Author Correction: A regulatory T cell Notch4-GDF15 axis licenses tissue inflammation in asthma.

A Correction to this paper has been published: https://doi.org/10.1038/s41590-021-00929-x.

A regulatory T cell Notch4-GDF15 axis licenses tissue inflammation in asthma.

Elucidating the mechanisms that sustain asthmatic inflammation is critical for precision therapies. We found that interleukin-6- and STAT3 transcription factor-dependent upregulation of Notch4 receptor on lung tissue regulatory T (Treg) cells is necessary for allergens and particulate matter pollutants to promote airway inflammation. Notch4 subverted Treg cells into the type 2 and type 17 helper (TH2 and TH17) effector T cells by Wnt and Hippo pathway-dependent mechanisms. Wnt activation induced growth and differentiation factor 15 expression in Treg cells, which activated group 2 innate lymphoid cells to provide a feed-forward mechanism for aggravated inflammation. Notch4, Wnt and Hippo were upregulated in circulating Treg cells of individuals with asthma as a function of disease severity, in association with reduced Treg cell-mediated suppression. Our studies thus identify Notch4-mediated immune tolerance subversion as a fundamental mechanism that licenses tissue inflammation in asthma.

Outdoor Ultrafine Particulate Matter and Risk of Lung Cancer in Southern California.

Rationale: Particulate matter ⩽2.5 µm in aerodynamic diameter (PM2.5) is an established cause of lung cancer, but the association with ultrafine particulate matter (UFP; aerodynamic diameter < 0.1 µm) is unclear. Objectives: To investigate the association between UFP and lung cancer overall and by histologic subtype. Methods: The Los Angeles Ultrafines Study includes 45,012 participants aged ⩾50 years in southern California at enrollment (1995-1996) followed through 2017 for incident lung cancer (n = 1,770). We estimated historical residential ambient UFP number concentrations via land use regression and back extrapolation using PM2.5. In Cox proportional hazards models adjusted for smoking and other confounders, we estimated associations between 10-year lagged UFP (per 10,000 particles/cm3 and quartiles) and lung cancer overall and by major histologic subtype (adenocarcinoma, squamous cell carcinoma, and small cell carcinoma). We also evaluated relationships by smoking status, birth cohort, and historical duration at the residence. Measurements and Main Results: UFP was modestly associated with lung cancer risk overall (hazard ratio [HR], 1.03 [95% confidence interval (CI), 0.99-1.08]). For adenocarcinoma, we observed a positive trend among men; risk was increased in the highest exposure quartile versus the lowest (HR, 1.39 [95% CI, 1.05-1.85]; P for trend = 0.01) and was also increased in continuous models (HR per 10,000 particles/cm3, 1.09 [95% CI, 1.00-1.18]), but no increased risk was apparent among women (P for interaction = 0.03). Adenocarcinoma risk was elevated among men born between 1925 and 1930 (HR, 1.13 [95% CI, 1.02-1.26] per 10,000) but not for other birth cohorts, and was suggestive for men with ⩾10 years of residential duration (HR, 1.11 [95% CI, 0.98-1.26]). We found no consistent associations for women or other histologic subtypes. Conclusions: UFP exposure was modestly associated with lung cancer overall, with stronger associations observed for adenocarcinoma of the lung.

Microglial TLR4 Mediates White Matter Injury in a Combined Model of Diesel Exhaust Exposure and Cerebral Hypoperfusion.

