Progranulin derivative attenuates lung neutrophilic infiltration from diesel exhaust particle exposure.

BACKGROUND: Air pollutants, such as diesel exhaust particles (DEPs), induce respiratory disease exacerbation with neutrophilic infiltration. Progranulin (PGRN), an epithelial cell and macrophage-derived secretory protein, is associated with neutrophilic inflammation. PGRN is digested into various derivatives at inflammatory sites and is involved in several inflammatory processes. PGRN and its derivatives likely regulate responses to DEP exposure in allergic airway inflammation. AIM: To investigate the role of PGRN and its derivatives in the regulation of responses to DEP exposure in allergic airway inflammation. METHODS: A murine model of allergic airway inflammation was generated in PGRN-deficient mice, and they were simultaneously exposed to DEP followed by intranasal administration of full-length recombinant PGRN (PGRN-FL) and a PGRN-derived fragment (FBAC). Inflammatory status was evaluated by bronchoalveolar lavage fluid and histopathologic analyses. Human bronchial epithelial cells were stimulated with DEPs and house dust mites (HDMs), and the effect of FBAC treatment was evaluated by assessing various intracellular signaling molecules, autophagy markers, inflammatory cytokines, and intracellular oxidative stress. RESULTS: DEP exposure exaggerated neutrophilic inflammation, enhanced IL-6 and CXCL15 secretions, and increased oxidative stress in the murine model; this effect was greater in PGRN-deficient mice than in wild-type mice. The DEP-exposed mice with PGRN-FL treatment revealed no change in neutrophil infiltration and higher oxidative stress status in the lungs. On the contrary, FBAC administration inhibited neutrophilic infiltration and reduced oxidative stress. In human bronchial epithelial cells, DEP and HDM exposure increased intracellular oxidative stress and IL-6 and IL-8 secretion. Decreased nuclear factor erythroid 2-related factor 2 (Nrf2) expression and increased phosphor-p62 and LC3B expression were also observed. FBAC treatment attenuated oxidative stress from DEP and HDM exposure. CONCLUSIONS: FBAC reduced neutrophilic inflammation exaggerated by DEP exposure in a mouse model of allergic airway inflammation by reducing oxidative stress. PGRN and PGRN-derived proteins may be novel therapeutic agents in attenuating asthma exacerbation induced by air pollutant exposure.

Air pollution amyloidogenesis is attenuated by the gamma-secretase modulator GSM-15606.

INTRODUCTION: Chronic air pollution (AirPoll) is associated with accelerated cognitive decline and risk of Alzheimer's disease (AD). Correspondingly, wild-type and AD-transgenic rodents exposed to AirPoll have increased amyloid peptides and behavioral impairments. METHODS: We examined the γ-secretase modulator GSM-15606 for potential AirPoll protection by its attenuating of amyloid beta (Aß)42 peptide production. Male and female wild-type mice were fed GSM-15606 during an 8-week inhalation exposure to AirPoll subfractions, ambient nanoparticulate matter (nPM), and diesel exhaust particles (DEP). RESULTS: GSM-15606 decreased Aß42 during nPM and DEP exposure without changing beta- or gamma-secretase activity or BACE1 and PS1 protein levels. DEP increased lateral ventricle volume by 25%. DISCUSSION: These enzyme responses are relevant to AD drug treatments, as well as to the physiological functions of the Aß42 peptide. GSM-15606 attenuation of Aß42 may benefit human exposure to AirPoll. HIGHLIGHTS: Gamma-secretase modulator (GSM-15606) attenuates the amyloidogenic amyloid beta (Aß)42 peptide during exposure to air pollution, which may be a mechanism by which air pollution increases Alzheimer's disease (AD) risk. AD drug treatments may also consider Aß homeostasis among the chronic effects of GSM-15606 and other amyloid reduction treatments on secretase enzymes.

Modulation of miR-466d-3p on Wnt signaling pathway in response to DEPs-induced blood-brain barrier disruption.

