2009 Progress Report: Project 2: The Role of Oxidative Stress in PM-induced Adverse Health Effects

EPA Grant Number: R832413C002
Subproject: this is subproject number 002 , established and managed by the Center Director under grant R832413
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: Southern California Particle Center
Center Director: Froines, John R.
Title: Project 2: The Role of Oxidative Stress in PM-induced Adverse Health Effects
Investigators: Nel, Andre E. , Kleinman, Michael T. , Lusis, Aldons , Harkema, Jack
Institution: University of California - Los Angeles , Michigan State University , University of California - Irvine
EPA Project Officer: Chung, Serena
Project Period: October 1, 2005 through September 30, 2010 (Extended to September 30, 2012)
Project Period Covered by this Report: August 1, 2008 through July 31,2009
RFA: Particulate Matter Research Centers (2004) RFA Text |  Recipients Lists
Research Category: Health Effects , Air

Objective:

The primary objective is to elucidate the mechanism(s) of PM-induced asthma and atherosclerosis exacerbation.  Mechanisms are investigated by performing in vivo animal studies in a mobile trailer suitable for exposure to ambient PM as well as executing in vitro studies of tissue culture cells.  Our goal is to build a predictive toxicological paradigm in which the in vitro mechanisms of injury is also applicable to disease pathogenesis in vivo.

Progress Summary:

Progress on studies looking at the effect of the pro-oxidative potential of ambient particles on their adjuvant effect on allergic inflammation in a murine asthma model. 
In collaboration with Dr. Jack Harkema and Dr. Sioutas, Dr Nel and Dr. Ning Li have continued their studies of the hypothesis that altered cellular redox equilibrium by PM and adsorbed redox cycling organic chemicals leads to the perturbation of immune function and Th2 skewing of the immune response.  We were able to clearly demonstrate the adjuvant effect of ambient ultrafine particles (UFP) as well as DEP on ovalbumin (OVA)-induced allergic sensitization in vivo.
 
In brief, we have established a highly sensitive murine model in which the pro-oxidant effects of ambient PM is linked to induction of allergic sensitization to OVA.  In this model intranasal sensitization of Balb/C mice with a total of four low-dose endotoxin-free OVA (10 mg) together with nanogram quantities (100-500 ng) of size-fractionated ambient UFP (< 0.15 mm) leads to mucosal sensitization after secondary OVA aerosol challenge compared to the mice in saline and OVA-only groups (Li et al, Environ Health Perspect, 2009).  At a dose of 0.5 mg/mouse, ambient UFP significantly enhanced OVA-induced eosinophilic airway inflammation and OVA-specific IgE and IgG1 production in the blood. UFP also increased the production of a number of pro-inflammatory cytokines in the lung including TNFa, IL-5, IL-6, IL-13, KC, MCP-1 and MIP-1a, whereas those in saline and OVA-only groups were unaffected. The increase of IL-5 and IL-13 by OVA/UFP is important indicator suggesting that ambient UFP be capable of skewing immune response towards Th2 immunity. Side-by-side comparison of UFP and fine particles (< 2.5 mm) indicate that this adjuvant effect is specific to the UFP since fine particles failed to enhance the effect of OVA. Moreover, using various controls, we were able to show that neither endotoxin nor ultrafine carbon black particles had any enhancing OVA sensitization.
 
Morphometric analysis of the lung showed that the major changes in the lungs of OVA/UFP-treated mice consisted of marked mucous cell metaplasia and a mixed inflammatory cell influx consisting mainly of eosinophils, lymphocytes and plasma cells (Li et al. Environ Health Perspect, 2009). In addition to the lower airway, the nasal mucosa of OVA/UFP-exposed animals had airway epithelial and inflammatory changes consistent with an acute allergic rhinitis, such as mucous cell metaplasia/hyperplasia and eosinophil influx, in the transitional or respiratory epithelium lining the maxilloturbinates.  These data suggest that UFP exert its adjuvant effect immediately upon contact with the allergen in the nasal turbinate and this may explain the association between air pollution and allergic rhinitis.
 
