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Environmental
Health Perspectives Supplements Volume 110, Number 4, August 2002
Pollutants and Asthma: Role of Air Toxics
David B. Peden
Department of Pediatrics, Division of Allergy, Immunology and Environmental
Medicine, and Center for Environmental Medicine and Lung Biology, School
of Medicine, University of North Carolina at Chapel Hill, Chapel Hill,
North Carolina, USA
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Full Article in PDF
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Abstract
Asthma is a disease characterized by intermittent bronchoconstriction
due to increased airway reactivity to both allergic and nonallergic stimuli.
Most asthma exacerbations that result in hospitalization are associated
with viral upper respiratory tract infections. Such infections typically
induce T-helper type 1 (TH1) responses in the airway, involving
activation of nuclear factor-kappaB (NF- B).
However, a more recently appreciated cause of asthma exacerbation is exposure
to pollutants, including ozone and various components of particulate matter
(PM), including transition metals, diesel exhaust, and biologicals such
as endotoxin. Although the role of air toxics in asthma pathogenesis remains
incompletely examined, many components of PM that are active exacerbants
of asthma are also prominent air toxics (metal ions and organic residues).
These agents have been observed to activate NF-B.
Reviewed in this article are the actions of specific air pollutants on
airway inflammation in humans and potential common response pathways for
ozone, PM, and several air toxics. Key words: air toxics, asthma,
exacerbation, TH1, TH2. Environ Health Perspect
110(suppl 4):565-568 (2002).
http://ehpnet1.niehs.nih.gov/docs/2002/suppl-4/565-568peden/abstract.html
This article is part of the monograph Environmental
Air Toxics: Role in Asthma Occurrence?
Address correspondence to D.B. Peden, Center for Environmental
Medicine and Lung Biology, 104 Mason Farm Rd., CB #7310, School of Medicine,
University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7310
USA. Telephone: (919) 962-0126. Fax: (919) 966-9863. E-mail: peden@med.unc.edu
Received 20 November 2001; accepted 4 March 2002.
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Introduction
Asthma is a disease characterized by intermittent bronchoconstriction due to
increased airway reactivity to both allergic and nonallergic stimuli. Underlying
these phenomena is a chronic, eosinophilic airway inflammation. Perhaps the
most common and significant risk factor for development of asthma in children
is induction of an immunoglobulin E (IgE; allergic) response against indoor
allergens (1,2). However, nonallergic stimuli, which do not directly
interact with IgE, are common causes of asthma exacerbation. Asthmatic individuals
have been identified as a population that is especially sensitive to the effect
of ambient air pollutants. Although pollutants might enhance IgE-mediated chronic
inflammation via T-helper type 2 (TH2) processes, they more likely
induce exacerbation of asthma. Indeed, many pollutants associated with asthma
exacerbation induce neutrophilic inflammation in nonallergic subjects.
Viral infections and pollutants typically induce TH1-type responses
in the airway, involving activation of nuclear factor-kappaB (NF-B).
Yet in asthmatic individuals, these processes may also exacerbate eosinophilic
inflammation. This observation suggests that chronic allergic airway inflammation
may modify the response to nonallergic stimuli, thus magnifying the impact of
such agents. The agents more commonly examined for asthma exacerbation are criteria
air pollutants, such as ozone and particulate matter (PM). The role of air toxics
in asthma has not been vigorously examined, despite the frequency in which they
are encountered. However, many of the agents identified in PM can also be considered
air toxics and demonstrate that this important class of pollutants likely has
a significant impact on asthma. Reviewed in this article are studies that exemplify
the impact of ozone, particulates, and toxic components of particulates on asthma.
Ozone and Asthma
Epidemiologic studies clearly demonstrate that increases in ambient air ozone
are linked with increased occurrence of acute asthma exacerbations. Markers
for such events, including increased hospitalizations and emergency room visits,
are usually noted 24 hr after the increase in inflammation, suggesting that
inflammation may play a role in such events (3-8). During the 1996
Summer Olympic games, an effort to decrease automobile traffic in Atlanta, Georgia,
resulted in decreases in ambient ozone levels. Asthma exacerbations decreased
as well, again demonstrating a link between ambient ozone levels and asthma
exacerbations (9).
Exposure to ozone is known to induce increases in airway inflammation (10-12).