BACKGROUND: Diesel exhaust particles (DEPs), a predominant component of ambient particulate matter (PM), are classified as ultrafine particles with the capacity to penetrate the cerebral blood-brain barrier (BBB). This penetration is implicated in the pathogenesis of central nervous system (CNS) disorders. The integrity of the BBB is inextricably linked to cerebrovascular homeostasis and the development of neurodegenerative disease, highlighting the importance of studying the effects and mechanisms of DEPs on BBB function damage. METHODS AND RESULTS: Utilizing mouse cerebral microvascular endothelial cells (bEnd.3 cells) as an in vitro model of the BBB, we explored the detrimental effects of DEPs exposure on BBB permeability and integrity, with particular focus on inflammation, cell apoptosis, and miRNA expression profiles. Our findings revealed that exposure to DEPs at varying concentrations for 48 h resulted in the inhibition of bEND.3 cell proliferation, induction of cell apoptosis, and an upregulation in the secretion of inflammatory cytokines/chemokines and adhesion molecules. The BBB integrity was further compromised, as evidenced by a decrease in trans-epithelial electrical resistance(TEER), a reduction in cytoskeletal F-actin, and diminished tight junction (TJ) protein expression. Microarray analysis revealed that 23 miRNAs were upregulated and 11 were downregulated in response to a 50 µg/mL DEPs treatment, with miR-466d-3p being notably differentially expressed. Wnt3 was identified as a target of miR-466d-3p, with the Wnt signaling pathway being significantly enriched. We validated that miR-466d-3p expression was downregulated, and the protein expression levels of Wnt/ß-catenin and Wnt/PCP signaling components were elevated. The modulation of the Wnt signaling pathway by miR-466d-3p was demonstrated by the transfection of miR-466d-3p mimic, which resulted in a downregulation of Wnt3 and ß-catenin protein expression, and the mRNA level of Daam1, as well as an enhancement of TJ proteins ZO-1 and Claudin-5 expression. CONCLUSIONS: Our study further confirmed that DEPs can induce the disruption of BBB integrity through inflammatory processes. We identified alterations in the expression profile of microRNAs (miRNAs) in endothelial cells, with miR-466d-3p emerging as a key regulator of tight junction (TJ) proteins, essential for maintaining BBB integrity. Additionally, our findings primarily demonstrated that the Wnt/ ß-catenin and Wnt/PCP signaling pathway can be activated by DEPs and are regulated by miR-466d-3p. Under the combined effects of Wnt/PCP and inflammation, there is an ultimate increase in BBB hyperpermeability.

Diesel exhaust particles alter mitochondrial bioenergetics and cAMP producing capacity in human bronchial epithelial cells.

Introduction: Air pollution from diesel combustion is linked in part to the generation of diesel exhaust particles (DEP). DEP exposure induces various processes, including inflammation and oxidative stress, which ultimately contribute to a decline in lung function. Cyclic AMP (cAMP) signaling is critical for lung homeostasis. The impact of DEP on cAMP signaling is largely unknown. Methods: We exposed human bronchial epithelial (BEAS-2B) cells to DEP for 24-72 h and evaluated mitochondrial bioenergetics, markers of oxidative stress and inflammation and the components of cAMP signaling. Mitochondrial bioenergetics was measured at 72 h to capture the potential and accumulative effects of prolonged DEP exposure on mitochondrial function. Results: DEP profoundly altered mitochondrial morphology and network integrity, reduced both basal and ATP-linked respiration as well as the glycolytic capacity of mitochondria. DEP exposure increased gene expression of oxidative stress and inflammation markers such as interleukin-8 and interleukin-6. DEP significantly affected mRNA levels of exchange protein directly activated by cAMP-1 and -2 (Epac1, Epac2), appeared to increase Epac1 protein, but left phospho-PKA levels unhanged. DEP exposure increased A-kinase anchoring protein 1, ß2-adrenoceptor and prostanoid E receptor subtype 4 mRNA levels. Interestingly, DEP decreased mRNA levels of adenylyl cyclase 9 and reduced cAMP levels stimulated by forskolin (AC activator), fenoterol (ß2-AR agonist) or PGE2 (EPR agonist). Discussion: Our findings suggest that DEP induces mitochondrial dysfunction, a process accompanied by oxidative stress and inflammation, and broadly dampens cAMP signaling. These epithelial responses may contribute to lung dysfunction induced by air pollution exposure.

Correlation between Exposure to UFP and ACE/ACE2 Pathway: Looking for Possible Involvement in COVID-19 Pandemic.

