with more clinical signs of hyperpigmentation. However, mechanistic evidence linking DEP exposure to pigmentation has been elusive. To develop an ex␣vivo skin model to allow for repetitive topical application of relevant ambient DEP, and to provide proof of concept in humans. We measured skin pigmentation, melanin and pigmentation-associated gene expression, and evaluated oxidative stress. Repetitive exposure of ex␣vivo skin to DEP at nontoxic concentrations increased skin pigmentation. This increase was visible to the naked eye, time dependent, and associated with an increase in melanin content and the transcription of genes involved in de novo melanin synthesis. Similarly, in healthy participants (n = 76), repetitive topical application of DEP at nontoxic concentrations increased skin pigmentation. DEP-induced pigmentation was mediated by an oxidative stress response. After the application of DEP, epidermal antioxidants were depleted, lipid peroxidation and oxidative DNA damage were enhanced, and in a vehicle-controlled, double-blind clinical study DEP-induced pigmentation was prevented by the topical application of an antioxidant mixture. Similar to solar radiation, air pollutants cause skin tanning. As eumelanin is an antioxidant, it is proposed that this response serves to protect human skin against air pollution-induced oxidative stress.

Diesel exhaust particles increase nasal symptoms and IL-17A in house dust mite-induced allergic mice

Diesel exhaust particles (DEPs), traffic-related air pollutants, are considered environmental factors adversely affecting allergic diseases. However, the immunological basis for the adjuvant effects of DEP in allergic rhinitis (AR) remains unclear. Therefore, this study aimed to investigate the effect of DEP exposure on AR using a mouse model. BALB/c mice sensitized to house dust mite (HDM) were intranasally challenged with HDM in the presence and absence of DEP. Allergic symptom scores, serum total and HDM-specific immunoglobulins (Igs), eosinophil infiltration in the nasal mucosa, cytological profiles in bronchoalveolar lavage fluid (BALF), and cytokine levels in the nasal mucosa and spleen cell culture were analyzed. Mice co-exposed to HDM and DEP showed increased allergic symptom scores compared with mice exposed to HDM alone. Reduced total IgE and HDM-specific IgE and IgG1 levels, decreased eosinophil infiltration in the nasal mucosa, and increased proportion of neutrophils in BALF were found in mice co-exposed to HDM and DEP. Interleukin (IL)-17A level was found to be increased in the nasal mucosa of the co-exposure group compared with that in the HDM-exposed group. The levels of IL-4, IL-13, interferon-γ, IL-25, IL-33, and TSLP expression showed no difference between the groups with and without DEP treatment. Increased expression of IL-17A in the nasal mucosa may contribute to DEP-mediated exacerbation of AR in HDM-sensitized murine AR model.

The effects of exercise training on the lungs and cardiovascular function of animals exposed to diesel exhaust particles and gases

Air pollution has been identified as one of the main environmental risks to health. Since exercise training seems to act as an anti-inflammatory modulator, our hypothesis is that exercise training prevents damage to respiratory and cardiovascular function caused by diesel exhaust particle (DEP) exposure. This study aimed to evaluate whether aerobic exercise training prior to DEP exposure prevents inflammatory processes in the pulmonary and cardiovascular systems. Therefore, BALB/C male mice were or were not submitted to a 10-week exercise training protocol (5×/week, 1 h/d), and after four weeks, they were exposed to DEP in a chamber with 24 μg/m3 PM2.5 or filtered air. Heart rate variability, lung mechanics and bronchoalveolar lavage fluid, cytokines and polymorphonuclear cells in the lung parenchyma were evaluated. Exposure to DEPs reduced heart rate variability and the elastance of the respiratory system and increased the number of cells in bronchoalveolar lavage fluid, as well as macrophages, neutrophils and lymphocytes, the density of polymorphonuclear cells and the proportion of collagen fibres in the lung parenchyma. Additionally, DEP-exposed animals showed increased expression of IL-23 and IL-12p40 (proinflammatory cytokines) and inducible nitric oxide synthase. Exercise training avoided the increases in all these inflammatory parameters, except the elastance of the respiratory system, the amount of collagen fibres and the expression of inducible nitric oxide synthase. Additionally, trained animals showed increased expression of the anti-inflammatory cytokine IL-1ra. Although our data showed a reduction in proinflammatory markers and an increase in markers of the anti-inflammatory pathway, these changes were not sufficient to prevent damage to the lung and cardiovascular function induced by DEPs. Based on these data, we propose that aerobic exercise training prevents the lung inflammatory process induced by DEPs, although it was not sufficient to avoid chronic damage, such as a loss of lung function or cardiovascular events.