In asthmatic individuals, the effect of ozone exposure is exaggerated, resulting
in either increased neutrophilic inflammation (13-15) or an augmentation
of eosinophilic inflammation (16,17). In addition to asthmatic individuals
being more sensitive to ozone per se, ozone appears to augment both the immediate
and late-phase response to allergens. Initially, Molfino and colleagues (18)
described increased sensitivity to inhaled allergen after exposure to a relatively
low level of ozone (0.12 ppm for 2 hr). Although other studies examining this
dose of ozone do not reveal such an effect (19), higher levels of ozone
clearly enhance the immediate effect of inhaled allergen on bronchoconstriction
(20,21). Nasal challenge studies also demonstrate that ozone exposure
might enhance the late-phase response to allergen (22,23). Thus, persons
with allergic inflammation of the airway are differentially susceptible to the
effect of ozone, an agent that in nonallergic subjects induces neutrophilic
inflammation (24-26).
Toxic Components of Particulate Matter and Asthma
Particulate matter is an important pollutant and is associated with increased
morbidity and mortality (24,27-30). PM is also associated with increased
disease severity in asthma (31-33). Indeed, increased admissions
to hospital for asthma are linked to increased PM exposure, as are decreased
peak flow measurements in children (31,34,35). An interesting study in
the Utah Valley, Utah, showed a marked decrease in admissions to hospital for
asthma and respiratory tract illnesses when a local steel mill was closed, with
subsequent increase in such events when it reopened (32,33).
Although a clear mechanism for the action of PM in asthma exacerbation has
not been identified, studies with model pollutants, including residual oil fly
ash (ROFA) and Utah Valley dust (UVD) particles, suggest that PM enhances TH1-like,
neutrophilic inflammation. Many of the active agents in various PM species also
fall into the broad category of air toxics. ROFA is a potent proinflammatory
agent that has oxidant activity, likely mediated by vanadium species and nickel
(36-40). UVD is another PM in which its biological activity is associated
with metal content and oxidant character (41-44). Diesel exhaust
particles (DEPs) contain polyaromatic aromatic hydrocarbons. Each of these PM
components can be considered air toxics. The specific impact of these agents
in humans is outlined below.
ROFA particles have been shown in vitro to affect prostaglandin metabolism
and induce cytokine production in epithelial cells (45-48). Animal
studies have also demonstrated that ROFA is associated with increased neutrophilic
airway inflammation (49). Animal studies also show that ROFA can exacerbate
allergic inflammation in mice and that it enhances sensitization to allergens
in a rat model (50-52).
UVD has also been shown to induce airway inflammation in animal studies and
to induce proinflammatory changes in epithelial cells in vitro. Perhaps
most intriguing is the decreased effect of UVD particles collected during the
time that the local steel mill was closed (44,53,54). In humans, instillation
of extracts made from UVD collected during the years the mill was open versus
those collected when it was closed was consistent with animal and in vitro
studies demonstrating that influx of neutrophils was associated with dust
collected during active years and was blunted in extracts made from UVD collected
during a year the mill was closed (42). Humans exposed to concentrated
ambient air particles also show subtle evidence of increased respiratory tract
inflammation (43). Thus, it seems clear that PM can induce inflammation,
not unlike ozone. This proinflammatory effect of PM may account for its ability
to exacerbate asthma.
Diesel exhaust and resultant DEPs are also an interesting component of PM.
Human challenge studies with diesel exhaust reveal increases in airway inflammation,
including increases in airway neutrophils and mast cells (55-57).
Diesel exhaust exposure has been shown to enhance nonspecific airway reactivity
in asthmatic individuals as well (58). DEPs, in nasal instillation studies,
have been shown to induce increases in total and antigen-specific IgE, increase
cellular response to nasally applied allergen, and enhance production of TH2
cytokines such as interleukin (IL)-4 and IL-13 (59-64). DEPs also
enhance sensitization to a neoantigen, keyhole limpet hemocyanin (KLH), such
that antigen-specific IgE against KLH is generated (65). In vitro
studies suggest that the active agents in DEPs that affect IgE production
are polyaromatic hydrocarbons (66). Animal studies also demonstrate that
polyaromatic hydrocarbons enhance IgE production in animals via actions on B
lymphocytes (67). Taken together, these data suggest that diesel particles
and DEPs may play a significant role not only in asthma exacerbation but also
in TH2 inflammation via the actions of polyaromatic hydrocarbons
on B lymphocytes.
Endotoxin and Asthma
Endotoxin is a common component of PM and is also encountered in domestic
(68,69) and occupational settings (70,71). A number of studies
have demonstrated increased airway symptoms in workers who encounter high levels
of endotoxin in the workplace (70,72-77). Endotoxin is known to
stimulate innate immune responses that have a TH1-type character
(neutrophilic inflammation, lack of IL-4 and IL-13). Endotoxin induces neutrophilic
airway inflammation in nonallergic, nonasthmatic volunteers (78-85).