The overlap between the geographic distribution of COVID-19 outbreaks and pollution levels confirmed a correlation between exposure to atmospheric particulate matter (PM) and the SARS-CoV-2 pandemic. The RAS system is essential in the pathogenesis of inflammatory diseases caused by pollution: the ACE/AngII/AT1 axis activates a pro-inflammatory pathway, which is counteracted by the ACE2/Ang(1-7)/MAS axis, which activates an anti-inflammatory and protective pathway. However, ACE2 is also known to act as a receptor through which SARS-CoV-2 enters host cells to replicate. Furthermore, in vivo systems have demonstrated that exposure to PM increases ACE2 expression. In this study, the effects of acute and sub-acute exposure to ultrafine particles (UFP), originating from different anthropogenic sources (DEP and BB), on the levels of ACE2, ACE, COX-2, HO-1, and iNOS in the lungs and other organs implicated in the pathogenesis of COVID-19 were analyzed in the in vivo BALB/c male mice model. Exposure to UFP alters the levels of ACE2 and/or ACE in all examined organs, and exposure to sub-acute DEP also results in the release of s-ACE2. Furthermore, as evidenced in this and our previous works, COX-2, HO-1, and iNOS levels also demonstrated organ-specific alterations. These proteins play a pivotal role in the UFP-induced inflammatory and oxidative stress responses, and their dysregulation is linked to the development of severe symptoms in individuals infected with SARS-CoV-2, suggesting a heightened vulnerability or a more severe clinical course of the disease. UFP and SARS-CoV-2 share common pathways; therefore, in a "risk stratification" concept, daily exposure to air pollution may significantly increase the likelihood of developing a severe form of COVID-19, explaining, at least in part, the greater lethality of the virus observed in highly polluted areas.

Long-term exposure to diesel exhaust particles induces concordant changes in DNA methylation and transcriptome in human adenocarcinoma alveolar basal epithelial cells.

BACKGROUND: Diesel exhaust particles (DEP), which contain hazardous compounds, are emitted during the combustion of diesel. As approximately one-third of the vehicles worldwide use diesel, there are growing concerns about the risks posed by DEP to human health. Long-term exposure to DEP is associated with airway hyperresponsiveness, pulmonary fibrosis, and inflammation; however, the molecular mechanisms behind the effects of DEP on the respiratory tract are poorly understood. Such mechanisms can be addressed by examining transcriptional and DNA methylation changes. Although several studies have focused on the effects of short-term DEP exposure on gene expression, research on the transcriptional effects and genome-wide DNA methylation changes caused by long-term DEP exposure is lacking. Hence, in this study, we investigated transcriptional and DNA methylation changes in human adenocarcinoma alveolar basal epithelial A549 cells caused by prolonged exposure to DEP and determined whether these changes are concordant. RESULTS: DNA methylation analysis using the Illumina Infinium MethylationEPIC BeadChips showed that the methylation levels of DEP-affected CpG sites in A549 cells changed in a dose-dependent manner; the extent of change increased with increasing dose reaching the statistical significance only in samples exposed to 30 µg/ml DEP. Four-week exposure to 30 µg/ml of DEP significantly induced DNA hypomethylation at 24,464 CpG sites, which were significantly enriched for DNase hypersensitive sites, genomic regions marked by H3K4me1 and H3K27ac, and several transcription factor binding sites. In contrast, 9,436 CpG sites with increased DNA methylation levels were significantly overrepresented in genomic regions marked by H3K27me3 as well as H3K4me1 and H3K27ac. In parallel, gene expression profiling by RNA sequencing demonstrated that long-term exposure to DEP altered the expression levels of 2,410 genes, enriching 16 gene sets including Xenobiotic metabolism, Inflammatory response, and Senescence. In silico analysis revealed that the expression levels of 854 genes correlated with the methylation levels of the DEP-affected cis-CpG sites. CONCLUSIONS: To our knowledge, this is the first report of genome-wide transcriptional and DNA methylation changes and their associations in A549 cells following long-term exposure to DEP.

Mechanism underlying the role of integrin α3ß1 in adhesive dysfunction between thyroid cells induced by diesel engine exhaust particles.

The role and mechanisms of DEP exposure on thyroid injury are not yet clear. This study explores thyroid damage induced by in vivo DEP exposure using a mouse model. This study has observed alterations in thyroid follicular architecture, including rupture, colloid overflow, and the formation of voids. Additionally, there was a significant decrease in the expression levels of proteins involved in thyroid hormone synthesis, such as thyroid peroxidase and thyroglobulin, their trend of change is consistent with the damage to the thyroid structure. Serum levels of triiodothyronine and tetraiodothyronine were raise. However, the decrease in TSH expression suggests that the function of the HPT axis is unaffected. To delve deeper into the intrinsic mechanisms of thyroid injury, we performed KEGG pathway enrichment analysis, which revealed notable alterations in the cell adhesion signaling pathway. Our immunofluorescence results show that DEP exposure impairs thyroid adhesion, and integrin α3ß1 plays an important role. CD151 binds to α3ß1, promoting multimolecular complex formation and activating adhesion-dependent small GTPases. Our in vitro model has confirmed the pivotal role of integrin α3ß1 in thyroid cell adhesion, which may be mediated by the CD151/α3ß1/Rac1 pathway. In summary, exposure to DEP disrupts the structure and function of the thyroid, a process that likely involves the regulation of cell adhesion through the CD151/α3ß1/Rac1 pathway, leading to glandular damage.

