Department of Environmental Medicine, National Institute of Public Health, P.O. Box 4404 Nydalen, N-0403 Oslo, Norway
Received February 26, 2001; accepted September 19, 2001
![]() |
INTRODUCTION |
---|
Experimental studies investigating the effect of particles on allergy-related immune responses have used different types of material: (1) mixtures of different particle types (e.g., total suspended particulate matter; Li et al., 1997; Ormstad, 2000
; Takafuji et al., 1989
); (2) single particle suspensions (natural or model particles; Diaz-Sanchez et al., 1999
; Fujieda et al., 1998
; Gilmour et al., 2000
; Granum et al., 2001a
; Imrich et al., 2000
; Løvik et al., 1997
; van Zijverden et al., 2000
); or (3) solutions containing chemical substances often found adsorbed onto environmental particles (extracts of a given particle type or chemical solutions containing one particular chemical; Bömmel et al., 2000
; Dreher et al., 1997
; Fahy et al., 2000
; Gilmour et al., 2000
; Lambert et al., 2000
; Takenaka et al., 1995
; Tsien et al., 1997
).
The main purpose of this article is to review studies on the effect of the particle core per se (that is the particle by itself), physical particle properties (e.g., size, number, surface area, dose-weight), and particle-bound chemical substances and metals on allergy-related immune responses. Allergy-related immune responses are also called Th2 (T helper 2) dependent, in contrast to Th1 dependent responses. The effect of particles on sensitization and provocation phases will be discussed, and the influence of the genetic background for the effect of particles will be reviewed. Some possible mechanisms behind the effect of particles will be considered briefly. However, a detailed discussion on this subject is beyond the scope of this article.
![]() |
Particulate Air Pollution |
---|
Environmental PM is generated from a wide range of natural and man-made sources, and the composition of the particulate air pollution in one area may vary enormously from the composition in another area. In developed countries, however, the PM2.5 fraction is reported to consist mainly of carbon particles that are mostly generated from human activities such as combustion of wood and fossil fuels, and secondary particles generated by chemical reactions in the atmosphere (acid condensates, sulfates, nitrates; Ormstad et al., 1997; Seaton et al., 1995
). The PM2.510 fraction predominantly consists of inorganic minerals, such as wind-blown dust from soil and sand (reviewed in Williams, 1999
). Table 1
shows the estimated contribution of the main sources of PM10, PM2.5, and PM0.1 emissions in Europe in 1993 (excluding the former Soviet Union; reviewed in Holman, 1999
). Important sources of PM2.5 and PM0.1 are power generation plants, road traffic, and ships. Two particle types generated from these sources are residual oil fly ash (ROFA) and diesel exhaust particles (DEP). Both ROFA and DEP consist of a carbonaceous particle core. High proportions of water-soluble sulfate and metals, especially vanadium, nickel, and iron are adsorbed to the carbon core of ROFA (Dreher et al., 1997
), whereas components most often found on the carbon core of DEP are elemental and organic carbon species (e.g., polyaromatic hydrocarbons; Løvik et al., 1997
; reviewed in Nel et al., 1998
). DEP will vary in composition depending on engine, engine load, and type of diesel fuel, and the different DEP may show variations in their biological effects (Sjögren et al., 1996
; van Zijverden, 2001
). We will, however, for the simplicity of the discussion regard DEP as one entity.
|
![]() |
The Effect of Particles Per Se |
---|
There are, in addition, several studies that have investigated the effect of particles on responses other than the adjuvant effect on antibody responses, such as inflammatory responses (Driscoll et al., 1997a; Finkelstein et al., 1997
; Granum et al., 2001b
; Løvik et al., 1997
; Oberdörster et al., 1992
). PSP or carbon black (CB) particles given subcutaneously (sc) in the hind footpad to mice (NIH/Ola and BALB/cA, respectively) were found to cause increased weight, cell numbers, and proliferation indexes in the draining popliteal lymph node (Granum et al., 2001b
; Løvik et al., 1997
). These results support the notion that particles per se may elicit cellular responses. In lung models, alveolar macrophages have been found to ingest both opsonized (antibody coated) and unopsonized latex particles rapidly and indiscriminately (Kobzik et al., 1993
). Kobzik et al. reported a marked induction of tumor necrosis factor (TNF) release after uptake of opsonized but not after uptake of unopsonized particles in vitro. This is to be expected since one of the main functions of alveolar macrophages is clearance of numerous inert and innocuous particles without triggering a substantial proinflammatory response, whereas uptake of opsonized particles indicates the presence of foreign organic material and creates a "danger" signal (Kobzik, 1995
). However, in other studies, alveolar macrophages have been shown to produce inflammatory mediators after exposure to unopsonized model particles (reviewed in Driscoll et al., 1997b
; Goldsmith et al., 1998
). These studies show that after internalization of different types of particles, alveolar macrophages and epithelial cells are activated to produce cytokines that are important for the recruitment of lymphocytes and inflammatory cells (reviewed in Driscoll et al., 1997b
; Finkelstein et al., 1997
). Several model particles, including ultrafine CB, TiO2, and latex particles, have also been shown to induce inflammation and oxidative stress (Donaldson et al., 2000
; reviewed in Driscoll et al., 1997b
; Stone et al., 2000
). Oxidative damage in the lung may contribute to increased epithelial permeability. In turn, an increased number of particles may enter the interstitium, which is hypothesized to be crucial for elicitation of inflammatory responses (reviewed in Driscoll et al., 1997b
; Oberdörster et al., 1992
).
Together, these studies give substantial evidence that particles per se, without release of chemical components, may induce inflammatory responses in the lung. The inflammatory response may be an important mechanism behind the adjuvant effect exerted on antibody production by particles, in that a large number of antigen-presenting and inflammatory cells will be present at the time and place of allergen entry.
