Short-term Diesel Exhaust Exposure Results in Neuroinflammation and White Matter Injury

Ambient air pollution (AAP) exposure is associated with white matter injury and cognitive decline in older adults(Chen et al. 2020,Erickson et al. 2020). Neuroinflammation and oxidative stress may contribute to this white matter injury. Diesel exhaust particulate matter (DEP) is a neurotoxic component of AAP.This study characterizes the time course by which neuroinflammation/oxidative stress occurs and results in white matter injury following DE exposure in a murine model. DEP (Sigma) was re-aerosolized for exposure. Mice were exposed to 100 µg/m3 DEP or filtered air (FA) for 5 hours (n=8/group), 100 hours (n=6/group), or 200 hours (n=6/group). Immunohistochemical analysis of degraded myelin basic protein (dMBP), a marker of myelin damage, was performed. Neuroinflammation and oxidative stress were assessed by histological analysis of complement C5a, an anaphylatoxin, and 4-Hydroxynonenal (4-HNE), a marker of lipid peroxidation.dMBP integrated density was increased in the corpus callosum of DEP mice at 5 (p<0.01), 100 (p<0.01), and 200 hours (p<0.001) compared to FA mice.C5a integrated density was increased in the corpus callosum of DEP mice at 5 (p<0.01), 100 (p<0.01), and 200 hours (p<0.01) compared to FA mice. 4-HNE integrated density was increased in the corpus callosum of DEP mice at 5 (p<0.001), 100 (p=0.001), and 200 hours (p<0.001) compared to FA mice. Neuroinflammation and oxidative stress are upregulated with associated white matter injury in the corpus callosum after 5 hours of DEP exposure.Short-term DEP exposure activates inflammatory/oxidative stress pathways, which may contribute to the pathogenesis of white matter injury.Erickson et al. 2020,PMID:32182984; Chen et al. 2020,PMID:32669395.

Geniposide, a Principal Component of Gardeniae Fructus, Protects Skin from Diesel Exhaust Particulate Matter-Induced Oxidative Damage

Gardeniae Fructus (GF) is the fruit of Gardenia jasminoides Ellis and is traditionally prescribed to treat pyogenic infections and skin ulcers. This study investigated the protective effects of GF and the underlying mechanism responsible for these effects on diesel exhaust particulate matter- (DEP-) induced skin damage. The protective effects of an ethanolic extract of GF (GFE) and its constituents (geniposidic acid, gardenoside, geniposide, chlorogenic acid, and genipin) were examined by analyzing reactive oxygen species (ROS) production, apoptosis, and tight junction (TJ) protein expression in HaCaT cells. Treatment with GFE dose-dependently inhibited intracellular ROS production and apoptosis by regulating the protein expressions of Bax, Bcl-2, and cytochrome C in DEP-stimulated (100 μg/ml) HaCaT cells. Mechanistic studies revealed that the protective effects of GFE were related to its activation of Nrf2 and HO-1 signaling in HaCaT cells. Geniposide, a main constituent of GFE, enhanced the expression of occludin in DEP-stimulated HaCaT cells. Furthermore, topical application of geniposide reduced the expressions of 8-OHdG and Bax and increased the expression of occludin in the dorsal skin lesions of DEP-stimulated mice. Gardeniae Fructus and its main component geniposide are potential candidates for the repair of DEP-induced skin damage due to their antioxidant and antiapoptotic activities.

Lactic Acid Bacteria Ameliorate Diesel Exhaust Particulate Matter-Exacerbated Allergic Inflammation in a Murine Model of Asthma