Detailed characterization showed that the ambient UFP had significantly higher organic chemical content (i.e. PAH) and stronger oxidant potential than the fine particles (Li et al. Environ Health Perspect, 2009). Moreover, ambient UFP also had a greater ability to induce antioxidant enzyme HO-1, a sensitive marker of oxidative stress.  Thus, this mouse model allows us to compare the contribution of particle chemical composition and accompanying differences in the oxidant potential to the asthma disease-enhancing effect of PM. In summary, our data suggest that the degree of adjuvancy is closely related to the OC content and the oxidant potential of PM.  A manuscript reporting this work is currently in press by Environmental Health Perspectives (Li, et al. Environ Health Perspect 2009).
 
We also made further progresses in studying the adjuvant effect of pro-oxidative PM on allergic inflammation.  These include (i) assessing the impact of ambient UFP on secondary immune response in already sensitized animals, (ii) evaluating the number of intranasal OVA/UFP instillations that is sufficient to demonstrate the adjuvant effect, and (iii) exploring the concept of inflammasome activation in PM adjuvancy. 
 
Relating to the question whether ambient PM could enhance the secondary immune response, we explored whether exposure to UFP could boost the response to OVA inhalation in mice that were already sensitized to this allergen.  In this study, the animals were sensitized by two intranasal instillations of OVA plus ambient UFP.  After resting for two weeks, the mice were exposed to the filtered air (FA) or UFP in our AirCare mobile laboratory located in downtown Los Angeles for five days during which two daily 1% OVA aerosol challenges were given. The results from this study show that exposure to ambient UFP during OVA challenge significantly enhanced allergic airway inflammation in mice already sensitized by OVA plus UFP compared to those in filtered air (FA) group or the animals sensitized by OVA alone and subsequently challenged with OVA/FA or OVA/UFP.  The mice that were exposed to UFP during both sensitization and challenge phases had significantly enhanced eosinophilic airway inflammation accompanied by increased OVA-IgG1 and OVA-IgE production in the blood and markedly elevated pro-inflammatory cytokine levels in the lung, including Th2 cytokines such as IL-5 and IL-13.  The expression of several asthma-related genes including Ym1/Ym2 and Fizz1 was also dramatically increased in these animals. The findings from this study indicate that pro-oxidative UFP are capable of promoting both primary and secondary immune responses.  This may help to explain increased asthma flares among atopic people after a sudden surge in PM levels.  A manuscript reporting the findings from this study is currently in preparation.
 
With regard to our dose-response studies, we found that in our intranasal sensitization model only a single intranasal exposure to 500 ng of UFP necessary to demonstrate the adjuvant effect of OVA sensitization. One-time intranasal instillation of OVA/UFP is sufficient to elicit allergic inflammation characterized by eosinophil influx in the lung and significantly elevation of OVA-IgG1 and IgE in the blood.  These results further confirm the high sensitivity of our mouse model.  The findings from this progress will enable us to conduct future animal experiments much faster.
 