![]() |
The Effect of Particle-Associated Chemical Substances |
---|
PAH extracted from DEP and other PAH (e.g., pyrene, phenanthrene), often adsorbed to DEP, have been found to have several effects on allergic immune responses, including upregulation of IL-4 production (Bömmel et al., 2000), increased production of IgE (Suzuki et al., 1993
; Takenaka et al., 1995
; Tsien et al., 1997
), and induction of inflammatory responses (Fahy et al., 1999
; Terada et al., 1997
).
Finally, it should be mentioned that endotoxin from Gram-negative bacteria is virtually ubiquitous, and can influence inflammatory and adjuvant activity caused by particles (Becker et al., 1996; Daniels et al., 2000
; Monn and Becker, 1999
; Ning et al., 2000
). Ning et al. (2000) studied the effect of concentrated air particle suspensions containing trace amounts of endotoxin on inflammatory responses in murine alveolar macrophages. Both water-soluble and solid components of the sampled air particles showed biological activity (induction of TNF-
and macrophage inflammatory protein-2), although the majority of the biological activity and endotoxin content was associated with the solid particle components. They concluded that there is a synergistic interaction between the trace endotoxin and other proinflammatory components of the particles.
![]() |
The Effect of the Particle Core Per Se versus Adsorbed Chemical Substances |
---|
Results from the studies we have cited suggest that particles per se have an adjuvant activity in that particles with widely different chemical composition can enhance antibody responses. However, there is evidence that the basic effect from particles per se may be modified or increased by properties of the particle surface, such as adsorbed chemical substances. In this way, the particle per se may act as a general "motor" for antibody production, while chemical substances and possibly other factors (e.g., surface charge, structure, size) may steer the increased response towards a polarized Th1- or Th2-like response.
![]() |
Physical Characteristics of Particles |
---|
|
The number of particles reaching the interstitial space of the lung has been reported to be directly proportional to the number of particles applied (Churg et al., 1998). A large surface area, on the other hand, may lead to a greater interaction with alveolar cells compared to a smaller surface area, thereby having the potential to elicit stronger cellular responses. The total surface area may also be important if the particles act as mediators of biochemical reactions (reviewed in Fubini, 1997
). In addition, a large surface area may have a greater capacity to adsorb chemical substances, allergens, endotoxin, and other biological components than a small surface area. However, the relative contribution from different particle properties, such as the number and surface area of particles, is difficult to assess since they are closely related to each other.
Particle doses are usually expressed in terms of particle mass-weight per volume units of air (µg/m3, mg/m3). However, PM is a very heterogeneous mass consisting of particles varying in size, shape, and specific weight. In a study in Erfurt, Germany, the number and mass concentration of PM was sampled during the winter season, 19911992 (Table 3; data from Peters et al., 1997
). The overall number of particles ranging from 0.01 to 2.5 µm was dominated by the number of ultrafine particles (< 0.1 µm in diameter), whereas most of the particle mass was found to consist of particles between 0.1 and 0.5 µm. In the cited study, adverse respiratory effects were associated with the number of the ultrafine particles. Similar findings were made in a study in Helsinki, Finland, in that the daily mean number concentration of particles was dominated by the ultrafine particles. The daily mean number concentration of particles, but not particle mass (PM10, PM2.510, PM2.5, and PM1, < 1 µm in diameter), was associated with daily deviations in peak expiratory flow. Particle number concentrations of ultrafine particles had the strongest effect (Penttinen et al., 2001
). These studies illustrate the fact that there can be a large number of small particles in ambient air that hardly contribute to the total mass and still have important biological effects. Weight measurements alone, therefore, leave out possibly important physical characteristics of PM, such as the number concentration, size distribution, and the total surface area. When particles have a smooth surface and a simple shape, their approximate geometric surface area can be calculated, but the estimation of the true surface area becomes more complicated when the particles have a complex shape (reviewed in Fubini, 1997
). Measurements of the total surface area in an automated way are, therefore, virtually impossible to perform, and other measures of particles must be sought (Ayres, 1998
). Since both the size distribution and number concentration of particles can be measured in an automated way (e.g., by using a photon correlation spectrometer), this procedure may be an appropriate alternative to the measurement of the total surface area. Therefore, in relation to allergy, relevant measurements of airborne PM would be weight measurements supplemented by the number of sized particles per volume unit of air.
|
![]() |
Particles and AllergySensitization and Provocation |
---|
|
It has been found that particles will increase the primary response when present either before the first exposure to allergen (Granum et al., 2001b; Lambert et al., 2000
; van Zijverden, 2001
) or when particles are coadministered with the first dose of allergen (Granum et al., 2001b
; Heo et al., 2001
; Løvik et al., 1997
; Takafuji et al., 1989
). However, the strongest adjuvant effect from particles was observed when particles were given simultaneously with all allergen doses (Granum et al., 2001b
; van Zijverden, 2001
). It should be noted that in experimental systems, particles may also have some adjuvant effect on the immune response when the particles are administered a short time after allergen exposure (Granum et al., 2001b
).
There is evidence that mast cells may be affected by particles resulting in an increased booster response in the sensitization phase. After intranasal administration of allergen and DEP to allergic humans, there was an increased production of IL-4 (Wang et al., 1999). During the local mucosal allergic response, cells of the mast cell/basophil lineages were reported to contribute considerably to the production of IL-4 in the initial reaction after the exposure. This IL-4 production was believed to polarize the immune response towards a Th2 response, and expand the number and type of cells producing IL-4. Subsequently, other cells (predominantly Th cells) became the major source of IL-4 as the polarized Th2 response was established (left and middle section in Fig. 1
).