This agent also has been found to enhance nonspecific airway reactivity in asthmatic
individuals (86-88).
Recent studies suggest that endotoxin may be a factor in increasing asthma
morbidity and wheeze (89,90). Conversely, exposure to endotoxin at a
very young age may protect against development of allergic responses to allergens
(68). However, in persons with ongoing allergic inflammation, the degree
of allergic inflammation, as determined by enumeration of airway eosinophils,
appears to correlate with increased response to endotoxin (91). Allergen
challenge enhances expression of CD14, an important endotoxin receptor, in asthmatic
individuals (92-94) and enhances nasal inflammatory responses to
endotoxin, including increases in neutrophils and eosinophils (95). Treatment
of asthmatic individuals with corticosteroids blunts response to endotoxin and
decreases CD14 expression in the airway (96). Taken together, these observations
suggest that allergic inflammation modifies the response to endotoxin, enhancing
the impact of this agent on asthma symptoms and morbidity.
Potential Common Mechanisms
Each of the pollutants outlined above can induce neutrophilic inflammation.
NF-B
is a key aspect of such activation. Ozone has been shown to activate NF-B
in epithelial cells (97) and to induce this transcription factor in
vivo in animal respiratory tissue (98,99). This activation is blunted
by treatment with corticosteroids. Metal ions and diesel exhaust also appear
to induce NF-B
(48). Endotoxin is a classic stimulus for NF-B
activation (100). Signal transduction of endotoxin after it binds to
the CD14 cell surface depends on interaction with the toll-like receptor (TLR)
4. An intriguing linkage between TLR 4, a key receptor for endotoxin, and the
action of ozone suggests that TLR4 (or other similar membrane-spanning molecules)
may mediate the ultimate activation of NF-B
by ozone as well (101,102). Future studies on the effect of environmental
stimuli in exacerbating asthma should examine potential common response elements
such as the TLR 4, which may mediate the effect of a number of apparently disparate
pollutants.
Summary
This article has outlined some of the examined effects of ozone, PM, and biological
agents on asthma exacerbation. The role of air toxics, an important and commonly
encountered air pollutant, in asthma has not been aggressively studied. Its
potential importance is demonstrated by studies of PM in which the active agents
are biologically active metal ions and organic residues, both of which can be
considered air toxics. This class of compounds may have significant effects
on asthma, especially modulating immune function, as demonstrated by the role
of polyaromatic hydrocarbons from diesel exhaust in IgE production. Examination
of the effect of air toxics in asthma as they exist either in gas, vapor, or
particulate form warrants further study.
References and Notes
1. Busse WW, Lemanske RF Jr. Asthma. N Engl J Med 344:350-362
(2001).
2. Gern JE, Lemanske RF Jr, Busse WW. Early life origins
of asthma. J Clin Invest 104:837-843 (1999).
3. Ostro B, Lipsett M, Mann J, Braxton-Owens H, White
M. Air pollution and exacerbation of asthma in African-American children in
Los Angeles. Epidemiology 12:200-208 (2001).
4. Tolbert PE, Mulholland JA, MacIntosh DL, Xu F, Daniels
D, Devine OJ, Carlin BP, Klein M, Dorley J, Butler AJ, et al. Air quality and
pediatric emergency room visits for asthma in Atlanta, Georgia, USA. Am J Epidemiol
151:798-810 (2000).
5. Romieu I, Meneses F, Ruiz S, Huerta J, Sienra JJ,
White M, Etzel R, Hernandez M. Effects of intermittent ozone exposure on peak
expiratory flow and respiratory symptoms among asthmatic children in Mexico
City. Arch Environ Health 52:368-376 (1997).
6. Romieu I, Meneses F, Ruiz S, Sienra JJ, Huerta J,
White MC, Etzel RA. Effects of air pollution on the respiratory health of asthmatic
children living in Mexico City. Am J Respir Crit Care Med 154:300-307 (1996).
7. Romieu I, Meneses F, Sienra-Monge JJ, Huerta J, Ruiz
VS, White MC, Etzel RA, Hernandez-Avila M. Effects of urban air pollutants on
emergency visits for childhood asthma in Mexico City. Am J Epidemiol 141:546-553
(1995).