Cardiotoxicity Induced by Intratracheal Instillation of Diesel Exhaust Particles in Mice, and the Protective Effects of Carnosol: Suppression of Inflammation and Oxidative and Nitrosative Stress via Modulation of NF-κb/MAPKs Signaling Pathways.

BACKGROUND/AIMS: Inhaled particulate air pollution is associated with cardiotoxicity with underlying mechanisms including oxidative stress and inflammation. Carnosol, commonly found in rosemary and sage, is known to possess a broad range of therapeutic properties such as antioxidant, anti-inflammatory and antiapoptotic. However, its cardioprotective effects on diesel exhaust particles (DEPs)-induced toxicity have not been studied yet. Hence, we evaluated the potential ameliorative effects of carnosol on DEPs-induced heart toxicity in mice, and the underlying mechanisms involved. METHODS: Mice were intratracheally instilled with DEPs (1 mg/kg) or saline, and 1 hour prior to instillation they were given intraperitoneally either carnosol (20 mg/kg) or saline. Twenty-four hours after the DEPs instillation, multiple parameters were evaluated in the heart by enzyme-linked immunosorbent assay, colorimetric assay, Comet assay and Western blot technique. RESULTS: Carnosol has significantly reduced the elevation in the plasma levels of lactate hydrogenase and brain natriuretic peptide induced by DEPs. Likewise, the augmented cardiac levels of proinflammatory cytokines, lipid peroxidation, and total nitric oxide in DEPs-treated groups were significantly normalized with the treatment of carnosol. Moreover, carnosol has markedly reduced the heart mitochondrial dysfunction, as well as DNA damage and apoptosis of mice treated with DEPs. Similarly, carnosol significantly reduced the elevated expressions of phosphorylated nuclear factor-кB (NF-кB) and mitogen-activated protein kinases (MAPKs) in the hearts. Furthermore, the treatment with carnosol has restored the decrease in the expression of sirtuin-1 in the hearts of mice exposed to DEPs. CONCLUSION: Carnosol significantly attenuated DEP-induced cardiotoxicity in mice by suppressing inflammation, oxidative stress, DNA damage, and apoptosis, at least partly via mechanisms involving sirtuin-1 activation and the inhibition of NF-кB and MAPKs activation.

Diesel exhaust particle extract elicits an oxPAPC-like transcriptomic profile in macrophages across multiple mouse strains.

Air pollution is a prominent cause of cardiopulmonary illness, but uncertainties remain regarding the mechanisms mediating those effects as well as individual susceptibility. Macrophages are highly responsive to particles, and we hypothesized that their responses would be dependent on their genetic backgrounds. We conducted a genome-wide analysis of peritoneal macrophages harvested from 24 inbred strains of mice from the Hybrid Mouse Diversity Panel (HMDP). Cells were treated with a DEP methanol extract (DEPe) to elucidate potential pathways that mediate acute responses to air pollution exposures. This analysis showed that 1247 genes were upregulated and 1383 genes were downregulated with DEPe treatment across strains. Pathway analysis identified oxidative stress responses among the most prominent upregulated pathways; indeed, many of the upregulated genes included antioxidants such as Hmox1, Txnrd1, Srxn1, and Gclm, with NRF2 (official gene symbol: Nfe2l2) being the most significant driver. DEPe induced a Mox-like transcriptomic profile, a macrophage subtype typically induced by oxidized phospholipids and likely dependent on NRF2 expression. Analysis of individual strains revealed consistency of overall responses to DEPe and yet differences in the degree of Mox-like polarization across the various strains, indicating DEPe × genetic interactions. These results suggest a role for macrophage polarization in the cardiopulmonary toxicity induced by air pollution.

Mononuclear phagocyte sub-types in vitro display diverse transcriptional responses to dust mite exposure.