There are both epidemiological and human experimental studies that give evidence for an involvement of particulate air pollution in the provocation phase of the allergic response (Diaz-Sanchez et al., 1997, 2000
; Fujieda et al., 1998
; Norris et al., 1999
; Schwartz and Neas, 2000
; Timonen and Pekkanen, 1997
; van der Zee et al., 1999
). In a study by Diaz-Sanchez et al. (2000), histamine levels and symptom scores (severity of nasal itching, nasal congestion and rhinorrhea, and number of sneezes) were measured after intranasal administration of DEP and allergen (house dust mite) to sensitized human subjects. Compared to subjects given allergen alone, subjects given DEP and allergen had higher symptom scores and a 3-fold increased release of histamine. DEP alone had no effect. This study indicates that DEP in combination with an allergen can aggravate allergic immune responses in sensitized subjects by increasing the release of histamine from mast cells and thus contribute the induction of the provocation phase (middle and right section in Fig. 1
). Another important mechanism for the effect of particles on the provocation phase may be particle-mediated induction of nonspecific inflammatory responses (that is allergen-independent responses; see right section in Fig. 1
). Since airway epithelial cells and alveolar macrophages are the initial target cells for interaction with particles, these cells are most likely to be affected by particles (reviewed in Salvi and Holgate, 1999
). After the particle-induced activation of epithelial cells, these cells produce cytokines such as IL-1, IL-6, IL-8, TNF-
, GM-CSF, and RANTES, whereas macrophages are shown to produce cytokines such as TNF-
and IL-8 (reviewed in Boland et al., 2000
; Driscoll et al., 1997b
; Nel et al., 1998
; Salvi and Holgate, 1999
). The nonspecific inflammatory effects of particles may add to the allergic inflammation.
![]() |
The Importance of the Genetic Background |
---|
With regard to particles, Ichinose et al. (1997) found interstrain differences for eosinophilic airway inflammation, goblet cell proliferation, and production of allergen-specific IgG1 after intratracheal instillations of DEP plus OVA to naïve mice. In a study by Granum et al. (2000b), the importance of genetic background concerning the adjuvant effect of PSP was explored. After ip injections with PSP plus OVA to naïve mice, there was a statistically significant adjuvant effect on the production of allergen-specific antibodies in NIH/Ola mice but not in C3H/HeJ mice. In BALB/c mice, on the other hand, PSP gave a weak, but not significant, antibody adjuvant activity. The C3H/HeJ mouse has a Lpsd mutation in the Tlr4 gene (Beutler, 2000; Hoshino et al., 1999
; Poltorak et al., 1998
). The most significant cell type that is affected by this mutation is the macrophage. The uptake of unopsonized particles (e.g., TiO2 and latex) has been shown to be mediated by scavenger receptors of types AI, AII, and MARCO (Palecanda et al., 1999
), and thus occur independently of Tlr4. However, mutant macrophages do not secrete inflammatory cytokines (e.g., IL-1, IL-6, TNF-
) on exposure to LPS, fail to phagocytize opsonized particles, and fail to produce reactive oxygen species or nitric oxide in response to LPS (Anderson, 2000
). The lack of an adjuvant effect of PSP in the C3H/HeJ mouse could, hypothetically, be due to reduced inflammatory response because of the defect in the Tlr4 gene.
Additional candidate susceptibility genes in mice that may be important for the adjuvant activity of particles have been identified. Ohtsuka et al. (2000b) identified susceptibility loci for alveolar macrophage immune dysfunction induced by inhalation of sulfate-associated carbon particles in C57BL/6J and C3H/HeJ mice. These two mouse strains display two easily distinguishable alveolar macrophage function phenotypes after challenge with particles, in which C57BL/6J is termed responsive (susceptible) and C3H/HeJ is termed resistant. A genome-wide linkage analysis of an intercross (F2) cohort identified significant and suggestive quantitative trait loci on chromosomes 17 and 11. A number of the candidate genes identified on chromosome 17 may be important for the particle-induced effect on allergy-related immune responses. Among these are the gene coding for TNF- and genes coding for mast cell proteases 6 and 7.
These findings in mice indicate that genetic variation in the response to both gaseous and particle pollutants may exist also in human individuals. In several studies, candidate susceptibility genes that may be important for the expression of asthma and allergic diseases have been identified (reviewed in Barnes and Marsh, 1998; Feijen et al., 2000
; Howard et al., 2000
). There are, on the other hand, a scarcity of studies identifying candidate genes that may be important for the effect of air pollution. However, it has been demonstrated in experimental studies that inflammatory and/or lung function responses to ozone and sulfur dioxide differ between asthmatic individuals (Holz et al., 1999
; Winterton et al., 2001
). Further, as mentioned earlier, there may be a synergistic interaction between particle-bound endotoxin and other proinflammatory components of particles (Ning et al., 2000
). CD14 is a high-affinity receptor for LPS expressed on macrophages and monocytes and to a lesser extent on polymorphonuclear neutrophils. CD14 lacks a transmembrane and cytoplasmic domain and is therefore believed not to be directly responsible for transmitting a signal across the plasma membrane. There is increasing evidence that CD14 act cooperatively with Tlr4 in the response to LPS. Thus, CD14 focuses LPS on the cell surface, whereas Tlr4 act as the signal transducer into the cell (reviewed in Beutler, 2000
; Ingalls et al., 1999
). This LPS-mediated activation induces the secretion of several proinflammatory cytokines such as IL-1, IL-6, and TNF-
(Daniels et al., 2000
). Results from human studies indicate that polymorphisms in CD14 and Tlr4 can affect the expression of allergic responses. Koppelman et al. (2001) studied the association of a polymorphism in the CD14 gene with phenotypes of atopy (e.g., total serum IgE levels, intracutaneous skin test, allergic rhinitis) and asthma (e.g., bronchial hyperresponsiveness, physician's diagnosis) in an adult Dutch population. They observed that a 159 C-to-T promoter polymorphism in the CD14 gene may result in expression of a more severe allergic phenotype. This is similar to the findings in reports on human CD14-polymorphism from the Martinez group (Baldini et al., 1999
; Vercelli et al., 2001
). A study by Arbour et al. has provided evidence that mutations in the Tlr4 gene are associated with differences in the LPS responsiveness in humans. However, not all subjects who were hyporesponsive to LPS had mutations in the Tlr4 gene, and not everyone with the Tlr4 mutations was hyporesponsive to inhaled LPS (Arbour et al., 2000
). Arbour et al. therefore suggested that mutations in the Tlr4 gene can act in concert with other genetic changes or acquired factors to influence the complex physiological response to inhaled LPS.