BACKGROUND: Air pollution particulate matter exposure and chronic cerebral hypoperfusion (CCH) contribute to white matter toxicity through shared mechanisms of neuroinflammation, oxidative stress, and myelin breakdown. Prior studies showed that exposure of mice to joint particulate matter and CCH caused supra-additive injury to corpus callosum white matter. This study examines the role of TLR4 (toll-like receptor 4) signaling in mediating neurotoxicity and myelin damage observed in joint particulate matter and CCH exposures. METHODS: Experiments utilized a novel murine model of inducible monocyte/microglia-specific TLR4 knockout (i-mTLR4-ko). Bilateral carotid artery stenosis (BCAS) was induced surgically to model CCH. TLR4-intact (control) and i-mTLR4-ko mice were exposed to 8 weeks of either aerosolized diesel exhaust particulate (DEP) or filtered air (FA) in 8 experimental groups: (1) control/FA (n=10), (2) control/DEP (n=10), (3) control/FA+BCAS (n=9), (4) control/DEP+BCAS (n=10), (5) i-mTLR4-ko/FA (n=9), (6) i-mTLR4-ko/DEP (n=8), (7) i-mTLR4-ko/FA+BCAS (n=8), and (8) i-mTLR4-ko/DEP+BCAS (n=10). Corpus callosum levels of 4-hydroxynonenal, 8-Oxo-2'-deoxyguanosine, Iba-1 (ionized calcium-binding adapter molecule 1), and dMBP (degraded myelin basic protein) were assayed via immunofluorescence to measure oxidative stress, neuroinflammation, and myelin breakdown, respectively. RESULTS: Compared with control/FA mice, control/DEP+BCAS mice exhibited increased dMBP (41%; P<0.01), Iba-1 (51%; P<0.0001), 4-hydroxynonenal (100%; P<0.0001), and 8-Oxo-2'-deoxyguanosine (65%; P<0.05). I-mTLR4 knockout attenuated responses to DEP/BCAS for all markers. CONCLUSIONS: i-mTLR4-ko markedly reduced neuroinflammation and oxidative stress and attenuated white matter degradation following DEP and CCH exposures. This suggests a potential role for targeting TLR4 signaling in individuals with vascular cognitive impairment, particularly those exposed to substantial ambient air pollution.

Subchronic inhalation exposure to ultrafine particulate matter alters the intestinal microbiome in various mouse models.

Exposure to ultrafine particles (UFPs) has been associated with multiple adverse health effects. Inhaled UFPs could reach the gastrointestinal tract and influence the composition of the gut microbiome. We have previously shown that oral ingestion of UFPs alters the gut microbiome and promotes intestinal inflammation in hyperlipidemic Ldlr-/- mice. Particulate matter (PM)2.5 inhalation studies have also demonstrated microbiome shifts in normolipidemic C57BL/6 mice. However, it is not known whether changes in microbiome precede or follow inflammatory effects in the intestinal mucosa. We hypothesized that inhaled UFPs modulate the gut microbiome prior to the development of intestinal inflammation. We studied the effects of UFP inhalation on the gut microbiome and intestinal mucosa in two hyperlipidemic mouse models (ApoE-/- mice and Ldlr-/- mice) and normolipidemic C57BL/6 mice. Mice were exposed to PM in the ultrafine-size range by inhalation for 6 h a day, 3 times a week for 10 weeks at a concentration of 300-350 µg/m3.16S rRNA gene sequencing was performed to characterize sequential changes in the fecal microbiome during exposures, and changes in the intestinal microbiome at the end. PM exposure led to progressive differentiation of the microbiota over time, associated with increased fecal microbial richness and evenness, altered microbial composition, and differentially abundant microbes by week 10 depending on the mouse model. Cross-sectional analysis of the small intestinal microbiome at week 10 showed significant changes in α-diversity, ß-diversity, and abundances of individual microbial taxa in the two hyperlipidemic models. These alterations of the intestinal microbiome were not accompanied, and therefore could not be caused, by increased intestinal inflammation as determined by histological analysis of small and large intestine, cytokine gene expression, and levels of fecal lipocalin. In conclusion, 10-week inhalation exposures to UFPs induced taxonomic changes in the microbiome of various animal models in the absence of intestinal inflammation.

Development and performance evaluation of online monitors for near real-time measurement of total and water-soluble organic carbon in fine and coarse ambient PM.