Study of the Antioxidant Effects of Coffee Phenolic Metabolites on C6 Glioma Cells Exposed to Diesel Exhaust Particles.

The contributing role of environmental factors to the development of neurodegenerative diseases has become increasingly evident. Here, we report that exposure of C6 glioma cells to diesel exhaust particles (DEPs), a major constituent of urban air pollution, causes intracellular reactive oxygen species (ROS) production. In this scenario, we suggest employing the possible protective role that coffee phenolic metabolites may have. Coffee is a commonly consumed hot beverage and a major contributor to the dietary intake of (poly) phenols. Taking into account physiological concentrations, we analysed the effects of two different coffee phenolic metabolites mixes consisting of compounds derived from bacterial metabolization reactions or phase II conjugations, as well as caffeic acid. The results showed that these mixes were able to counteract DEP-induced oxidative stress. The cellular components mediating the downregulation of ROS included extracellular signal-regulated kinase 1/2 (ERK1/2), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and uncoupling protein 2 (UCP2). Contrary to coffee phenolic metabolites, the treatment with N-acetylcysteine (NAC), a known antioxidant, was found to be ineffective in preventing the DEP exposure oxidant effect. These results revealed that coffee phenolic metabolites could be promising candidates to protect against some adverse health effects of daily exposure to air pollution.

Dopaminergic and serotonergic changes in rabbit fetal brain upon repeated gestational exposure to diesel engine exhaust.

Limited studies in humans and in animal models have investigated the neurotoxic risks related to a gestational exposure to diesel exhaust particles (DEP) on the embryonic brain, especially those regarding monoaminergic systems linked to neurocognitive disorders. We previously showed that exposure to DEP alters monoaminergic neurotransmission in fetal olfactory bulbs and modifies tissue morphology along with behavioral consequences at birth in a rabbit model. Given the anatomical and functional connections between olfactory and central brain structures, we further characterized their impacts in brain regions associated with monoaminergic neurotransmission. At gestational day 28 (GD28), fetal rabbit brains were collected from dams exposed by nose-only to either a clean air or filtered DEP for 2h/day, 5days/week, from GD3 to GD27. HPLC dosage and histochemical analyses of the main monoaminergic systems, i.e., dopamine (DA), noradrenaline (NA), and serotonin (5-HT) and their metabolites were conducted in microdissected fetal brain regions. DEP exposure increased the level of DA and decreased the dopaminergic metabolites ratios in the prefrontal cortex (PFC), together with sex-specific alterations in the hippocampus (Hp). In addition, HVA level was increased in the temporal cortex (TCx). Serotonin and 5-HIAA levels were decreased in the fetal Hp. However, DEP exposure did not significantly modify NA levels, tyrosine hydroxylase, tryptophan hydroxylase or AChE enzymatic activity in fetal brain. Exposure to DEP during fetal life results in dopaminergic and serotonergic changes in critical brain regions that might lead to detrimental potential short-term neural disturbances as precursors of long-term neurocognitive consequences.

In vitro and in vitro toxicity study of diesel exhaust particles using BEAS-2B cell line and the nematode Caenorhabditis elegans as biological models.

It is well accepted that diesel exhaust particles (DEPs) are highly associated with improper function of organ systems. In this study, DEP toxicity was performed by using in vitro human BEAS-2B cell line and in vivo animal model, namely, Caenorhabditis elegans (C. elegans). The potential toxicity of DEP was assessed by the apical endpoints of BEAS-2B cell line and reflections of C. elegans under exposure scenarios of 0~50 μg mL-1 DEP. With the increase of DEP exposure concentration, microscopic accumulations in the cytoplasm of cell line and intestine of C. elegans were observed. Such invasion of DEP impaired the behaviors of C. elegans as well as its un-exposed offspring and caused significant impeded locomotion. Moreover, the disorders of dopaminergic function were observed simultaneously under DEP exposure, specifically manifested by the decreased transcriptional expression of dat-1. The stress responses instructed by the expression of hsp-16.2were also increased sharply in TJ375 strain of C. elegans at DEP concentrations of 1 and 10 μg mL-1. In the case of cellular reactions to DEP exposure, the injuries of membrane integrity and the decreased viability of cell line were simultaneously identified, and reactive oxygen species (ROS), damaged DNA fragment, and upregulated apoptosis were monotonically elevated in cell lines with the increase of DEP concentrations. This study provided a systematic insight into toxicity of DEP both in vivo and vitro, demonstrating that DEP exposure could disturb the stability of cell system and further threat the stability of organism.