It can be hypothesized that the influence of particulate air pollution on both allergic sensitization, provocation and inflammatory responses, is a result of complex gene-gene interactions and gene-environment interactions, and that polymorphism in the different candidate susceptibility genes for both allergy and environmental components may determine the severity of the allergic phenotype (Fig. 2).
|
![]() |
Concluding Remarks |
---|
The effect of particles on allergic immune responses may differ between individuals, that is particles may have a strong effect only in certain individuals that are genetically susceptible to the influence from particles. The genes in question may determine, for example, the cytokine response to irritative stimuli in general, or may act more specifically on the cellular response to particles or particle-associated components. Thus, gene-environment interactions in the development and manifestations of allergy may include not only gene-allergen interactions, but also gene-particle interactions.
There is considerable evidence that both the physical particle core and adsorbed chemical substances may enhance allergy-related immune responses. The particle core may function as a general "motor," in that particles with widely different chemical compositions have been shown to increase both inflammatory responses and antibody production. Particle-associated components (e.g., chemical substances, allergens, endotoxin) and possible other factors may increase and/or modify the effect from the particle core and steer the response towards a polarized Th1- or Th2-like response.
![]() |
NOTES |
---|
![]() |
REFERENCES |
---|
Anderson, H. R. (1997). Air pollution and trends in asthma. In The Rising Trends in Asthma (D. J. Chadwick and G. Cardew, Eds.), pp. 190207. Wiley, Chichester, UK.
Anderson, K. V. (2000). Toll signaling pathways in the innate immune response. Curr. Opin. Immunol. 12, 1319.[ISI][Medline]
Arbour, N. C., Lorenz, E., Schutte, B. C., Zabner, J., Kline, J. N., Jones, M., Frees, K., Watt, J. L., and Schwartz, D. A. (2000). TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat. Genet. 25, 187191.[ISI][Medline]
Ayres, J. G. (1998). Particle mass or particle numbers? Eur. Respir. Rev. 8, 135138.
Baldini, M., Lohman, I. C., Halonen, M., Erickson, R. P., Holt, P. G., and Martinez, F. D. (1999). A polymorphism in the 5` flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E. Am. J. Respir. Cell Mol. Biol. 20, 976983.
Barnes, K. C., and Marsh, D. G. (1998). The genetics and complexity of allergy and asthma. Immunol. Today 19, 325332.[ISI][Medline]
Becker, S., Soukup, J. M., Gilmour, M. I., and Devlin, R. B. (1996). Stimulation of human and rat alveolar macrophages by urban air particulates: Effects on oxidant radical generation and cytokine production. Toxicol. Appl. Pharmacol. 141, 637648.[ISI][Medline]
Beutler, B. (2000). Tlr4: Central component of the sole mammalian LPS sensor. Curr. Opin. Immunol. 12, 2026.[ISI][Medline]
Boland, S., Bonvallot, V., Fournier, T., Baeza-Squiban, A., Aubier, M., and Marano, F. (2000). Mechanisms of GM-CSF increase by diesel exhaust particles in human airway epithelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 278, L25L32.
Bömmel, H., Li-Weber, M., Serfling, E., and Duschl, A. (2000). The environmental pollutant pyrene induces the production of IL-4. J. Allergy Clin. Immunol. 105, 796802.[ISI][Medline]
Churg, A., Stevens, B., and Wright, J. L. (1998). Comparison of the uptake of fine and ultrafine TiO2 in a tracheal explant system. Am. J. Physiol. 274, L81L86.