Mononuclear phagocytes (MNP), including macrophages and dendritic cells form an essential component of primary responses to environmental hazards and toxic exposures. This is particularly important in disease conditions such as asthma and allergic airway disease, where many different cell types are present. In this study, we differentiated CD34+ haematopoietic stem cells towards different populations of MNP in an effort to understand how different cell subtypes present in inflammatory disease microenvironments respond to the common allergen house dust mite (HDM). Using single cell mRNA sequencing, we demonstrate that macrophage subtypes MCSPP1+ and MLCMARCO+ display different patterns of gene expression after HDM challenge, noted especially for the chemokines CXCL5, CXCL8, CCL5 and CCL15. MLCCD206Hi alternatively activated macrophages displayed the greatest changes in expression, while neutrophil and monocyte populations did not respond. Further work investigated how pollutant diesel exhaust particles could modify these transcriptional responses and revealed that CXC but not CC type chemokines were further upregulated. Through the use of diesel particles with adsorbed material removed, we suggest that soluble pollutants on these particles are the active constituents responsible for the modifying effects on HDM. This study highlights that environmental exposures may influence tissue responses dependent on which MNP cell type is present, and that these should be considerations when modelling such events in vitro. Understanding the nuanced responsiveness of different immune cell types to allergen and pollutant exposure also contributes to a better understanding of how these exposures influence the development and exacerbation of human disease.

The stress-responsive cytotoxic effect of diesel exhaust particles on lymphatic endothelial cells.

Diesel exhaust particles (DEPs) are very small (typically < 0.2 µm) fragments that have become major air pollutants. DEPs are comprised of a carbonaceous core surrounded by organic compounds such as polycyclic aromatic hydrocarbons (PAHs) and nitro-PAHs. Inhaled DEPs reach the deepest sites in the respiratory system where they could induce respiratory/cardiovascular dysfunction. Additionally, a previous study has revealed that a portion of inhaled DEPs often activate immune cells and subsequently induce somatic inflammation. Moreover, DEPs are known to localize in lymph nodes. Therefore, in this study we explored the effect of DEPs on the lymphatic endothelial cells (LECs) that are a constituent of the walls of lymph nodes. DEP exposure induced cell death in a reactive oxygen species (ROS)-dependent manner. Following exposure to DEPs, next-generation sequence (NGS) analysis identified an upregulation of the integrated stress response (ISR) pathway and cell death cascades. Both the soluble and insoluble components of DEPs generated intracellular ROS. Three-dimensional Raman imaging revealed that DEPs are taken up by LECs, which suggests internalized DEP cores produce ROS, as well as soluble DEP components. However, significant cell death pathways such as apoptosis, necroptosis, ferroptosis, pyroptosis, and parthanatos seem unlikely to be involved in DEP-induced cell death in LECs. This study clarifies how DEPs invading the body might affect the lymphatic system through the induction of cell death in LECs.

Differential impact of diesel exhaust particles on glutamatergic and dopaminergic neurons in Caenorhabditis elegans: A neurodegenerative perspective.

The growing body of evidence links exposure to particulate matter pollutants with an increased risk of neurodegenerative diseases. In the present study, we investigated whether diesel exhaust particles can induce neurobehavioral alterations associated with neurodegenerative effects on glutamatergic and dopaminergic neurons in Caenorhabditis elegans (C. elegans). Exposure to DEP at concentrations of 0.167 µg/cm2 and 1.67 µg/cm2 resulted in significant developmental delays and altered locomotion behaviour. These effects were accompanied by discernible alterations in the expressions of antioxidant genes sod-3 and gst-4 observed in transgenic strains. Behaviour analysis demonstrated a significant reduction in average speed (p < 0.001), altered paths, and decreased swimming activities (p < 0.01), particularly at mid and high doses. Subsequent assessment of neurodegeneration markers in glutamatergic (DA1240) and dopaminergic (BZ555) transgenic worms revealed notable glutamatergic neuron degeneration at 0.167 µg/cm2 (∼30 % moderate, ∼20 % advanced) and 1.67 µg/cm2 (∼28 % moderate, ∼24 % advanced, p < 0.0001), while dopaminergic neurons exhibited structural deformities (∼16 %) without significant degeneration in terms of blebs and breaks. Furthermore, in silico docking simulations suggest the presence of an antagonistic competitive inhibition induced by DEP in the evaluated neuro-targets, stronger for the glutamatergic transporter than for the dopaminergic receptor from the comparative binding affinity point of view. The results underscore DEP's distinctive neurodegenerative effects and suggest a link between locomotion defects and glutamatergic neurodegeneration in C. elegans, providing insights into environmental health risks assessment.