8. White MC, Etzel RA, Wilcox WD, Lloyd C. Exacerbations
of childhood asthma and ozone pollution in Atlanta. Environ Res 65:56-68
(1994).
9. Perkins RC, Scheule RK, Hamilton R, Gomes G, Freidman
G, Holian A. Human alveolar macrophage cytokine release in response to in vitro
and in vivo asbestos exposure. Exp Lung Res 19:55-65 (1993).
10. Koren HS. Environmental risk factors in atopic asthma.
Int Arch Allergy Immunol 113:65-68 (1997).
11. Koren HS. Associations between criteria air pollutants
and asthma. Environ Health Perspect 103(suppl 6):235-242 (1995).
12. Koren HS, Bromberg PA. Respiratory responses of asthmatics
to ozone. Int Arch Allergy Immunol 107:236-238 (1995).
13. Scannell C, Chen L, Aris RM, Tager I, Christian D,
Ferrando R, Welch B, Kelly T, Balmes JR. Greater ozone-induced inflammatory
responses in subjects with asthma. Am J Respir Crit Care Med 154:24-29
(1996).
14. Balmes JR, Aris RM, Chen LL, Scannell C, Tager IB,
Finkbeiner W, Christian D, Kelly T, Hearne PQ, Ferrando R, et al. Effects of
ozone on normal and potentially sensitive human subjects. Part I: Airway inflammation
and responsiveness to ozone in normal and asthmatic subjects. Res Rep Health
Eff Inst 78:1-37 (1997).
15. Basha MA, Gross KB, Gwizdala CJ, Haidar AH, Popovich
J Jr. Bronchoalveolar lavage neutrophilia in asthmatic and healthy volunteers
after controlled exposure to ozone and filtered purified air. Chest 106:1757-1765
(1994).
16. Peden DB, Boehlecke B, Horstman D, Devlin R. Prolonged
acute exposure to 0.16 ppm ozone induces eosinophilic airway inflammation in
asthmatic subjects with allergies. J Allergy Clin Immunol 100:802-808 (1997).
17. Frampton MW, Balmes JR, Cox C, Krein PM, Speers DM,
Tsai Y, Utell MJ. Effects of ozone on normal and potentially sensitive human
subjects. Part III: Mediators of inflammation in bronchoalveolar lavage fluid
from nonsmokers, smokers, and asthmatic subjects exposed to ozone: a collaborative
study. Res Rep Health Eff Inst 78:73-79 (1997).
18. Molfino NA, Wright SC, Katz I, Tarlo S, Silverman
F, McClean PA, Szalai JP, Raizenne M, Slutsky AS, Zamel N. Effect of low concentrations
of ozone on inhaled allergen responses in asthmatic subjects. Lancet 338:199-203
(1991).
19. Ball BA, Folinsbee LJ, Peden DB, Kehrl HR. Allergen
bronchoprovocation of patients with mild allergic asthma after ozone exposure.
J Allergy Clin Immunol 98:563-572 (1996).
20. Jorres R, Nowak D, Magnussen H. The effect of ozone
exposure on allergen responsiveness in subjects with asthma or rhinitis. Am
J Respir Crit Care Med 153:56-64 (1996).
21. Kehrl HR, Peden DB, Ball B, Folinsbee LJ, Horstman
D. Increased specific airway reactivity of persons with mild allergic asthma
after 7.6 hours of exposure to 0.16 ppm ozone. J Allergy Clin Immunol 104:1198-1204
(1999).
22. Bascom R, Naclerio RM, Fitzgerald TK, Kagey-Sobotka
A, Proud D. Effect of ozone inhalation on the response to nasal challenge with
antigen of allergic subjects. Am Rev Respir Dis 142:594-601 (1990).
23. Peden DB, Setzer RW Jr, Devlin RB. Ozone exposure
has both a priming effect on allergen-induced responses and an intrinsic inflammatory
action in the nasal airways of perennially allergic asthmatics. Am J Respir
Crit Care Med 151:1336-1345 (1995).
24. Committee of the Environmental and Occupational Health
Assembly of the American Thoracic Society. Health effects of outdoor air pollution.
Am J Respir Crit Care Med 153:3-50 (1996).
25. Koren HS, Devlin RB, Graham DE, Mann R, McGee MP,
Horstman DH, Kozumbo WJ, Becker S, House DE, McDonnell WF. Ozone-induced inflammation
in the lower airways of human subjects. Am Rev Respir Dis 139:407-415 (1989).