Daniels, A. U., Barnes, F. H., Charlebois, S. J., and Smith, R. A. (2000). Macrophage cytokine response to particles and lipopolysaccharide in vitro. J. Biomed. Mater. Res. 49, 469478.[ISI][Medline]
Devalia, J. L., Rusznak, C., Herdman, M. J., Trigg, C. J., Tarraf, H., and Davies, R. J. (1994). Effect of nitrogen dioxide and sulphur dioxide on airway response of mild asthmatic patients to allergen inhalation. Lancet 344, 16681671.[ISI][Medline]
Diaz-Sanchez, D., Garcia, M. P., Wang, M., Jyrala, M., and Saxon, A. (1999). Nasal challenge with diesel exhaust particles can induce sensitization to a neoallergen in the human mucosa. J. Allergy Clin. Immunol. 104, 11831188.[ISI][Medline]
Diaz-Sanchez, D., Penichet-Garcia, M., and Saxon, A. (2000). Diesel exhaust particles directly induce activated mast cells to degranulate and increase histamine levels and symptom severity. J. Allergy Clin. Immunol. 106, 11401146.[ISI][Medline]
Diaz-Sanchez, D., Tsien, A., Fleming, J., and Saxon, A. (1997). Combined diesel exhaust particulate and ragweed allergen challenge markedly enhances human in vivo nasal ragweed-specific IgE and skews cytokine production to a T helper cell 2-type pattern. J. Immunol. 158, 24062413.[Abstract]
Donaldson, K., Stone, V., Gilmour, P. S., Brown, D. M., and MacNee, W. (2000). Ultrafine particles: Mechanisms of lung injury. Phil. Trans. R. Soc. Lond. A 358, 27412749.[ISI]
Dreher, K. L., Jaskot, R. H., Lehmann, J. R., Richards, J. H., McGee, J. K., Ghio, A. J., and Costa, D. L. (1997). Soluble transition metals mediate residual oil fly ash induced acute lung injury. J. Toxicol. Environ. Health 50, 285305.[ISI][Medline]
Driscoll, K. E., Carter, J. M., Hassenbein, D. G., and Howard, B. (1997b). Cytokines and particle-induced inflammatory cell recruitment. Environ. Health Perspect. 105(Suppl.), 11591164.[ISI][Medline]
Driscoll, K. E., Deyo, L. C., Carter, J. M., Howard, B. W., Hassenbein, D. G., and Bertram, T. A. (1997a). Effects of particle exposure and particle-elicited inflammatory cells on mutation in rat alveolar epithelial cells. Carcinogenesis 18, 423430.[Abstract]
Fahy, O., Hammad, H., Sénéchal, S., Pestel, J., Tonnel, A. B., Wallaert, B., and Tsicopoulos, A. (2000). Synergistic effect of diesel organic extracts and allergen Der p 1 on the release of chemokines by peripheral blood mononuclear cells from allergic subjects: Involvement of the map kinase pathway. Am. J. Respir. Cell Mol. Biol. 23, 247254.
Fahy, O., Tsicopoulos, A., Hammad, H., Pestel, J., Tonnel, A. B., and Wallaert, B. (1999). Effects of diesel organic extracts on chemokine production by peripheral blood mononuclear cells. J. Allergy Clin. Immunol. 103, 11151124.[ISI][Medline]
Feijen, M., Gerritsen, J., and Postma, D. S. (2000). Genetics of allergic disease. Br. Med. Bull. 56, 894907.[Abstract]
Finkelstein, J. N., Johnston, C., Barrett, T., and Oberdörster, G. (1997). Particulate-cell interactions and pulmonary cytokine expression. Environ. Health Perspect. 105(Suppl.), 11791182.[ISI][Medline]
Fubini, B. (1997). Surface reactivity in the pathogenic response to particulates. Environ. Health Perspect. 105(Suppl.), 10131020.[ISI][Medline]
Fujieda, S., Diaz-Sanchez, D., and Saxon, A. (1998). Combined nasal challenge with diesel exhaust particles and allergen induces in vivo IgE isotype switching. Am. J. Respir. Cell Mol. Biol. 19, 507512.
Gehr, P., Geiser, M., Hof, V. I., and Schürch, S. (2000). Surfactant-ultrafine particle interactions: what can we learn from PM10 studies. Phil. Trans. R. Soc. Lond. A 358, 27072718.[ISI]
Gerrity, T. R. (1995). Regional deposition of gases and particles in the lung: Implications for mixtures. Toxicology 105, 327334.[ISI][Medline]
Gilmour, M. I., Selgrade, M. J. K., and Lambert, A. L. (2000). Enhanced allergic sensitization in animals exposed to particulate air pollution. Inhal. Toxicol. 12(Suppl.), 373380.[ISI]
Goldsmith, C. A. W., Imrich, A., Danaee, H., Ning, Y. Y., and Kobzik, L. (1998). Analysis of air pollution particulate-mediated oxidant stress in alveolar macrophages. J. Toxicol. Environ. Health A 54, 529545.[ISI][Medline]
Granum, B., Gaarder, P. I., Eikeset, Å., Stensby, B. A., and Løvik, M. (2000b). The adjuvant effect of particlesimportance of genetic background and pre-sensitisation. Int. Arch. Allergy Immunol. 122, 167173.[ISI][Medline]
Granum, B., Gaarder, P. I., Groeng, E. C., Leikvold, R. B., Namork, E., and Løvik, M. (2001a). Fine particles of widely different composition have an adjuvant effect on the production of allergen-specific antibodies. Toxicol. Lett. 118, 171181.[ISI][Medline]
Granum, B., Gaarder, P. I., and Løvik, M. (2000a). IgE adjuvant activity of particleswhat physical characteristics are important? Inhal. Toxicol. 12(Suppl. 3), 365372.[ISI]
Granum, B., Gaarder, P. I., and Løvik, M. (2001b). IgE adjuvant effect caused by particlesimmediate and delayed effects. Toxicology 156, 149159.[ISI][Medline]
Heinrich, J., Hoelscher, B., Wjst, M., Ritz, B., Cyrys, J., and Wichmann, H. E. (1999). Respiratory diseases and allergies in two polluted areas in East Germany. Environ. Health Perspect. 107, 5362.[ISI][Medline]
Heo, Y., Saxon, A., and Hankinson, O. (2001). Effect of diesel exhaust particles and their components on the allergen-specific IgE and IgG1 response in mice. Toxicology 159, 143158.[ISI][Medline]
Holman, C. (1999). Sources of air pollution. In Air Pollution and Health (S. T. Holgate, J. M. Samet, H. S. Koren, and R. L. Maynard, Eds.), pp. 115148. Academic Press, London.
Holz, O., Jörres, R. A., Timm, P., Mücke, M., Richter, K., Koschyk, S., and Magnussen, H. (1999). Ozone-induced airway inflammatory changes differ between individuals and are reproducible. Am. J. Respir. Crit. Care Med. 159, 776784.