Several air pollution components such as sulfur dioxide, ozone, nitrogen dioxide, and diesel exhaust particulate matter (DEPM) have been linked to the development of asthma. In this study, we investigated the therapeutic potential of three lactic acid bacteria species, Lactobacillus plantarum GREEN CROSS Wellbeing (GCWB)1001, Pediococcus acidilactici GCWB1085, and Lactobacillus rhamnosus GCWB1156, in preventing DEPM-exacerbated asthma in mice. BALB/c mice were first sensitized with ovalbumin (OVA) and were either challenged with OVA or DEPM (DEPM-exacerbated asthma model) by intranasal instillation. All three strains showed no hemolytic activity, suggesting a good safety profile. Oral administration of lactic acid bacteria reduced OVA + DEPM-induced inflammatory infiltration, goblet cell hyperplasia, airway remodeling, and the levels of proinflammatory cytokines and chemokines in bronchoalveolar lavage fluid (BALF). The probiotics also attenuated OVA + DEPM-induced immunoglobulin E (IgE) levels in serum and in BALF, and significantly reduced caspase-3 activity, total collagen level, and matrix metalloproteinase (MMP)-9 activity. In conclusion, lactic acid bacteria such as L. plantarum GCWB1001, P. acidilactici GCWB1085, and L. rhamnosus treatment in mice with asthma showed significant efficacy in preventing lung inflammation exacerbated by DEPM administration.

Modulation of TRPV-1 by prostaglandin-E2 and bradykinin changes cough sensitivity and autonomic regulation of cardiac rhythm in healthy subjects

A neurogenic pathway, involving airway TRPV-1, has been implicated in acute cardiovascular events occurring after peaks of air pollution. We tested whether inhaled prostaglandin-E2 (PGE2) and bradykinin (BK) regulate TRPV-1 activity in vivo by changing cough response to capsaicin (CPS) and affecting heart rate variability (HRV), while also taking into account the influence of TRPV-1 polymorphisms (SNPs). Moreover, we assessed the molecular mechanism of TRPV-1 modulation in vitro. Seventeen healthy volunteers inhaled 100 μg PGE2, 200 μg BK or diluent in a randomized double-blind fashion. Subsequently, the response to CPS was assessed by cough challenge and the sympathetic activity by HRV, expressed by low (nLF) and high (nHF) normalized frequency components, as well as nLF/nHF ratio. Intracellular [Ca2+] was measured in HeLa cells, transfected with wild-type TRPV-1, pre-treated with increasing doses of PGE2, BK or diesel exhaust particulate (DEP), after CPS stimulation. Six functional TRPV-1 SNPs were characterized in DNA from each subject. Inhalation of PGE2 and BK was associated with significant increases in cough response induced by 30 μM of CPS (cough number after PGE2 = 4.20 ± 0.42; p < 0.001, and after BK = 3.64 ± 0.37; p < 0.01), compared to diluent (2.77 ± 0.29) and in sympathetic activity (nLF/nHF ratio after PGE2 = 6.1; p < 0.01, and after BK = 4.2; p < 0.05), compared to diluent (2.5–3.3). No influence of SNPs was observed on autonomic regulation and cough sensitivity. Unlike PGE2 and BK, DEP directly activated TRPV-1. Inhalation of PGE2 and BK sensitizes TRPV-1 and is associated with autonomic dysregulation of cardiac rhythm in healthy subjects.

Diesel Exhaust Extract Exposure Induces Neuronal Toxicity by Disrupting Autophagy

The vast majority of neurodegenerative disease cannot be attributed to genetic causes alone and as a result, there is significant interest in identifying environmental modifiers of disease risk. Epidemiological studies have supported an association between long-term exposure to air pollutants and disease risk. Here, we investigate the mechanisms by which diesel exhaust, a major component of air pollution, induces neurotoxicity. Using a zebrafish model, we found that exposure to diesel exhaust particulate extract caused behavioral deficits and a significant decrease in neuron number. The neurotoxicity was due, at least in part, to reduced autophagic flux, which is a major pathway implicated in neurodegeneration. This neuron loss occurred alongside an increase in aggregation-prone neuronal protein. Additionally, the neurotoxicity induced by diesel exhaust particulate extract in zebrafish was mitigated by co-treatment with the autophagy-inducing drug nilotinib. This study links environmental exposure to altered proteostasis in an in vivo model system. These results shed light on why long-term exposure to traffic-related air pollution increases neurodegenerative disease risk and open up new avenues for exploring therapies to mitigate environmental exposures and promote neuroprotection.