Concordance between In Vitro and In Vivo Relative Toxic Potencies of Diesel Exhaust Particles from Different Biodiesel Blends.

Diesel exhaust particles (DEPs) contribute to air pollution exposure-related adverse health impacts. Here, we examined in vitro, and in vivo toxicities of DEPs from a Caterpillar C11 heavy-duty diesel engine emissions using ultra-low-sulfur diesel (ULSD) and biodiesel blends (20% v/v) of canola (B20C), soy (B20S), or tallow-waste fry oil (B20T) in ULSD. The in vitro effects of DEPs (DEPULSD, DEPB20C, DEPB20S, and DEPB20T) in exposed mouse monocyte/macrophage cells (J774A.1) were examined by analyzing the cellular cytotoxicity endpoints (CTB, LDH, and ATP) and secreted proteins. The in vivo effects were assessed in BALB/c mice (n = 6/group) exposed to DEPs (250 µg), carbon black (CB), or saline via intratracheal instillation 24 h post-exposure. Bronchoalveolar lavage fluid (BALF) cell counts, cytokines, lung/heart mRNA, and plasma markers were examined. In vitro cytotoxic potencies (e.g., ATP) and secreted TNF-α were positively correlated (p < 0.05) with in vivo inflammatory potency (BALF cytokines, lung/heart mRNA, and plasma markers). Overall, DEPULSD and DEPB20C appeared to be more potent compared to DEPB20S and DEPB20T. These findings suggested that biodiesel blend-derived DEP potencies can be influenced by biodiesel sources, and inflammatory process- was one of the potential underlying toxicity mechanisms. These observations were consistent across in vitro and in vivo exposures, and this work adds value to the health risk analysis of cleaner fuel alternatives.

Prenatal diesel exhaust exposure alters hippocampal synaptic plasticity in offspring.

Diesel exhaust particles (DEPs) are major air pollutants emitted from automobile engines. Prenatal exposure to DEPs has been linked to neurodevelopmental and neurodegenerative diseases associated with aging. However, the specific mechanism by DEPs impair the hippocampal synaptic plasticity in the offspring remains unclear. Pregnant C57BL/6 mice were administered DEPs solution via the tail vein every other day for a total of 10 injections, then the male offsprings were studied to assess learning and memory by the Morris water maze. Additionally, protein expression in the hippocampus, including CPEB3, NMDAR (NR1, NR2A, NR2B), PKA, SYP, PSD95, and p-CREB was analyzed using Western blotting and immunohistochemistry. The alterations in the histomorphology of the hippocampus were observed in male offspring on postnatal day 7 following prenatal exposure to DEPs. Furthermore, 8-week-old male offspring exposed to DEPs during prenatal development exhibited impairments in the Morris water maze test, indicating deficits in learning and memory. Mechanistically, the findings from our study indicate that exposure to DEPs during pregnancy may alter the expression of CPEB3, SYP, PSD95, NMDAR (NR1, NR2A, and NR2B), PKA, and p-CREB in the hippocampus of both immature and mature male offspring. The results offer evidence for the role of the NMDAR/PKA/CREB and CPEB3 signaling pathway in mediating the learning and memory toxicity of DEPs in male offspring mice. The alterations in signaling pathways may contribute to the observed damage to synaptic structure and transmission function plasticity caused by DEPs. The findings hold potential for informing future safety assessments of DEPs.

Role of diesel exhaust particle-induced cellular senescence in the development of asthma in young and old mice.

BACKGROUND: Although it has been reported that cellular senescence is important in the pathogenesis of asthma, the differential effects of diesel exhaust particle (DEP)-induced cellular senescence on the development of asthma according to age have not been thoroughly studied. METHODS: We first confirmed that DEP induced cellular senescence in mouse lungs, and then that DEP-induced cellular senescence followed by intranasal instillation of a low-dose house dust mite (HDM) allergen resulted in murine asthma. Second, we examined age-dependent differential effects using 6-week-old (young) and 18-month-old mice (old), and tested whether the mammalian target of the rapamycin (mTOR) pathway plays an important role in this process. Finally, we performed in vitro experiments using human bronchial epithelial cells (HBEC) originating from young and elderly adults to identify the underlying mechanisms. RESULTS: DEP induced cellular senescence in the airway epithelial cells of young and old mice characterized by increased senescence-associated beta-galactosidase, S100A8/9, and high mobility group box 1 (HMGB1) expressions. DEP-induced cellular senescence with subsequent exposure to a low-dose HDM allergen resulted in asthma in young and old mice. Rapamycin (mTOR pathway inhibitor) administration before DEP instillation significantly attenuated these asthmatic features. In addition, after treatment with a low-dose HDM allergen, S100A9 and HMGB1 over-expressed HBEC originating from young and elderly adults greatly activated co-cultured monocyte-derived dendritic cells (DCs). CONCLUSIONS: This study showed that DEP-induced senescence made both young and old mice susceptible to allergic sensitization and resultant asthma development by enhancing DC activation. Public health efforts to reduce DEP exposure are warranted.