Hopkin, J. M. (1997). Mechanisms of enhanced prevalence of asthma and atopy in developed countries. Curr. Opin. Immunol. 9, 788792.[ISI][Medline]
Hoshino, K., Takeuchi, O., Kawai, T., Sanjo, H., Ogawa, T., Takeda, Y., Takeda, K., and Akira, S. (1999). Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J. Immunol. 162, 37493752.
Howard, T. D., Meyers, D. A., and Bleecker, E. R. (2000). Mapping susceptibility genes for asthma and allergy. J. Allergy Clin. Immunol. 105, C477481.
Howarth, P. H. (1998). Is allergy increasing?Early life influences. Clin. Exp. Allergy 28(Suppl.), 27.[ISI][Medline]
Ichinose, T., Takano, H., Miyabara, Y., Yanagisawa, R., and Sagai, M. (1997). Murine strain differences in allergic airway inflammation and immunoglobulin production by a combination of antigen and diesel exhaust particles. Toxicology 122, 183192.[ISI][Medline]
Imrich, A., Ning, Y. Y., and Kobzik, L. (2000). Insoluble components of concentrated air particles mediate alveolar macrophage responses in vitro. Toxicol. Appl. Pharmacol. 167, 140150.[ISI][Medline]
Ingalls, R. R., Heine, H., Lien, E., Yoshimura, A., and Golenbock, D. (1999). Lipopolysaccharide recognition, CD14, and lipopolysaccharide receptors. Infect. Dis. Clin. North Am. 13, 341353.[ISI][Medline]
Jörres, R., Nowak, D., Magnussen, H., Speckin, P., and Koschyk, S. (1996). The effect of ozone exposure on allergen responsiveness in subjects with asthma or rhinitis. Am. J. Respir. Crit. Care Med. 153, 5664.[Abstract]
Kleeberger, S. R. (1995). Genetic susceptibility to ozone exposure. Toxicol. Lett. 8283, 295300.
Kleeberger, S. R., Reddy, S., Zhang, L. Y., and Jedlicka, A. E. (2000). Genetic susceptibility to ozone-induced lung hyperpermeability: Role of toll-like receptor 4. Am. J. Respir. Cell Mol. Biol. 22, 620627.
Knox, R. B., Suphioglu, C., Taylor, P., Desai, R., Watson, H. C., Peng, J. L., and Bursill, L. A. (1997). Major grass pollen allergen Lol p 1 binds to diesel exhaust particles: implications for asthma and air pollution. Clin. Exp. Allergy 27, 246251.[ISI][Medline]
Kobzik, L. (1995). Lung macrophage uptake of unopsonized environmental particulates. Role of scavenger-type receptors. J. Immunol. 155, 367376.[Abstract]
Kobzik, L., Huang, S., Paulauskis, J. D., and Godleski, J. J. (1993). Particle opsonization and lung macrophage cytokine response. In vitro and in vivo analysis. J. Immunol. 151, 27532759.
Koppelman, G. H., Reijmerink, N. E., Stine, O. C., Howard, T. D., Whittaker, P. A., Meyers, D. A., Postma, D. S., and Bleecker, E. R. (2001). Association of a promoter polymorphism of the CD14 gene and atopy. Am. J. Respir. Crit. Care Med. 163, 965969.
Kurup, V. P., Seymour, B. W. P., Choi, H., and Coffman, R. L. (1994). Particulate Aspergillus fumigatus antigens elicit a TH2 response in BALB/c mice. J. Allergy Clin. Immunol. 93, 10131020.[ISI][Medline]
Lambert, A. L., Dong, W., Selgrade, M. K., and Gilmour, M. I. (2000). Enhanced allergic sensitization by residual oil fly ash particles is mediated by soluble metal constituents. Toxicol. Appl. Pharmacol. 165, 8493.[ISI][Medline]
Lambert, A. L., Dong, W., Winsett, D. W., Selgrade, M. K., and Gilmour, M. I. (1999). Residual oil fly ash exposure enhances allergic sensitization to house dust mite. Toxicol. Appl. Pharmacol. 158, 269277.[ISI][Medline]
Li, X. Y., Gilmour, P. S., Donaldson, K., and MacNee, W. (1997). In vivo and in vitro proinflammatory effects of particulate air pollution (PM10). Environ. Health Perspect. 105(Suppl.), 12791283.[ISI][Medline]
Løvik, M., Høgseth, A. K., Gaarder, P. I., Hagemann, R., and Eide, I. (1997). Diesel exhaust particles and carbon black have adjuvant activity on the local lymph node response and systemic IgE production to ovalbumin. Toxicology 121, 165178.[ISI][Medline]
Miyabara, Y., Yanagisawa, R., Shimojo, N., Takano, H., Lim, H. B., Ichinose, T., and Sagai, M. (1998). Murine strain differences in airway inflammation caused by diesel exhaust particles. Eur. Respir. J. 11, 291298.
Molfino, N. A., Wright, S. C., Katz, I., Tarlo, S., Silverman, F., McClean, T. A., Szalai, J. P., Raizenne, M., Slutsky, A. S., and Zamel, N. (1991). Effect of low concentrations of ozone on inhaled allergen responses in asthmatic subjects. Lancet 338, 199203.[ISI][Medline]
Monn, C. and Becker, S. (1999). Cytotoxicity and induction of proinflammatory cytokines from human monocytes exposed to fine (PM2.5) and coarse particles (PM102.5) in outdoor and indoor air. Toxicol. Appl. Pharmacol. 155, 245252.[ISI][Medline]
Nel, A. E., Diaz-Sanchez, D., Ng, D., Hiura, T., and Saxon, A. (1998). Enhancement of allergic inflammation by the interaction between diesel exhaust particles and the immune system. J. Allergy Clin. Immunol. 102, 539554.[ISI][Medline]
Nicolai, T. (1997). Epidemiology of pollution-induced airway disease: Urban/rural differences in East and West Germany. Allergy 52(Suppl.), 2629.