Alveolar epithelial inter-alpha-trypsin inhibitor heavy chain 4 deficiency associated with senescence-regulated apoptosis by air pollution.

Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) is a type II acute-phase protein; however, the role of pulmonary ITIH4 after exposure to air pollution remains unclear. In this study, we investigated the role of ITIH4 in the lungs in response to air pollution. ITIH4 expression in bronchoalveolar lavage fluid (BAL) of 47 healthy human subjects and of Sprague-Dawley rats whole-body exposed to air pollution was determined, and the underlying antiapoptotic and matrix-stabilizing pathways in alveolar epithelial A549cells induced by diesel exhaust particles (DEPs) as well as ITIH4-knockdown were investigated. We found that an interquartile range (IQR) increase in PM2.5 was associated with a decrease of 2.673ng/mL in ITIH4, an increase of 1.104pg/mL of 8-isoprostane, and an increase of 6.918pg/mL of interleukin (IL)-6 in human BAL. In rats, increases in 8-isoprostane, IL-6, and p53 and a decrease in sirtuin-1 (Sirt1) in the lungs and decreases in ITIH4 in the BAL, lungs, and serum were observed after PM2.5 and gaseous exposure. ITIH4 levels in lung lysates were correlated with levels in BAL samples (r=0.377, p<0.01), whereas ITIH4 levels in BAL were correlated with IL-6 levels (r=-0.420, p<0.01). ITIH4 expression was significantly reduced in alveolar epithelial A549cells by DEP in a dose-dependent manner. A decrease in Sirt1 and increases in phosphorylated extracellular signal-regulated kinase (p-ERK) and caspase-3 were observed after DEP exposure and ITIH4-knockdown. In conclusion, air pollution decreased ITIH4 expression in the lungs, which was associated with alveolar epithelial cell senescence and apoptosis. ITIH4 could be a vital protein in regulating alveolar cell destruction and its inhibition after exposure to air pollution.

DEP-induced ZEB2 promotes nasal polyp formation via epithelial-to-mesenchymal transition

Diesel exhaust particles (DEPs) are associated with the prevalence and exacerbation of allergic respiratory diseases, including allergic rhinitis and allergic asthma. However, DEP-induced mechanistic pathways promoting upper airway disease and their clinical implications remain unclear. We sought to investigate the mechanisms by which DEP exposure contributes to nasal polyposis using human-derived epithelial cells and a murine nasal polyp (NP) model. Gene set enrichment and weighted gene coexpression network analyses were performed. Cytotoxicity, epithelial-to-mesenchymal transition (EMT) markers, and nasal polyposis were assessed. Effects of DEP exposure on EMT were determined using epithelial cells from normal people or patients with chronic rhinosinusitis with or without NPs. BALB/c mice were exposed to DEP through either a nose-only exposure system or nasal instillation, with or without house dust mite, followed by zinc finger E-box-binding homeobox (ZEB)2 small hairpin RNA delivery. Bioinformatics analyses revealed that DEP exposure triggered EMT features in airway epithelial cells. Similarly, DEP-exposed human nasal epithelial cells exhibited EMT characteristics, which were dependent on ZEB2 expression. Human nasal epithelial cells derived from patients with chronic rhinosinusitis presented more prominent EMT features after DEP treatment, when compared with those from control subjects and patients with NPs. Coexposure to DEP and house dust mite synergistically increased the number of NPs, epithelial disruptions, and ZEB2 expression. Most importantly, ZEB2 inhibition prevented DEP-induced EMT, thereby alleviating NP formation in mice. Our data show that DEP facilitated NP formation, possibly via the promotion of ZEB2-induced EMT. ZEB2 may be a therapeutic target for DEP-induced epithelial damage and related airway diseases, including NPs.

The Acute Effect of Diesel Exhaust Particles and Different Fractions Exposure on Blood Coagulation Function in Mice.