Text Box: A. PAH content and redox potential
DEP
Sample	PAH Content	Redox
Activity
DEP-2	180.7	0.0033
DEP-3	303.2	0.0047
DEP-4	875.0	0.0092
DEP-5	438.6	0.0086
B. IL-1b levels in cell culture media
C. Cleavage of Pro-IL-1b by DEP
Fig. 1. Increased pro-IL-1b cleavage and IL-1b secretion by DEP samples with higher PAH content and stronger oxidant potential. A. PAH content (mg/g DEP) and redox activity (activity/mg DEP) determined by the dithiothreitol assay. B. IL-1b levels in BMDC culture media determined by ELISA. C. Western blotting showing cleavage of LPS-induced pro-IL-1b by DEP. DEP = 50 mg/ml; Carbon black (CB) = 50 mg/ml;
LPS = 10 ng/ml. *p < 0.05 compared to control without LPS, #p < 0.01 compared to control plus LPS.
In the past few years, a new concept termed “inflammasome” has been introduced as a molecular sensor to explain how the innate immune system functions. The NOD-like receptors (NLR), a family of intracellular sensors of microbial motifs and ‘danger signals’, have been considered as being crucial components of the innate immune responses and inflammation. The NALP3 inflammasome is a caspase-1-activating multiprotein complex that processes proinflammatory cytokines. This inflammasome detects a number of danger signals such as bacterial muramyldipeptide, monosodium urate crystals and reactive oxygen species (ROS), which leads to assembly of it subunits and association with pro-caspase-1.  Through the ability to activate caspase-1 and subsequent release of IL-1b from it its pro-peptide form, the NALP3 inflammasome plays an important role in the immunomodulatory effects of danger signals. In addition, it has been demonstrated that alum, a classical adjuvant for murine asthma model, stimulates inflammatory dendritic cells (DC) through the activation of NALP3 inflammasome.  Based on these published reports, we have begun to investigate the role of NALP3 inflammasome in the adjuvant effect of ambient PM with a focus on DC.  Using four out of seven DEP samples that we recently obtained from U.S. Environmental Protection Agency, we have found that the ability of these DEP collections to increase IL-1b secretion from bone marrow-derived DC (BMDC) is linked to their oxidant potential (Fig. 1A and 1B).  Moreover, the ability of these DEP samples to cleave lipopolysaccharide (LPS)-induced pro-IL-1b was also associated to their PAH content and oxidant potential (Fig. 1A and 1C).  Taken together, our preliminary data suggest that pro-oxidative PM may exert its adjuvant effect through the activation of NALP3 inflammasome in DC.
 
Progress in our studies on genome wide analysis and gene clustering in lung tissue.
In last year's progress report we outlined publication of our collaborative studies with Dr. Jake Lusis and Jesus Araujo using human microvascular endothelial cells (HMEC) to test the hypothesis that pollutant particles synergize with known pro-atherogenic stimuli, such as oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (ox-PAPC) to elicit oxidative stress responses that promote atherosclerosis. In brief, the study showed that HMEC treated in triplicate wells with an organic DEP extract (5 mg/ml), ox-PAPC (10, 20 and 40 mg/ml) or combination of both compounds for 4 hours exhibited synergistic induction of cellular oxidative stress, as evidenced by the synergistic upregulation of heme oxygenase 1 (HO-1), where the combination of DEP and ox-PAPC at various concentrations led to HO-1 protein levels that were significantly higher than each compound alone or the sum of both. We determined that this synergy was present at a large scale by a genomic approach that included the use of Illumina microarray technology. Both the DEP extract and ox-PAPC co-regulated a large number of genes. We used network analysis to identify co-expressed gene modules and found three modules that were most highly enriched in genes that were differentially regulated by the stimuli. These modules were also enriched in synergistically coregulated genes and pathways relevant to vascular inflammation. We validated this synergy in vivo by demonstrating that liver gene expression of hypercholesterolemic mice exposed to ambient ultrafine particles exhibited significant upregulation of the module genes.
 
Based on the results obtained on the preferential upregulation of hepatic antioxidant and unfolded protein response genes by UFP as compared with fine particles (FP = PM2.5) or filtered air, we decided to perform genomic expression analysis on lung tissue from apoE KO mice exposed to CAPs of different sizes (UFP and FP) vs. filtered air (FA), in collaboration with Dr. Araujo and Lusis. We conducted two different CAPs inhalation exposures, in our mobile laboratory (AIRCARE 1) located in downtown Los Angeles, designated as short-term and long-term exposures. In the short-term exposures, 9~10-weeks old male apoE null mice were exposed to CAPs vs. FA for 5 hours/day for 4 days while in the long-term exposures, similar mice of 6 weeks of age were exposed to ambient particles for 5 hours/day, 3 days/week for 5 weeks. Lungs were harvested upon euthanasia, mRNA was prepared and Illumina microarrays performed. In the short-term exposures, analysis of genomic expression profiles unveiled that there were 804 differentially expressed genes in the FP and UFP groups as compared with the FA controls (Beadstudio detection score > 0.95,  student T-test, p<0.05, FDR<0.5%). Both FP and UFP mice exhibited similar number of differentially expressed genes, ~ 27% of which were shared. Approximately a third of the regulated genes displayed levels that were over 20% of FA controls. Interestingly, UFP exposures regulated as many as three times more genes than FP exposure. Network analysis allowed us to identify gene cluster that were preferentially regulated by FP and UFP exposures. Ingenuity pathway analysis unveiled inflammatory pathways centered on NF-kB, both stimulatory and inhibitory. Although we could not detect evidence of NF-KB activation at pathway level, increased expression of CXCL12 denotes activation of a NF-kB-driven pathway. Long-term exposures resulted in a much greater number of regulated genes with a greater degree of differential expression. Pathway analysis confirmed involvement of similar pathways as in the short-term exposures.
 