Nightingale, J. A., Rogers, D. F., and Barnes, P. J. (1999). Effect of inhaled ozone on exhaled nitric oxide, pulmonary function, and induced sputum in normal and asthmatic subjects. Thorax 54, 10611069.
Ning, Y. Y., Imrich, A., Goldsmith, C. A., Qin, G., and Kobzik, L. (2000). Alveolar macrophage cytokine production in response to air particles in vitro: Role of endotoxin. J. Toxicol. Environ. Health A 59, 165180.[ISI][Medline]
Norris, G., YoungPong, S. N., Koenig, J. Q., Larson, T. V., Sheppard, L., and Stout, J. W. (1999). An association between fine particles and asthma emergency department visits for children in Seattle. Environ. Health Perspect. 107, 489493.[ISI][Medline]
Oberdörster, G. (2000). Toxicology of ultrafine particles : In vivo studies. Phil. Trans. R. Soc. Lond. A 358, 27192740.[ISI]
Oberdörster, G., Ferin, J., Gelein, R., Soderholm, S. C., and Finkelstein, J. (1992). Role of the alveolar macrophage in lung injury: Studies with ultrafine particles. Environ. Health Perspect. 97, 193199.[ISI][Medline]
Ohtsuka, Y., Brunson, K. J., Jedlicka, A. E., Mitzner, W., Clarke, R. W., Zhang, L. Y., Eleff, S. M., and Kleeberger, S. R. (2000b). Genetic linkage analysis of susceptibility to particle exposure in mice. Am. J. Respir. Cell Mol. Biol. 22, 574581.
Ohtsuka, Y., Clarke, R. W., Mitzner, W., Brunson, K., Jakab, G. J., and Kleeberger, S. R. (2000a). Interstrain variation in murine susceptibility to inhaled acid-coated particles. Am. J. Physiol. Lung Cell. Mol. Physiol. 278, L469L476.
Ormstad, H. (2000). Suspended particulate matter in indoor air: Adjuvants and allergen carriers. Toxicology 152, 5368.[ISI][Medline]
Ormstad, H., Gaarder, P. I., and Johansen, B. V. (1997). Quantification and characterisation of suspended particulate matter in indoor air. Sci. Tot. Environ. 193, 185196.[ISI]
Palecanda, A., Paulauskis, J., Al-Mutairi, E., Imrich, A., Qin, G., Suzuki, H., Kodama, T., Tryggvason, K., Koziel, H., and Kobzik, L. (1999). Role of the scavenger receptor MARCO in alveolar macrophage binding of unopsonized environmental particles. J. Exp. Med. 189, 14971506.
Pauluhn, J., Thiel, A., Emura, M., and Mohr, U. (2000). Respiratory sensitization to diphenyl-methane-4,4`-diisocyanate (MDI) in guinea pigs: Impact of particle size on induction and elicitation of response. Tox. Sci. 56, 105113.[ISI]
Penttinen, P., Timonen, K. L., Tiittanen, P., Mirme, A., Ruuskanen, J., and Pekkanen, J. (2001). Ultrafine particles in urban air and respiratory health among adult asthmatics. Eur. Respir. J. 17, 428435.
Peters, A., Wichmann, H. E., Tuch, T., Heinrich, J., and Heyder, J. (1997). Respiratory effects are associated with the number of ultrafine particles. Am. J. Respir. Crit. Care Med. 155, 13761383.[Abstract]
Poltorak, A., He, X., Smirnova, I., Liu, M. Y., Van Huffel, C., Du, X., Birdwell, D., Alejos, E., Silva, M., Galanos, C., Freudenberg, M., Ricciardi-Castagnoli, P., Layton, B., and Beutler, B. (1998). Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: Mutations in Tlr4 gene. Science 282, 20852088.
Pope, C. A. (2000). Epidemiology of fine particulate air pollution and human health: Biologic mechanisms and who's at risk? Environ. Health Perspect. 108(Suppl.), 713723.[ISI][Medline]
Quay, J. L., Reed, W., Samet, J., and Devlin, R. B. (1998). Air pollution particles induce IL-6 gene expression in human airway epithelial cells via NF-B activation. Am. J. Respir. Cell Mol. Biol. 19, 98106.