In this study, we developed two online monitors for total organic carbon (TOC) and water-soluble organic carbon (WSOC) measurements in fine (dp < 2.5µm) and coarse (2.5µm < dp < 10µm) particulate matter (PM), respectively. Their performance has been evaluated in laboratory and field tests to demonstrate the feasibility of using these monitors to measure near real-time concentrations, with consideration of their potential for being employed in long-term measurements. The fine PM collection setup was equipped with a versatile aerosol concentration enrichment system (VACES) connected to an aerosol-into-liquid-sampler (AILS), whereas two virtual impactors (VIs) in tandem with a modified BioSampler were used to collect coarse PM. These particle collection setups were in tandem with a Sievers M9 TOC analyzer to read TOC and WSOC concentrations in aqueous samples hourly. The average hourly TOC concentration measured by our developed monitors in fine and coarse PM were 5.17 ± 2.41 and 0.92 ± 0.29 µg/m3, respectively. In addition, our TOC readings showed good agreement and were comparable with those quantified using Sunset Lab EC/OC analyzer operating in parallel as a reference. Furthermore, we conducted field tests to produce diurnal profiles of fine PM-bound WSOC, which can show the effects of ambient temperature on maximum values in the nighttime chemistry of the winter, as well as on increased photochemical activities in afternoon peaks during the summer. According to our experimental campaign, WSOC mean values during the study period (3.07 µg/m3 for the winter and 2.7 µg/m3 for the summer) were in a comparable range with those of earlier studies in Los Angeles. Overall, our results corroborate the performance of our developed monitors in near real-time measurements of TOC and WSOC, which can be employed for future source apportionment studies in Los Angeles and other areas, aiding in understanding the health impacts of different pollution sources.

Los Angeles Basin's air quality transformation: a long-term investigation on the impacts of PM regulations on the trends of ultrafine particles and co-pollutants.

This study investigates the long-term trends of ambient ultrafine particles (UFPs) and associated airborne pollutants in the Los Angeles Basin from 2007 to 2022, focusing on the indirect effects of regulations on UFP levels. The particle number concentration (PNC) of UFPs was compiled from previous studies in the area, and associated co-pollutant data, including nitrogen oxides (NOx), carbon monoxide (CO), elemental carbon (EC), organic carbon (OC), and ozone (O3), were obtained from the chemical speciation network (CSN) database. Over the study period, a general decrease was noted in the PNC of UFPs, NOx, EC, and OC, except for CO, the concentration trends of which did not exhibit a consistent pattern. UFPs, NOx, EC, and OC were positively correlated, while O3 had a negative correlation, especially with NOx. Our analysis discerned two distinct subperiods in pollutant trends: 2007-2015 and 2016-2022. For example, there was an overall decrease in the PNC of UFPs at an annual rate of -850.09 particles/cm3/year. This rate was more pronounced during the first sub-period (2007-2015) at -1814.9 particles/cm3/year and then slowed to -227.21 particles/cm3/year in the second sub-period (2016-2023). The first sub-period (2007-2015) significantly influenced pollutant level changes, exhibiting more pronounced and statistically significant changes than the second sub-period (2016-2022). Since 2016, almost all primary pollutants have stabilized, indicating a reduced impact of current regulations, and emphasizing the need for stricter standards. In addition, the study included an analysis of Vehicle Miles Traveled (VMT) trends from 2007 to 2022 within the Los Angeles Basin. Despite the general increase in VMT, current regulations and cleaner technologies seem to have successfully mitigated the potential increase in increase in PNC. Overall, while a decline in UFPs and co-pollutant levels was observed, the apparent stabilization of these levels underscores the need for more stringent regulatory measures and advanced emission standards.

Particulate matter exposure and chronic cerebral hypoperfusion promote oxidative stress and induce neuronal and oligodendrocyte apoptosis in male mice.