Differential pulmonary toxicity and autoantibody formation in genetically distinct mouse strains following combined exposure to silica and diesel exhaust particles.

BACKGROUND: Inhalation of airborne particulate matter, such as silica and diesel exhaust particles, poses serious long-term respiratory and systemic health risks. Silica exposure can lead to silicosis and systemic autoimmune diseases, while DEP exposure is linked to asthma and cancer. Combined exposure to silica and DEP, common in mining, may have more severe effects. This study investigates the separate and combined effects of occupational-level silica and ambient-level DEP on lung injury, inflammation, and autoantibody formation in two genetically distinct mouse strains, thereby aiming at understanding the interplay between genetic susceptibility, particulate exposure, and disease outcomes. Silica and diesel exhaust particles were administered to mice via oropharyngeal aspiration. Assessments of lung injury and host response included in vivo lung micro-computed tomography, lung function tests, bronchoalveolar lavage fluid analysis including inflammatory cytokines and antinuclear antibodies, and histopathology with particle colocalization. RESULTS: The findings highlight the distinct effects of silica and diesel exhaust particles (DEP) on lung injury, inflammation, and autoantibody formation in C57BL/6J and NOD/ShiLtJ mice. Silica exposure elicited a well-established inflammatory response marked by inflammatory infiltrates, release of cytokines, and chemokines, alongside mild fibrosis, indicated by collagen deposition in the lungs of both C57BL/6J and NOD/ShilLtJ mice. Notably, these strains exhibited divergent responses in terms of respiratory function and lung volumes, as assessed through micro-computed tomography. Additionally, silica exposure induced airway hyperreactivity and elevated antinuclear antibody levels in bronchoalveolar lavage fluid, particularly prominent in NOD/ShiLtJ mice. Moreover, antinuclear antibodies correlated with extent of lung inflammation in NOD/ShiLTJ mice. Lung tissue analysis revealed DEP loaded macrophages and co-localization of silica and DEP particles. However, aside from contributing to airway hyperreactivity specifically in NOD/ShiLtJ mice, the ambient-level DEP did not significantly amplify the effects induced by silica. There was no evidence of synergistic or additive interaction between these specific doses of silica and DEP in inducing lung damage or inflammation in either of the mouse strains. CONCLUSION: Mouse strain variations exerted a substantial influence on the development of silica induced lung alterations. Furthermore, the additional impact of ambient-level DEP on these silica-induced effects was minimal.

Impact of diesel exhaust particles on infections with Mycobacterium bovis BCG in in vitro human macrophages and an in vivo Galleria mellonella model.

There are strong suggestions for a link between pulmonary tuberculosis (TB) and air quality. Diesel exhaust is one of the main contributors to pollution and it is reported to be able to modify susceptibility to lung infections. In this study we exposed THP-1 human macrophages and Mycobacterium bovis BCG to diesel exhaust particles (DEPs). High cytotoxicity and activation of apoptosis was found in THP-1 cells at 3 and 6 days, but no effect was found on the growth of M. bovis BCG. Infection of THP-1 cells exposed to a non-cytotoxic DEP concentration showed a limited capacity to engulf latex beads. However, M. bovis BCG infection of macrophages did not result in an increase in the bacterial burden, but it did result in an increase in the bacteria recovered from the extracellular media, suggesting a poor contention of M. bovis BCG. We also observed that DEP exposure limited the production of cytokines. Using the Galleria mellonella model of infection, we observed that larvae exposed to low levels of DEPs were less able to survive after infection with M. bovis BCG and had a higher internal bacterial load after 4 days of infection. Unraveling the links between air pollution and impairment of human antimycobacterial immunity is vital, because pollution is rapidly increasing in areas where TB incidence is extremely high.

Effects of polycyclic aromatic hydrocarbon exposure on mitochondrial DNA copy number.