Salvaggio J. E. (1994). Inhaled particles and respiratory disease. J. Allergy Clin. Immunol. 94, 304309.[ISI][Medline]
Salvi, S. and Holgate, S. T. (1999). Mechanisms of particulate matter toxicity. Clin. Exp. Allergy 29, 11871194.[ISI][Medline]
Schlesinger, R. B. (1995). Interaction of gaseous and particulate pollutants in the respiratory tract: Mechanisms and modulators. Toxicology 105, 315325.[ISI][Medline]
Schwartz, J., and Neas, L. M. (2000). Fine particles are more strongly associated than coarse particles with acute respiratory health effects in schoolchildren. Epidemiology 11, 610.[ISI][Medline]
Schwartz, J., Norris, G., Larson, T., Sheppard, L., Claiborne, C., and Koenig, J. (1999). Episodes of high coarse particle concentrations are not associated with increased mortality. Environ. Health Perspect. 107, 339342.[ISI][Medline]
Seaton, A., MacNee, W., Donaldson, K., and Godden, D. (1995). Particulate air pollution and acute health effects. Lancet 345, 176178.[ISI][Medline]
Siegel, T. D., Al-Humadi, N. H., Nelson, E. R., Lewis, D. M., and Hubbs, A. F. (1997). Adjuvant effect of respiratory irritation on pulmonary allergic sensitization: Time and site dependency. Toxicol. Appl. Pharmacol. 144, 356362.[ISI][Medline]
Sjögren, M., Li, H., Banner, C., Rafter, J., Westerholm, R., and Rannug, U. (1996). Influence of physical and chemical characteristics of diesel fuels and exhaust emissions on biological effects of particle extracts: A multivariate statistical analysis of ten diesel fuels. Chem. Res. Toxicol. 9, 197207.[ISI][Medline]
Smith, K. R., Veranth, J. M., Hu, A. A., Lighty, J. S., and Aust, A. E. (2000). Interleukin-8 levels in human lung epithelial cells are increased in response to coal fly ash and vary with the bioavailability of iron, as a function of particle size and source of coal. Chem. Res. Toxicol. 13, 118125.[ISI][Medline]
Stone, V., Brown, D. M., Watt, N., Wilson, M., Donaldson, K., Ritchie, H., and MacNee, W. (2000). Ultrafine particle-mediated activation of macrophages: Intracellular calcium signalling and oxidative stress. Inhal. Tox. 12(Suppl.), 345351.[ISI]
Studnicka, M., Hackl, E., Pischinger, J., Fangmeyer, C., Haschke, N., Kühr, J., Urbanek, R., Neumann, M., and Frischer, T. (1997). Traffic-related NO2 and the prevalence of asthma and respiratory symptoms in seven year olds. Eur. Respir. J. 10, 22752278.
Suzuki, T., Kanoh, T., Kanbayashi, M., Todome, Y., and Ohkuni, H. (1993). The adjuvant activity of pyrene in diesel exhaust on IgE antibody production in mice. Arerugi 42, 963968.[Medline]
Takafuji, S., Suzuki, S., Koizumi, K., Tadokoro, K., Ohashi, H., Muranaka, M., and Miyamoto, T. (1989). Enhancing effect of suspended particulate matter on the IgE antibody production in mice. Int. Arch. Allergy Appl. Immunol. 90, 17.
Takenaka, H., Zhang, K., Diaz-Sanchez, D., Tsien, A., and Saxon, A. (1995). Enhanced human IgE production results from exposure to the aromatic hydrocarbons from diesel exhaust: Direct effects on B-cell IgE production. J. Allergy Clin. Immunol. 95, 103115.[ISI][Medline]
Terada, N., Maesako, K., Hiruma, K., Hamano, N., Houki, G., Konno, A., Ikeda, T., and Sai, M. (1997). Diesel exhaust particulates enhance eosinophil adhesion to nasal epithelial cells and cause degranulation. Int. Arch. Allergy Immunol. 114, 167174.[ISI][Medline]
Timonen, K. L., and Pekkanen, J. (1997). Air pollution and respiratory health among children with asthmatic or cough symptoms. Am. J. Respir. Crit. Care Med. 156, 546552.
Tsien, A., Diaz-Sanchez, D., Ma, J., and Saxon, A. (1997). The organic component of diesel exhaust particles and phenanthrene, a major polyaromatic hydrocarbon constituent, enhances IgE production by IgE-secreting EBV-transformed human B cells in vitro. Toxicol. Appl. Pharmacol. 142, 256263.[ISI][Medline]
van der Zee, S., Hoek, G., Boezen, H. M., Schouten, J. P., van Wijnen, J. H., and Brunekreef, B. (1999). Acute effects of urban air pollution on respiratory health of children with and without chronic respiratory symptoms. Occup. Environ. Med. 56, 802812.[Abstract]
van Zijverden, M. (2001). Adjuvant Activity of Particulate Air Pollutants Thesis (ISBN 9039326703), University of Utrecht, Utrecht.
van Zijverden, M., van der Pijl, A., Bol, M., van Pinxteren, F. A., de Haar, C., Penninks, A. H., van Loveren, H., and Pieters, R. (2000). Diesel exhaust, carbon black, and silica particles display distinct Th1/Th2 modulating activity. Toxicol. Appl. Pharmacol. 168, 131139.[ISI][Medline]
Vercelli, D., Baldini, M., and Martinez, F. (2001). The monocyte/IgE connection: May polymorphisms in the CD14 gene teach us about IgE regulation? Int. Arch. Allergy Immunol. 124, 2024.[ISI][Medline]
Wang, M., Saxon, A., and Diaz-Sanchez, D. (1999). Early IL-4 production driving Th2 differentiation in a human in vivo allergic model is mast cell derived. Clin. Immunol. 90, 4754.[ISI][Medline]
Wichmann, H. E., and Peters, A. (2000). Epidemiological evidence for the effects of ultrafine particle exposure. Phil. Trans. R. Soc. Lond. A 358, 27512769.[ISI]
Williams, M. L. (1999). Patterns of air pollution in developed countries. In Air Pollution and Health (S. T. Holgate, J. M. Samet, H. S. Koren, and R. L. Maynard, Eds.), pp. 83104. Academic Press, London.
Winterton, D. L., Kaufman, J., Keener, C. V., Quigley, S., Farin, F. M., Williams, P. V., and Koenig, J. Q. (2001). Genetic polymorphisms as biomarkers of sensitivity to inhaled sulfur dioxide in subjects with asthma. Ann. Allergy Asthma Immunol. 86, 232238.[ISI][Medline]
Wyler, C., Braun-Fahrländer, C., Künzli, N., Schindler, C., Ackermann-Liebrich, U., Perruchoud, A. P., Leuenberger, P., and Wüthrich, B. (2000). Exposure to motor vehicle traffic and allergic sensitization. The Swiss Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) Team. Epidemiology 11, 450456.[ISI][Medline]