Chronic cerebral hypoperfusion (CCH) may amplify the neurotoxicity of nanoscale particulate matter (nPM), resulting in white matter injury. This study characterized the joint effects of nPM (diameter ≤ 200 nm) and CCH secondary to bilateral carotid artery stenosis (BCAS) exposure on neuronal and white matter injury in a murine model. nPM was collected near a highway and re-aerosolized for exposure. Ten-week-old C57BL/6 male mice were randomized into four groups: filtered air (FA), nPM, FA + BCAS, and nPM + BCAS. Mice were exposed to FA or nPM for 10 weeks. BCAS surgeries were performed. Markers of inflammation, oxidative stress, and apoptosis were examined. nPM + BCAS exposure increased brain hemisphere TNFα protein compared to FA. iNOS and HNE immunofluorescence were increased in the corpus callosum and cerebral cortex of nPM + BCAS mice compared to FA. While nPM exposure alone did not decrease cortical neuronal cell count, nPM decreased corpus callosum oligodendrocyte cell count. nPM exposure decreased mature oligodendrocyte cell count and increased oligodendrocyte precursor cell count in the corpus callosum. nPM + BCAS mice exhibited a 200% increase in cortical neuronal TUNEL staining and a 700% increase in corpus callosum oligodendrocyte TUNEL staining compared to FA. There was a supra-additive interaction between nPM and BCAS on cortical neuronal TUNEL staining (2.6× the additive effects of nPM + BCAS). nPM + BCAS exposure increased apoptosis, neuroinflammation, and oxidative stress in the cerebral cortex and corpus callosum. nPM + BCAS exposure increased neuronal apoptosis above the separate responses to each exposure. However, oligodendrocytes in the corpus callosum demonstrated a greater susceptibility to the combined neurotoxic effects of nPM + BCAS exposure.

Size-segregated source identification of water-soluble and water-insoluble metals and trace elements of coarse and fine PM in central Los Angeles.

In this study, the water-solubility and sources of metals and trace elements in both fine and coarse particulate matter (PM) were investigated in Central Los Angeles. Sampling was performed in the winter, spring, and summer of 2022 at the Particle Instrumentation Unit (PIU) of the University of Southern California located in the proximity of I-110 freeway. Both fine and coarse PM samples were collected using Personal Cascade Impactors (PCIS) and chemically analyzed to determine their water-soluble and water-insoluble metal content. Principal Component Analysis (PCA) and Multiple Linear Regression (MLR) were used to determine the sources of soluble and insoluble metals and obtain their contributions to total metal concentration. Our results indicate that the water-solubility of most of the metals is higher in the fine size fraction compared to the coarse fraction. Seasonal variations in the water solubility of selected metals for both coarse and fine fractions were observed, with higher water-soluble metal concentrations in summer for several species (e.g., Fe, S, Pb, Cu, La, Ni, and Al), possibly due to higher photochemical processing, while in winter, almost all species exhibited higher insoluble fraction concentrations. The PCA and MLR analyses results showed that tire and brake wear was the most significant contributor to the total metals for both fine soluble and insoluble portions, accounting for 35% and 75% of the total metals, respectively. Combustion sources also contributed substantially to water-soluble metals for fine and coarse size ranges, representing 40% and 32% of the total metal mass, respectively. In addition, mineral dust and soil and re-suspended dust were identified as the highest contributors to coarse metals. The MLR analysis also revealed that secondary aerosols contributed 11% to the fine water-soluble metals. Our results suggest that non-tailpipe emissions significantly contribute to both coarse and fine PM metals in the Central Los Angeles region.

Development and performance evaluation of a two-stage cascade impactor equipped with gelatin filter substrates for the collection of multi-sized particulate matter.