26. Devlin RB, McDonnell WF, Mann R, Becker S, House
DE, Schreinemachers D, Koren HS. Exposure of humans to ambient levels of ozone
for 6.6 hours causes cellular and biochemical changes in the lung. Am J Respir
Cell Mol Biol 4:72-81 (1991).
27. Dockery DW. Epidemiologic evidence of cardiovascular
effects of particulate air pollution. Environ Health Perspect 109(suppl 4):483-486
(2001).
28. Peters A, Dockery DW, Muller JE, Mittleman MA. Increased
particulate air pollution and the triggering of myocardial infarction. Circulation
103:2810-2815 (2001).
29. Samet JM, Zeger SL, Dominici F, Curriero F, Coursac
I, Dockery DW, Schwartz J, Zanobetti A. The National Morbidity, Mortality, and
Air Pollution Study. Part II: Morbidity and mortality from air pollution in
the United States. Res Rep Health Eff Inst 94:5-70 (2000).
30. Dockery DW, Schwartz J. Particulate air pollution
and mortality: more than the Philadelphia story. Epidemiology 6:629-632
(1995).
31. Hoek G, Dockery DW, Pope A, Neas L, Roemer W, Brunekreef
B. Association between PM10 and decrements in peak expiratory flow
rates in children: reanalysis of data from five panel studies. Eur Respir J
11:1307-1311 (1998).
32. Pope CA III. Respiratory hospital admissions associated
with PM10 pollution in Utah, Salt Lake, and Cache valleys. Arch Environ
Health 46:90-97 (1991).
33. Pope CA III. Respiratory disease associated with
community air pollution and a steel mill, Utah Valley. Am J Public Health 79:623-628
(1989).
34. Guo YL, Lin YC, Sung FC, Huang SL, Ko YC, Lai JS,
Su HJ, Shaw CK, Lin RS, Dockery DW. Climate, traffic-related air pollutants,
and asthma prevalence in middle-school children in Taiwan. Environ Health Perspect
107:1001-1006 (1999).
35. Peters A, Dockery DW, Heinrich J, Wichmann HE. Short-term
effects of particulate air pollution on respiratory morbidity in asthmatic children.
Eur Respir J 10:872-879 (1997).
36. Dye JA, Adler KB, Richards JH, Dreher KL. Epithelial
injury induced by exposure to residual oil fly-ash particles: role of reactive
oxygen species? Am J Respir Cell Mol Biol 17:625-633 (1997).
37. Gavett SH, Madison SL, Dreher KL, Winsett DW, McGee
JK, Costa DL. Metal and sulfate composition of residual oil fly ash determines
airway hyperreactivity and lung injury in rats. Environ Res 72:162-172
(1997).
38. Kodavanti UP, Schladweiler MC, Richards JR, Costa
DL. Acute lung injury from intratracheal exposure to fugitive residual oil fly
ash and its constituent metals in normo- and spontaneously hypertensive rats.
Inhal Toxicol 13:37-54 (2001).
39. Galbreath KC, Toman DL, Zygarlicke CJ, Huggins FE,
Huffman GP, Wong JL. Nickel speciation of residual oil fly ash and ambient particulate
matter using X-ray absorption spectroscopy. J Air Waste Manag Assoc 50:1876-1886
(2000).
40. Ghio AJ, Silbajoris R, Carson JL, Samet JM. Biologic
effects of oil fly ash. Environ Health Perspect 110(suppl 1):89-94 (2002).
41. Soukup JM, Ghio AJ, Becker S. Soluble components
of Utah Valley particulate pollution alter alveolar macrophage function in vivo
and in vitro. Inhal Toxicol 12:401-414 (2000).
42. Ghio AJ, Devlin RB. Inflammatory lung injury after
bronchial instillation of air pollution particles. Am J Respir Crit Care Med
164:704-708 (2001).
43. Ghio AJ, Kim C, Devlin RB. Concentrated ambient air
particles induce mild pulmonary inflammation in healthy human volunteers. Am
J Respir Crit Care Med 162:981-988 (2000).
44. Frampton MW, Ghio AJ, Samet JM, Carson JL, Carter
JD, Devlin RB. Effects of aqueous extracts of PM(10) filters from the Utah Valley
on human airway epithelial cells. Am J Physiol 277:L960-L967 (1999).
45. Samet JM, Graves LM, Quay J, Dailey LA, Devlin RB,
Ghio AJ, Wu W, Bromberg PA, Reed W. Activation of MAPKs in human bronchial epithelial
cells exposed to metals. Am J Physiol 275:L551-L558 (1998).