In the long-term exposures, we have determined that both FP and UFP exposures promote the formation of dysfunctional HDL, as determined by a monocyte chemotactic assay developed at UCLA. In collaboration with Drs. Ralph Delfino, Jesus Araujo, Diana Shih and Jake Lusis, we are evaluating whether exposure to PM, as encountered at ambient levels, correlates with the induction of HDL dysfunction in human subjects in Dr. Delfino’s CHAPS study. Upon collection of the blood samples, plasma samples were separated and preserved by mixing with a cryopreservative sucrose solution and storing at -70 degrees until use. Dr. Delfino has sent ~ 150 plasma samples corresponding to 17 subjects, participants of the Riverside component of his study. Their HDL anti-oxidant capacity is currently being tested in a fluorescent cell-free assay that allows us to evaluate the ability of HDL to inhibit LDL oxidation. Briefly, HDL fractions have been isolated by magnetic bead separation. HDL fractions are currently being tested, where 0.625 μg of HDL samples are preincubated with 0.25 μg standard LDL in triplicates on 96-well microplates at 37 ºC for 30 minutes. 5 μg DCF is then incubated at 37 ºC for 1 hour. Reactive oxygen species are determined by the degree of DCF-fluorescence read in a fluorescence plate reader at an excitation of 485 nm and emission of 530 nm. HDL anti-oxidant/anti-inflammatory capacity will be expressed in HDL inflammatory index (HII) units, calculated as the ratio of LDL-induced DCF fluorescence in the presence vs. absence of HDL. HII > 1 indicates a pro-inflammatory potential.
Text Box: Table 1. Proteins with significant expression level changes in BALF from mice sensitized with OVA or OVA plus UFP
In response to an invitation by the Particle, Fibre and Toxicology journal, we submitted an article on the role of particle size and chemical composition in the development of atherosclerosis (Araujo and Nel, Particle, Fibre & Toxicology, 2009). In this paper, we reviewed the epidemiological, clinical and experimental animal evidence that support the association of particulate matter with atherogenesis. We also discuss the possible pathogenic mechanisms involved, the physicochemical variables of importance in the enhanced toxicity of small particles, interaction with genes and other proatherogenic factors as well as important elements to consider in the design of future mechanistic studies.
 
Proteome analysis of the oxidative stress responses in a bronchial epithelial cell line BAL fluid.
In collaboration with Dr. Joseph Loo from the Keck Proteomics facility at UCLA, we have utilized proteomics technologies to identify new proteins that may be useful biomarkers in allergic inflammation related to air pollutants. We have reported previously that 2D-PAGE (polyacrylamide gel electrophoresis) coupled with mass spectrometry can identify oxidative stress markers in bronchoalveolar lavage fluid (BALF) and lung tissue in a murine OVA model.  In our present study, we used the newly developed murine intranasal sensitization model (Li et al, Environ Health Perspect, 2009) to observe whether an adjuvant effect of ambient PM leads to an altered proteome profile in BALF.  We hypothesize that the mechanistic link between the adjuvant effect of PM and changes observed in the proteome profile can be used to develop biomarkers for allergic inflammatory responses caused by air pollutants, confirm the hierarchical oxidative stress model, and elucidate the mechanism of the adjuvant effect. Bronchoalveolar lavage fluid proteins from control and sensitized mice were resolved by two-dimensional gel electrophoresis, and identified by mass spectrometry. A total of 30 protein spots from 16 proteins were significantly changed in OVA sensitized mice and even more significantly changed in mice exposed to an OVA plus UFP combination (Table 1).  The 7 proteins showing the highest protein expression level changes were confirmed by western blotting and RT-PCR.  These proteins include surfactant protein-D, polymeric immunoglobulin receptor (PIGR), complement C3, neutrophil gelatinase-associated lipocalin (NGAL), and a family of chitinases, including chitinase-3-like protein 3 (Ym1), chitinase-3-like protein 4 (Ym2), and acidic mammalian chitinase.  Among them, Ym1, Ym2, acidic mammalian chitinase, PIGR, complement C3, and NGAL demonstrated significantly enhanced up-regulation by UFP with a polycyclic aromatic hydrocarbon (PAH) content and a higher oxidant potential.
 