This study presents the development and evaluation of a high flow rate gelatin cascade impactor (GCI) to collect different PM particle sizes on water-soluble gelatin substrates. The GCI operates at a flow rate of 100 lpm, and consists of two impaction stages, followed by a filter holder to separate particles in the following diameter ranges: >2.5 µm, 0.2-2.5 µm, and <0.2 µm. Laboratory characterization of the GCI performance was conducted using monodisperse polystyrene latex (PSL) particles as well as polydisperse ammonium sulfate, sodium chloride, and ammonium nitrate aerosols to obtain the particle collection efficiency curves for both impaction stages. In addition to the laboratory characterization, we performed concurrent field experiments to collect PM2.5 employing both GCI equipped with gelatin filter and personal cascade impactor sampler (PCIS) equipped with PTFE filter for further toxicological analysis using macrophage-based reactive oxygen species (ROS) and dithiothreitol consumption (DTT) assays. Our results showed that the experimentally determined cut-point diameters for the first and second impaction stages were 2.4 µm and 0.21 µm, respectively, which agreed with the theoretical predictions. Although the GCI has been developed primarily to collect particles on gelatin filters, the use of a different type of substrate (i.e., quartz) led to similar particle separation characteristics. The findings of the field tests demonstrated the advantage of using the GCI in toxicological studies due to its ability to collect considerable PM-toxic constituents, as corroborated by the DTT and ROS values for the GCI-collected particles which were 26.44 nmoles/min/mg PM and 8813.2 µg Zymosan Units/mg PM, respectively. These redox activity values were more than twice those of particles collected concurrently on PTFE filter using the PCIS. This high-flow-rate impactor can collect considerable amounts of size-fractionated PM on water-soluble filters (i.e., gelatin), which can completely dissolve in water allowing for the extraction of soluble and insoluble PM species for further toxicological analysis.

Design, optimization, and evaluation of a wet electrostatic precipitator (ESP) for aerosol collection.

In this study, we developed, optimized, and evaluated in lab and field experiments a wet electrostatic precipitator (ESP) for the collection of ambient PM2.5 (particulate matter with aerodynamic diameter < 2.5 µm) into ultrapure water by applying an electrostatic charge to the particles. We operated the wet ESP at different flow rates and voltages to identify the optimal operating conditions. According to our experimental measurements, a flow rate of 125 lpm and an applied positive voltage of 11 kV resulted in a lower ozone generation of 133 ppb and a particle collection efficiency exceeding 80-90% in all size ranges. For the field tests, the wet ESP was compared with the versatile aerosol concentration enrichment system (VACES) connected to a BioSampler, a PTFE filter sampler, and an OC/EC analyzer (Sunset Laboratory Inc., USA) as a reference. The chemical analysis results indicated the wet ESP concentrations of metal and trace elements were in very good agreement with those measured by the VACES/BioSampler and PTFE filter sampler. Moreover, our results showed comparable total organic carbon (TOC) concentrations measured by the wet ESP, BioSampler, and OC/EC analyzer, while somewhat lower TOC concentrations were measured by the PTFE filter sampler, possibly due to the limitations of extracting water-insoluble organic carbon (WIOC) from a dry substrate in the latter sampler. The comparable TOC content in the wet ESP and BioSampler samples differs from previous findings that showed higher TOC content in BioSampler samples compared to those collected by dry ESP. The results of the Dithiothreitol (DTT) assay showed comparable DTT activity in the VACES/BioSampler and wet ESP PM samples while slightly lower in the PTFE filter samples. Overall, our results suggest that the wet ESP could be a promising alternative to other conventional sampling methods.

A common IL-4 receptor variant promotes asthma severity via a Treg cell GRB2-IL-6-Notch4 circuit.

BACKGROUND: The mechanisms by which genetic and environmental factors interact to promote asthma remain unclear. Both the IL-4 receptor alpha chain R576 (IL-4RαR576) variant and Notch4 license asthmatic lung inflammation by allergens and ambient pollutant particles by subverting lung regulatory T (Treg ) cells in an IL-6-dependent manner. OBJECTIVE: We examined the interaction between IL-4RαR576 and Notch4 in promoting asthmatic inflammation. METHODS: Peripheral blood mononuclear cells (PBMCs) of asthmatics were analyzed for T helper type 2 cytokine production and Notch4 expression on Treg cells as a function of IL4RR576 allele. The capacity of IL-4RαR576 to upregulate Notch4 expression on Treg cells to promote severe allergic airway inflammation was further analyzed in genetic mouse models. RESULTS: Asthmatics carrying the IL4RR576 allele had increased Notch4 expression on their circulating Treg cells as a function of disease severity and serum IL-6. Mice harboring the Il4raR576 allele exhibited increased Notch4-dependent allergic airway inflammation that was inhibited upon Treg cell-specific Notch4 deletion or treatment with an anti-Notch4 antibody. Signaling via IL-4RαR576 upregulated the expression in lung Treg cells of Notch4 and its downstream mediators Yap1 and beta-catenin, leading to exacerbated lung inflammation. This upregulation was dependent on growth factor receptor-bound protein 2 (GRB2) and IL-6 receptor. CONCLUSION: These results identify an IL-4RαR576-regulated GRB2-IL-6-Notch4 circuit that promotes asthma severity by subverting lung Treg cell function.