46. Silbajoris R, Ghio AJ, Samet JM, Jaskot R, Dreher
KL, Brighton LE. In vivo and in vitro correlation of pulmonary MAP kinase activation
following metallic exposure. Inhal Toxicol 12:453-468 (2000).
47. Wu W, Graves LM, Jaspers I, Devlin RB, Reed W, Samet
JM. Activation of the EGF receptor signaling pathway in human airway epithelial
cells exposed to metals. Am J Physiol 277:L924-L931 (1999).
48. Quay JL, Reed W, Samet J, Devlin RB. Air pollution
particles induce IL-6 gene expression in human airway epithelial cells via NF-kappaB
activation. Am J Respir Cell Mol Biol 19:98-106 (1998).
49. Costa DL, Dreher KL. Bioavailable transition metals
in particulate matter mediate cardiopulmonary injury in healthy and compromised
animal models. Environ Health Perspect 105(suppl 5):1053-1060 (1997).
50. Gavett SH, Madison SL, Stevens MA, Costa DL. Residual
oil fly ash amplifies allergic cytokines, airway responsiveness, and inflammation
in mice. Am J Respir Crit Care Med 160:1897-1904 (1999).
51. Lambert AL, Dong W, Selgrade MK, Gilmour MI. Enhanced
allergic sensitization by residual oil fly ash particles is mediated by soluble
metal constituents. Toxicol Appl Pharmacol 165:84-93 (2000).
52. Lambert AL, Dong W, Winsett DW, Selgrade MK, Gilmour
MI. Residual oil fly ash exposure enhances allergic sensitization to house dust
mite. Toxicol Appl Pharmacol 158:269-277 (1999).
53. Dye JA, Lehmann JR, McGee JK, Winsett DW, Ledbetter
AD, Everitt JI, Ghio AJ, Costa DL. Acute pulmonary toxicity of particulate matter
filter extracts in rats: coherence with epidemiologic studies in Utah Valley
residents. Environ Health Perspect 109(suppl 3):395-403 (2001).
54. Ghio AJ, Stonehuerner J, Dailey LA, Carter JD. Metals
associated with both the water-soluble and insoluble fractions of an ambient
air pollution particle catalyze an oxidative stress. Inhal Toxicol 11:37-49
(1999).
55. Nordenhall C, Pourazar J, Blomberg A, Levin JO, Sandstrom
T, Adelroth E. Airway inflammation following exposure to diesel exhaust: a study
of time kinetics using induced sputum. Eur Respir J 15:1046-1051 (2000).
56. Salvi S, Blomberg A, Rudell B, Kelly F, Sandstrom
T, Holgate ST, Frew A. Acute inflammatory responses in the airways and peripheral
blood after short-term exposure to diesel exhaust in healthy human volunteers.
Am J Respir Crit Care Med 159:702-709 (1999).
57. Salvi SS, Nordenhall C, Blomberg A, Rudell B, Pourazar
J, Kelly FJ, Wilson S, Sandstrom T, Holgate ST, Frew AJ. Acute exposure to diesel
exhaust increases IL-8 and GRO-alpha production in healthy human airways. Am
J Respir Crit Care Med 161:550-557 (2000).
58. Nordenhall C, Pourazar J, Ledin MC, Levin JO, Sandstrom
T, Adelroth E. Diesel exhaust enhances airway responsiveness in asthmatic subjects.
Eur Respir J 17:909-915 (2001).
59. Diaz-Sanchez D, Tsien A, Fleming J, Saxon A. 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 158:2406-2413 (1997).
60. Diaz-Sanchez D, Dotson AR, Takenaka H, Saxon A. Diesel
exhaust particles induce local IgE production in vivo and alter the pattern
of IgE messenger RNA isoforms. J Clin Invest 94:1417-1425 (1994).
61. Diaz-Sanchez D, Penichet-Garcia M, Saxon A. Diesel
exhaust particles directly induce activated mast cells to degranulate and increase
histamine levels and symptom severity. J Allergy Clin Immunol 106:1140-1146
(2000).
62. Diaz-Sanchez D, Tsien A, Casillas A, Dotson AR, Saxon
A. Enhanced nasal cytokine production in human beings after in vivo challenge
with diesel exhaust particles. J Allergy Clin Immunol 98:114-123 (1996).
63. Diaz-Sanchez D, Jyrala M, Ng D, Nel A, Saxon A. In
vivo nasal challenge with diesel exhaust particles enhances expression of the
CC chemokines rantes, MIP-1alpha, and MCP-3 in humans. Clin Immunol 97:140-145
(2000).