The proteins identified in this study may be the important specific elements targeted by PM, through the ability to generate reactive oxygen species in the immune system, and may be involved in allergen sensitization and asthma pathogenesis.  A manuscript reporting these new findings is in preparation (Kang et al. 2009, manuscript in preparation). The Proteomics efforts have yielded data to support a PM-induced oxidative stress induced model in BAL fluid and in the lung.  Potential protein markers to follow oxidative stress responses in the lung and in human nasal lavage fluid have been revealed.

Future Activities:

1.  We will continue to work on the OVA adjuvancy model including performing studies that will investigate the role of oxidative stress at the level of antigen presenting cells as outlined in our studies using dendritic cells and diesel exhaust particle extracts in year two.
 

We will determine whether the adjuvant effect of ambient PM and DEP is mediated though the activation of inflammasome in DC.  We will also assess whether PM-induced oxidative stress could act as a “danger signal” to DC.  We will continue to validate our intranasal sensitization mouse model using seven different DEP samples collected by EPA.  Characterization studies have shown that these DEP samples have different chemical composition and oxidant potential (Fig. 1A).  They also differ in their ability to induce cellular oxidative stress and pro-inflammatory cytokine production, i.e. IL-8 and IL-1b.  We will determine whether our mouse model could discern the differences among these DEP samples based on their differences in their chemical composition and oxidant potential. In collaboration with Dr. Sioutas and Dr. Harkema, we will also use our in vivo model to compare the ambient PM samples collected in different cities in the country, i.e. Los Angeles and Detroit, to determine how differences in ambient PM chemical composition affect asthma disease severity.

 
2.  In collaboration with Project 3, Project 1 and Dr William Hinds, we are attempting to develop online instrumentation that can be used to monitor the oxidant potential of ambient UFP as a metric for their biological potency.  This study is premised on the DTT assay that Dr. Art Cho and Dr. John Froines have previously developed to measure PM oxidant potential based on thiol chemistry.  These studies are being conducted by Dr. Allen Haddrell, who has proposed to design and build instrumentation with the ability to monitor the oxidative stress potential of a given sample of UFP in near real time.  The proposed operation of the device is as follows: Particles are pulled from the air via a vacuum, once in the system the particles are charged via a corona discharge.  The charged particles are then directed into an AC levitation trap where they can be held indefinitely.  The levitated particles are subsequently introduced to a primary thiol in the vapor phase.  The particles oxidize the thiol vapor, generating thiol radicals that are ionized with a deep UV laser.  The thiol ions are ejected from the levitation chamber into an ion trap where they are counted.  The number of thiol ions produced is used to predict the oxidative potential of the particles held within the trap.  Through the use of standardized materials, the data will be converted to report the oxidative stress potential of the suspended particles in a given fraction of air rather than simply reporting the absolute number.
 
 
Progress in the last year was the development of a sample preparation device designed for use in the study of heterogeneous reactions on particulate matter suspended in air has been developed and characterized.  The device first imparts a slight net charge onto the particles, then subsequently exploits this net charge to manipulate their trajectory with an electrodynamic field to eject a significant portion of the suspended particles into a secondary gas flow wherein the gas can be any vaporous chemical species that could interact with the particle surface.  The electrostatic ejection is only possible on particles smaller than 700 nm.  However, for the particles within this size range the electrostatic ejection resulted in no significant fractionation wherein no additional particles were ejected into the secondary air flow.  This lack of fractionation will prove to be highly useful as it will allow for the accurate measurement of heterogeneous reaction rates without having to make corrections for changes in particle concentration ratios.