Tailpipe and Nontailpipe Emission Factors and Source Contributions of PM10 on Major Freeways in the Los Angeles Basin.

In this study, the emission factors of PM10 and its chemical constituents from various contributing sources including nontailpipe and tailpipe emissions were estimated on two interstate freeways in the Los Angeles basin. PM10 samples were collected on the I-110 and I-710 freeways as well as at the University of Southern California (USC) campus as the urban background site, while freeway and urban background CO2 levels were measured simultaneously. PM10 samples were analyzed for their content of chemical species which were used to estimate the emission factors of PM10 and its constituents on both I-110 and I-710 freeways. The estimated values were employed to determine the emission factors for light (LDV) and heavy-duty vehicles (HDV). The quantified species were also processed by the positive matrix factorization (PMF) model to produce PM10 freeway source profiles and their contribution to PM10 mass concentrations. Using the PMF factor profiles and emission factors on the two freeways, we characterized the emission factors for light-duty and heavy-duty vehicles by each nontailpipe source. Our findings indicated higher nontailpipe emission factors of PM10 and metal elements on the I-710 freeway compared to the I-110 freeway, due to the higher fraction of heavy-duty vehicles (HDVs) on that freeway. Furthermore, the generation of nontailpipe PM10 from resuspension of road dust was twice of tire and brake wear. The results of this study provide significant insights into PM10 freeway emissions and particularly the overall contribution of nontailpipe and tailpipe sources in Los Angeles, which can be helpful to modelers and air quality officials in assessing the importance of individual traffic-related emissions on the overall population exposure.

Long-term trends in the contribution of PM2.5 sources to organic carbon (OC) in the Los Angeles basin and the effect of PM emission regulations.

This study aimed to investigate the long-term variations in the contributions of emission sources to ambient PM2.5 organic carbon (OC) in central Los Angeles (CELA) and Riverside using the Chemical Speciation Network (CSN) database in the 2005-2015 period, during which several federal and state PM-based regulations were implemented to reduce tailpipe emissions in the region. The measured concentrations of OC, OC volatility fractions (i.e., OC1, OC2, and OC3), elemental carbon (EC), ozone (O3), sulfate, the ratio of potassium ion to potassium (K+/K), and selected metal elements were used as the input to the positive matrix factorization (PMF) model. PMF resolved tailpipe emissions, non-tailpipe emissions, secondary organic aerosols (SOA), biomass burning, and local industrial activities as the main sources contributing to ambient OC at both sampling sites. Vehicular exhaust emissions, non-tailpipe emissions, and SOA were dominant sources of OC across our sampling sites, accounting cumulatively for more than 80% of total OC mass throughout the study period. Our findings showed a significant reduction in the absolute and relative contributions of tailpipe emissions to the ambient OC levels in CELA and Riverside over the time period of 2005-2015. The contribution of exhaust emissions to total OC in CELA decreased from 3.5 µg m-3 (49%) in 2005 to 1.5 µg m-3 (34%) in 2015, while similar trends were observed at Riverside during this period. These reductions are mainly attributed to the implementation of several federal, state, and local air quality regulations targeting tailpipe emissions in the area. The implementation of these regulations furthermore reduced the emissions of primary organic precursors of secondary aerosols, resulting in an overall decrease (although not statistically significant, P values ranging from 0.4 to 0.6) in SOA mass concentration in both locations over the study period. In contrast to the tailpipe emissions, we observed an increasing trend (by ∼4 to 14%) in the relative contribution of non-tailpipe emissions to OC over this time period at both sites. Our results demonstrated the effectiveness of air quality regulations in reducing direct tailpipe emissions in the area, but also underpinned the need to develop equally effective mitigation policies targeting non-tailpipe PM emissions.