64. Fujieda S, Diaz-Sanchez D, Saxon A. Combined nasal
challenge with diesel exhaust particles and allergen induces in vivo IgE isotype
switching. Am J Respir Cell Mol Biol 19:507-512 (1998).
65. Diaz-Sanchez D, Garcia MP, Wang M, Jyrala M, Saxon
A. Nasal challenge with diesel exhaust particles can induce sensitization to
a neoallergen in the human mucosa. J Allergy Clin Immunol 104:1183-1188
(1999).
66. Tsien A, Diaz-Sanchez D, Ma J, Saxon A. 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 142:256-263 (1997).
67. Takenaka H, Zhang K, Diaz-Sanchez D, Tsien A, Saxon
A. 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 95:103-115 (1995).
68. Gereda JE, Leung DY, Thatayatikom A, Streib JE, Price
MR, Klinnert MD, Liu AH. Relation between house-dust endotoxin exposure, type
1 T-cell development, and allergen sensitisation in infants at high risk of
asthma. Lancet 355:1680-1683 (2000).
69. Park JH, Spiegelman DL, Burge HA, Gold DR, Chew GL,
Milton DK. Longitudinal study of dust and airborne endotoxin in the home. Environ
Health Perspect 108:1023-1028 (2000).
70. Milton DK, Christiani DC, Greaves IA. Airborne endotoxin
associated with industrial-scale production of protein products in gram-negative
bacteria. Am Ind Hyg Assoc J 50:A-596 (1989).
71. Milton DK, Chawla RK. Cotton dust contains proteolytic
and elastolytic enzymes not inhibited by alpha-1-proteinase inhibitor. Am J
Ind Med 9:247-260 (1986).
72. Cormier Y, Merlaux A, Duchaine C. Respiratory health
impact of working in sawmills in eastern Canada. Arch Environ Health 55:424-430
(2000).
73. Rylander R, Vesterlund J. Airborne endotoxins in
various occupational environments. Prog Clin Biol Res 93:399-409 (1982).
74. Rylander R, Haglind P. Airborne endotoxins and humidifier
disease. Clin Allergy 14:109-112 (1984).
75. Teeuw KB, Vandenbroucke-Grauls CM, Verhoef J. Airborne
gram-negative bacteria and endotoxin in sick building syndrome. A study in Dutch
governmental office buildings. Arch Intern Med 154:2339-2345 (1994).
76. Vogelzang PF, van der Gulden JW, Folgering H, Kolk
JJ, Heederik D, Preller L, Tielen MJ, van Schayck CP. Endotoxin exposure as
a major determinant of lung function decline in pig farmers. Am J Respir Crit
Care Med 157:15-18 (1998).
77. Wang Z, Larsson K, Palmberg L, Malmberg P, Larsson
P, Larsson L. Inhalation of swine dust induces cytokine release in the upper
and lower airways. Eur Respir J 10:381-387 (1997).
78. Sandstrom T, Bjermer L, Rylander R. Lipopolysaccharide
(LPS) inhalation in healthy subjects increases neutrophils, lymphocytes and
fibronectin levels in bronchoalveolar lavage fluid. Eur Respir J 5:992-996
(1992).
79. Sandstrom T, Bjermer L, Rylander R. Lipopolysaccharide
(LPS) inhalation in healthy subjects causes bronchoalveolar neutrophilia, lymphocytosis,
and fibronectin increase. Am J Ind Med 25:103-104 (1994).
80. Michel O, Nagy AM, Schroeven M, Duchateau J, Neve
J, Fondu P, Sergysels R. Dose-response relationship to inhaled endotoxin in
normal subjects. Am J Respir Crit Care Med 156:1157-1164 (1997).
81. Michel O, Dentener M, Corazza F, Buurman W, Rylander
R. Healthy subjects express differences in clinical responses to inhaled lipopolysaccharide
that are related with inflammation and with atopy. J Allergy Clin Immunol 107:797-804
(2001).
82. Michel O. Systemic and local airways inflammatory
response to endotoxin. Toxicology 152:25-30 (2000).
83. Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline
JN, Jones M, Frees K, Watt JL, Schwartz DA. TLR4 mutations are associated with
endotoxin hyporesponsiveness in humans. Nat Genet 25:187-191 (2000).
84. Kline JN, Cowden JD, Hunninghake GW, Schutte BC,
Watt JL, Wohlford-Lenane CL, Powers LS, Jones MP, Schwartz DA. Variable airway
responsiveness to inhaled lipopolysaccharide. Am J Respir Crit Care Med 160:297-303
(1999).