The toxicity and widespread exposure opportunity of diesel exhaust particles (DEP) has aroused public health concerns. This study aimed to investigate the acute effect of DEP and different fractions exposure on blood coagulation function in mice. In this study, nine- week-old C57BL/6J male mice were divided into four exposure groups (with 15 mice in each group). The water-soluble (WS) and water-insoluble (WIS) fractions of DEP were isolated, and intratracheal instillation was used for DEP, WS and WIS exposure. The phosphate buffer saline (PBS) exposure group was set as the control group. After 24 h exposure, the mice were sacrificed for blood routine, coagulation function and bleeding time examinations to estimate the acute effect of DEP, WS and WIS exposure on the blood coagulation function. In our results, no statistically significant difference in weight of body, brain and lung was observed in different exposure groups. While several core indexes in blood coagulation like bleeding time (BT), fibrinogen (FIB), activated partial thromboplastin time (APTT) and prothrombin time (PT) altered or showed a lower tendency after DEP, WS and WIS exposure. For example, BT was lower In WIS exposure group (211.00 s) compared with PBS exposure group (238.50 s) (p < 0.01), and FIB was lower in WS exposure group (233.00 g/L) compared with PBS exposure group (249.50 g/L) (p < 0.05). Additionally, systemic inflammation-related indexes like white blood cell count (WBC), neutrophil count (NEUT), lymphocyte count (LYMPH) altered after DEP, WS and WIS exposure. In conclusion, DEP, WS and WIS fractions exposure could result in the hypercoagulable state of blood in mice. The noteworthy effects of WS and WIS fractions exposure on blood coagulation function deserve further investigation of the potential mechanism.

Urinary 1-aminopyrene level in Koreans as a biomarker for the amount of exposure to atmospheric 1-nitropyrene

1-Nitropyrene (1-NP) is a major nitro-polycyclic aromatic hydrocarbon (nitro-PAH), and a common constituent in diesel exhaust particles (DEPs). Absorbed 1-nitropyrene is partly metabolized to 1-aminopyrene and excreted in urine. Recently, the number of diesel cars has been increasing, which could be a major cause of air pollution, resulting elevated levels of traffic-related DEPs around cities. The aim of this study was to investigate the usability of 1-aminopyrene (1-AP) as a biomarker for DEP exposure by examining the association between urinary 1-AP concentration and the amount of exposure to atmospheric 1-NP. The study subjects included 65 individuals who work on vehicular roads or bus terminals. Their 24 h urine samples were collected, and atmospheric air was sampled using a personal air sampler for 24 h. Urinary 1-AP and atmospheric nitro-PAH levels were measured using a high-pressure liquid chromatography-fluorescence detector (HPLC-FD). The average urine 1-AP concentration was 0.334 pg/g creatinine. Urinary 1-AP levels were significantly correlated with 1-NP level exposure (r = 0.385, p = 0.002) but not with the other nitro-PAHs. When the subjects were classified into high-and low-exposure groups, a significant association was only found in the high exposure group (r = 0.357, p = 0.045). In conclusion, there was a significant correlation between 1-NP exposure and urinary 1-AP concentration; therefore, urinary 1-AP level could be used as an exposure biomarker for DEP.

Differential effects of intense exercise and pollution on the airways in a murine model

BackgroundExercise-induced bronchoconstriction (EIB) is a transient airway narrowing, occurring during or shortly after intensive exercise. It is highly prevalent in non-asthmatic outdoor endurance athletes suggesting an important contribution of air pollution in the development of EIB. Therefore, more research is necessary to investigate the combination of exercise and pollutants on the airways.MethodsBalbc/ByJ mice were intranasally challenged 5 days a week for 3 weeks with saline or 0.2 mg/ml diesel exhaust particles (DEP), prior to a daily incremental running session or non-exercise session. Once a week, the early ventilatory response was measured and lung function was determined at day 24. Airway inflammation and cytokine levels were evaluated in bronchoalveolar lavage fluid. Furthermore, innate lymphoid cells, dendritic cells and tight junction mRNA expression were determined in lung tissue.ResultsSubmaximal exercise resulted in acute alterations of the breathing pattern and significantly improved FEV0.1 at day 24. DEP exposure induced neutrophilic airway inflammation, accompanied with increased percentages of CD11b+ DC in lung tissue and pro-inflammatory cytokines, such as IL-13, MCP-1, GM-CSF and KC. Occludin and claudin-1(Cldn-1) expression were respectively increased and decreased by DEP exposure. Whereas, exercise increased Cldn-3 and Cldn-18 expression. Combining exercise and DEP exposure resulted in significantly increased SP-D levels in the airways.ConclusionDEP exposure induced typical airway neutrophilia, DC recruitment and pro-inflammatory cytokine production. Whereas, intensive exercise induced changes of the breathing pattern. The combination of both triggers resulted in a dysregulation of tight junction expression, suggesting that intensive exercise in polluted environments can induce important changes in the airway physiology and integrity.