Iron Speciation in Particulate Matter (PM2.5) from Urban Los Angeles Using Spectro-microscopy Methods.

The speciation, oxidation states, and relative abundance of iron (Fe) phases in PM2.5 samples from two locations in urban Los Angeles were investigated using a combination of bulk and spatially resolved, element-specific spectroscopy and microscopy methods. Synchrotron X-ray absorption spectroscopy (XAS) of bulk samples in situ (i.e., without extraction or digestion) was used to quantify the relative fractions of major Fe phases, which were corroborated by spatially resolved spectro-microscopy measurements. Ferrihydrite (amorphous Fe(III)-hydroxide) comprised the largest Fe fraction (34-52%), with hematite (α-Fe2O3; 13-23%) and magnetite (Fe3O4; 10-24%) identified as major crystalline oxide components. An Fe-bearing phyllosilicate fraction (16-23%) was fit best with a reference spectrum of a natural illite/smectite mineral, and metallic Fe(0) was a relatively small (2-6%) but easily identified component. Sizes, morphologies, oxidation state, and trace element compositions of Fe-bearing PM from electron microscopy, electron energy loss spectroscopy (EELS), and scanning transmission X-ray microscopy (STXM) revealed variable and heterogeneous mixtures of Fe species and phases, often associated with carbonaceous material with evidence of surface oxidation. Ferrihydrite (or related Fe(III) hydroxide phases) was ubiquitous in PM samples. It forms as an oxidation or surface alteration product of crystalline Fe phases, and also occurs as coatings or nanoparticles dispersed with other phases as a result of environmental dissolution and re-precipitation reactions. The prevalence of ferrihydrite (and adsorbed Fe(III) has likely been underestimated in studies of ambient PM because it is non-crystalline, non-magnetic, more soluble than crystalline phases, and found in complex mixtures. Review of potential sources of different particle types suggests that the majority of Fe-bearing PM from these urban sites originates from anthropogenic activities, primarily abrasion products from vehicle braking systems and engine emissions from combustion and/or wear. These variable mixtures have a high probability for electron transfer reactions between Fe, redox-active metals such as copper, and reactive carbon species such as quinones. Our findings suggest the need to assess biological responses of specific Fe-bearing phases both individually and in combination to unravel mechanisms of adverse health effects of particulate Fe.

Effects of ambient particulate matter on vascular tissue: a review.

Fine and ultra-fine particulate matter (PM) are major constituents of urban air pollution and recognized risk factors for cardiovascular diseases. This review examined the effects of PM exposure on vascular tissue. Specific mechanisms by which PM affects the vasculature include inflammation, oxidative stress, actions on vascular tone and vasomotor responses, as well as atherosclerotic plaque formation. Further, there appears to be a greater PM exposure effect on susceptible individuals with pre-existing cardiovascular conditions.

Semi-volatile components of PM2.5 in an urban environment: volatility profiles and associated oxidative potential.