References:

 


Journal Articles on this Report : 8 Displayed | Download in RIS Format

Other subproject views: All 34 publications 23 publications in selected types All 23 journal articles
Other center views: All 241 publications 157 publications in selected types All 157 journal articles
Type Citation Sub Project Document Sources
Journal Article Araujo JA, Barajas B, Kleinman M, Wang X, Bennett BJ, Gong KW, Navab M, Harkema J, Sioutas C, Lusis AJ, Nel AE. Ambient particulate pollutants in the ultrafine range promote early atherosclerosis and systemic oxidative stress. Circulation Research 2008;102(5):589-596. R832413 (2008)
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  • Journal Article Chatila TA, Li N, Garcia-Lloret M, Kim H-J, Nel AE. T-cell effector pathways in allergic diseases:transcriptional mechanisms and therapeutic targets. Journal of Allergy and Clinical Immunology 2008;121(4):812-823. R832413 (2007)
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  • Journal Article Li N, Xia T, Nel AE. The role of oxidative stress in ambient particulate matter-induced lung diseases and its implications in the toxicity of engineered nanoparticles. Free Radical Biology and Medicine 2008;44(9):1689-1699. R832413 (2007)
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  • Journal Article Li N, Wang M, Bramble LA, Schmitz DA, Schauer JJ, Sioutas C, Harkema JR, Nel AE. The adjuvant effect of ambient particulate matter is closely reflected by the particulate oxidant potential. Environmental Health Perspectives 2009;117(7):1116-1123. R832413 (2009)
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  • Journal Article Liong M, Lu J, Kovochich M, Xia T, Ruehm SG, Nel AE, Tamanoi F, Zink JI. Multifunctional inorganic nanoparticles for imaging, targeting, and drug delivery. ACS Nano 2008;2(5):889-896. R832413 (2010)
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  • Journal Article Xia T, Kovochich M, Liong M, Zink JI, Nel AE. Cationic polystyrene nanosphere toxicity depends on cell-specific endocytic and mitochondrial injury pathways. ACS Nano 2008;2(1):85-96. R832413 (2010)
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  • Journal Article Xia T, Kovochich M, Liong M, Madler L, Gilbert B, Shi H, Yeh JI, Zink JI, Nel AE. Comparison of the mechanism of toxicity of zinc oxide and cerium oxide nanoparticles based on dissolution and oxidative stress properties. ACS Nano 2008;2(10):2121-2134. R832413 (2010)
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  • Journal Article Xia T, Li N, Nel AE. Potential health impact of nanoparticles. Annual Review of Public Health 2009;30:137-150. R832413 (2008)
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  • Supplemental Keywords:

    Asthma, atherosclerosis, oxidative stress, ambient PM, health effects, sensitive populations, human health, animal, PAH, gene co-expression network analysis, synergy, dendritic cell, adjuvant, RFA, Health, Scientific Discipline, Air, particulate matter, Toxicology, Health Risk Assessment, Risk Assessments, Biochemistry, Ecology and Ecosystems, particulates, atmospheric particulate matter, human health effects, PM 2.5, airway disease, cardiovascular vulnerability, animal model, airborne particulate matter, air pollution, human exposure, vascular dysfunction, cardiovascular disease, human health risk

    Relevant Websites:

     

    Progress and Final Reports:

    Original Abstract
  • 2006 Progress Report
  • 2007 Progress Report
  • 2008 Progress Report
  • 2010 Progress Report
  • 2011
  • Final Report

  • Main Center Abstract and Reports:

    R832413    Southern California Particle Center

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R832413C001 Contribution of Primary and Secondary PM Sources to Exposure & Evaluation of Their Relative Toxicity
    R832413C002 Project 2: The Role of Oxidative Stress in PM-induced Adverse Health Effects
    R832413C003 The Chemical Properties of PM and their Toxicological Implications
    R832413C004 Oxidative Stress Responses to PM Exposure in Elderly Individuals With Coronary Heart Disease
    R832413C005 Ultrafine Particles on and Near Freeways