85. Schwartz DA, Thorne PS, Yagla SJ, Burmeister LF,
Olenchock SA, Watt JL, Quinn TJ. The role of endotoxin in grain dust-induced
lung disease. Am J Respir Crit Care Med 152:603-608 (1995).
86. Michel O, Duchateau J, Sergysels R. Effect of inhaled
endotoxin on bronchial reactivity in asthmatic and normal subjects. J Appl Physiol
66:1059-1064 (1989).
87. Michel O, Ginanni R, Le Bon B, Content J, Duchateau
J, Sergysels R. Inflammatory response to acute inhalation of endotoxin in asthmatic
patients. Am Rev Respir Dis 146:352-357 (1992).
88. Michel O, Ginanni R, Sergysels R. Relation between
the bronchial obstructive response to inhaled lipopolysaccharide and bronchial
responsiveness to histamine. Thorax 47:288-291 (1992).
89. Park JH, Gold DR, Spiegelman DL, Burge HA, Milton
DK. House dust endotoxin and wheeze in the first year of life. Am J Respir Crit
Care Med 163:322-328 (2001).
90. Michel O, Kips J, Duchateau J, Vertongen F, Robert
L, Collet H, Pauwels R, Sergysels R. Severity of asthma is related to endotoxin
in house dust. Am J Respir Crit Care Med 154:1641-1646 (1996).
91. Alexis N, Eldridge M, Reed W, Bromberg P, Peden DB.
CD14-dependent airway neutrophil response to inhaled LPS: role of atopy. J Allergy
Clin Immunol 107:31-35 (2001).
92. Dubin W, Martin TR, Swoveland P, Leturcq DJ, Moriarty
AM, Tobias PS, Bleecker ER, Goldblum SE, Hasday JD. Asthma and endotoxin: lipopolysaccharide-binding
protein and soluble CD14 in bronchoalveolar compartment. Am J Physiol 270:L736-L744
(1996).
93. Virchow JC Jr, Julius P, Matthys H, Kroegel C, Luttmann
W. CD14 expression and soluble CD14 after segmental allergen provocation in
atopic asthma. Eur Respir J 11:317-323 (1998).
94. Lensmar C, Prieto J, Dahlen B, Eklund A, Grunewald
J, Roquet A. Airway inflammation and altered alveolar macrophage phenotype pattern
after repeated low-dose allergen exposure of atopic asthmatic subjects. Clin
Exp Allergy 29:1632-1640 (1999).
95. Eldridge MW, Peden DB. Allergen provocation augments
endotoxin-induced nasal inflammation in subjects with atopic asthma. J Allergy
Clin Immunol 105:475-481 (2000).
96. Alexis NE, Peden DB. Blunting airway eosinophilic
inflammation results in a decreased airway neutrophil response to inhaled LPS
in patients with atopic asthma: a role for CD14. J Allergy Clin Immunol 108:577-580
(2001).
97. Nichols BG, Woods JS, Luchtel DL, Corral J, Koenig
JQ. Effects of ozone exposure on nuclear factor-kappaB activation and tumor
necrosis factor-alpha expression in human nasal epithelial cells. Toxicol Sci
60:356-362 (2001).
98. Chung KF, Adcock IM. Induction of nuclear factor-kappa
B by exposure to ozone and inhibition by glucocorticoids. Methods Enzymol 319:551-562
(2000).
99. Haddad EB, Salmon M, Koto H, Barnes PJ, Adcock I,
Chung KF. Ozone induction of cytokine-induced neutrophil chemoattractant (CINC)
and nuclear factor-kappa b in rat lung: inhibition by corticosteroids. FEBS
Lett 379:265-268 (1996).
100. Muller JM, Ziegler-Heitbrock HW, Baeuerle PA. Nuclear
factor kappa B, a mediator of lipopolysaccharide effects. Immunobiology 187:233-256
(1993).
101. Kleeberger SR, Reddy S, Zhang LY, Jedlicka AE. Genetic
susceptibility to ozone-induced lung hyperpermeability: role of toll-like receptor
4. Am J Respir Cell Mol Biol 22:620-627 (2000).
102. Kleeberger SR, Reddy SP, Zhang LY, Cho HY, Jedlicka
AE. Toll-like receptor 4 mediates ozone-induced murine lung hyperpermeability
via inducible nitric oxide synthase. Am J Physiol Lung Cell Mol Physiol 280:L326-L333
(2001).
Last Updated: August 6, 2002