Airborne polycyclic aromatic hydrocarbon (PAH) exposure can adversely affect human health by generating reactive oxygen species (ROS) and increasing oxidative stress, which causes changes in mitochondrial DNA copy number (mtDNAcn), a key indicator of mitochondrial damage and dysfunction. This study aimed to determine the effects of atmospheric benzo[a]pyrene (BaP) and 1-nitropyrene (1-NP) exposure on mtDNAcn in humans. One hundred and eight adults living in Cheongju, South Korea, were included in this study. Atmospheric BaP and 1-NP concentrations and urinary 6-hydroxy-1-nitropyrene (6-OHNP), N-acetyl-1-aminopyrene (1-NAAP), and 1-hydroxypyrene concentrations were measured. Blood samples were also collected to assess mtDNAcn. The mean mtDNAcn was 9.74 (SD 4.46). mtDNAcn decreased significantly with age but was not significantly associated with sex, sampling season, or smoking habit. While there was a borderline significant increase in mtDNAcn with increasing ambient total PAH levels, ambient PAH or urinary 1-hydroxypyrene concentrations showed no significant association with mtDNAcn. However, urinary 6-OHNP or 1-NAAP concentrations, 1-NP metabolites, were significantly associated with mtDNAcn. These results suggest that the metabolism of absorbed NPs generates excess ROS, which damages mitochondrial DNA, resulting in increased mtDNAcn.

Diesel exhaust particles exposure exacerbates pro-thrombogenic plasma features ex-vivo after cerebral ischemia and accelerates tPA-induced clot-lysis in hypertensive subjects.

The combustion of fossil fuels, mainly by diesel engines, generates Diesel Exhaust Particles (DEP) which are the main source of Particulate Matter (PM), a major air pollutant in urban areas. These particles are a risk factor for stroke with 5.6% of cases attributed to PM exposure. Our aim was to evaluate the effect of DEP exposure on clot formation and lysis in the context of stroke. An ex-vivo clot formation and lysis turbidimetric assay has been conducted in human and mouse plasma samples from ischemic stroke or control subjects exposed to DEP or control conditions. Experimental DEP exposure was achieved by nasal instillation in mice, or by ex-vivo exposure in human plasma. Results show consistent pro-thrombogenic features in plasma after human ischemic stroke and mouse cerebral ischemia (distal MCAo), boosted by the presence of DEP. Otherwise, thrombolysis times were increased after ischemia in chronically exposed mice but not in the DEP exposed group. Finally, subjects living in areas with high PM levels presented accelerated thrombolysis compared to those living in low polluted areas. Overall, our results point at a disbalance of the thrombogenic/lytic system in presence of DEP which could impact on ischemic stroke onset, clot size and thrombolytic treatment.

Differential Pulmonary Toxicity and Autoantibody Formation in Genetically Distinct Mouse Strains Following Combined Exposure to Silica and Diesel Exhaust Particles.

Background: Inhalation of airborne particulate matter, such as silica and diesel exhaust particles, poses serious long-term respiratory health risks. Silica exposure can lead to silicosis and systemic autoimmune diseases, while DEP exposure is linked to asthma and cancer. Combined exposure to silica and DEP, common in mining, may have more severe effects. This study investigates the separate and combined effects of silica and DEP on lung injury, inflammation, and autoantibody formation in two genetically distinct mouse strains, thereby aiming at understanding the interplay between genetic susceptibility, particulate exposure, and disease outcomes. Silica and diesel exhaust particles were administered to mice via oropharyngeal aspiration. Assessments of lung injury and host response included in vivo lung micro-computed tomography, lung function tests, bronchoalveolar lavage fluid analysis including inflammatory cytokines and antinuclear antibodies, and histopathology with particle colocalization. Results: Silica exposure elicited a well-established inflammatory response marked by inflammatory infiltrates, release of cytokines, and chemokines, alongside limited fibrosis, indicated by collagen deposition in the lungs of both C57BL/6J and NOD/ShilLtJ mice. Notably, these strains exhibited divergent responses in terms of respiratory function and lung volumes, as assessed through micro-computed tomography. Additionally, silica exposure induced airway hyperreactivity and elevated antinuclear antibody levels in bronchoalveolar lavage fluid, particularly prominent in NOD/ShiLtJ mice. Lung tissue analysis revealed DEP loaded macrophages and co-localization of silica and DEP particles. Conclusion: Mouse strain variations exerted a substantial influence on the development of silica induced lung alterations. Furthermore, the additional impact of diesel exhaust particles on these silica-induced effects was minimal.