The volatility profiles of PM2.5 semi-volatile compounds and relationships to the oxidative potential of urban airborne particles were investigated in central Los Angeles, CA. Ambient and thermodenuded fine (PM2.5) particles were collected during both warm and cold seasons by employing the Versatile Aerosol Concentration Enrichment System (VACES) combined with a thermodenuder. When operated at 50 °C and 100 °C, the VACES/thermodenuder system removed about 50% and 75% of the PM2.5 volume concentration, respectively. Most of the quantified PM2.5 semi-volatile species including organic carbon (OC), water soluble organic carbon (WSOC), polycyclic aromatic hydrocarbons (PAHs), organic acids, n-alkanes, and levoglucosan, as well as inorganic ions (i.e., nitrate, sulfate, and ammonium) exhibited concentration losses in the ranges of 40-66% and 67-92%, respectively, as the thermodenuder temperature increased to 50 °C and 100 °C. Species in the PM2.5 such as elemental carbon (EC) and inorganic elements (including trace metals) were minimally impacted by the heating process - thus can be considered refractory. On average, nearly half of the PM2.5 oxidative potential (as measured by the dichlorodihydrofluorescein (DCFH) alveolar macrophage in vitro assay) was associated with the semi-volatile species removed by heating the aerosols to only 50 °C, highlighting the importance of this quite volatile compartment to the ambient PM2.5 toxicity. The fraction of PM2.5 oxidative potential lost upon heating the aerosols to 100 °C further increased to around 75-85%. Furthermore, we document statistically significant correlations between the PM2.5 oxidative potential and different semi-volatile organic compounds originating from primary and secondary sources, including OC (Rwarm, and Rcold) (0.86, and 0.74), WSOC (0.60, and 0.98), PAHs (0.88, and 0.76), organic acids (0.76, and 0.88), and n-alkanes (0.67, and 0.83) in warm and cold seasons, respectively, while a strong correlation between oxidative potential and levoglucosan, a tracer of biomass burning, was observed only during the cold season (Rcold=0.81).

Seasonal and Annual Source Appointment of Carbonaceous Ultrafine Particulate Matter (PM0.1) in Polluted California Cities.

Samples of ultrafine particle matter mass (PM0.1) were collected over 12 months at three cities in California: Los Angeles, East Oakland, San Pablo, and over six months at Fresno. Molecular markers adjusted for volatility and reactivity were used to calculate PM0.1 source contributions. Wood burning was a significant source of PM0.1 organic carbon (OC) during the winter months in northern California (17-47%) but made smaller contributions in other months (0-8%) and was minor in all seasons in Los Angeles (0-5%), except December (17%) during holiday celebrations. Meat cooking was the largest source of PM0.1 OC across all sites (13-29%), followed by gasoline combustion (7-21%). Motor oil and diesel fuel combustion made smaller contributions to PM0.1 OC (3-10% and 3-7%, respectively). Unresolved sources accounted for 22-56% of the PM0.1 OC. The lack of a clear seasonal profile for this unresolved OC suggests that it may be a primary source rather than secondary organic aerosol (SOA). PM0.1 elemental carbon (EC) was dominated by diesel fuel combustion with less than 15% contribution from other sources. All sources besides wood smoke exhibited relatively constant seasonal source contributions to PM0.1 OC reflecting approximately constant emissions over the annual cycle. Annual-average source contributions to PM0.1 OC calculated with traditional molecular markers were similar to the source contributions calculated with the modified molecular markers that account for volatility and reactivity.

A Jagged 1-Notch 4 molecular switch mediates airway inflammation induced by ultrafine particles.

BACKGROUND: Exposure to traffic-related particulate matter promotes asthma and allergic diseases. However, the precise cellular and molecular mechanisms by which particulate matter exposure acts to mediate these effects remain unclear. OBJECTIVE: We sought to elucidate the cellular targets and signaling pathways critical for augmentation of allergic airway inflammation induced by ambient ultrafine particles (UFP). METHODS: We used in vitro cell-culture assays with lung-derived antigen-presenting cells and allergen-specific T cells and in vivo mouse models of allergic airway inflammation with myeloid lineage-specific gene deletions, cellular reconstitution approaches, and antibody inhibition studies. RESULTS: We identified lung alveolar macrophages (AM) as the key cellular target of UFP in promoting airway inflammation. Aryl hydrocarbon receptor-dependent induction of Jagged 1 (Jag1) expression in AM was necessary and sufficient for augmentation of allergic airway inflammation by UFP. UFP promoted TH2 and TH17 cell differentiation of allergen-specific T cells in a Jag1- and Notch 4-dependent manner. Treatment of mice with an anti-Notch 4 antibody abrogated exacerbation of allergic airway inflammation induced by UFP. CONCLUSION: UFP exacerbate allergic airway inflammation by promoting a Jag1-Notch 4-dependent interaction between AM and allergen-specific T cells, leading to augmented TH cell differentiation.