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(Chest. 2004;126:198-204.)
© 2004 American College of Chest Physicians

Effect of Nitrogen Dioxide Exposure on Allergic Asthma in a Murine Model*

Iftikhar Hussain, MD; Vipul V. Jain, MD; Patrick O’Shaughnessy, PhD; Thomas R. Businga, MS and Joel Kline, MD, FCCP

* From the Department of Medicine (Dr. Hussain), Washington University School of Medicine, St. Louis, MO; the Division of Pulmonary Medicine (Mr. Businga and Dr. Kline), Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, and the Department of Occupational and Environmental Medicine (Dr. O’Shaughnessy), College of Public Health, University of Iowa, Iowa City, IA; and the Department of Medicine (Dr. Jain), University of California San Francisco-Fresno, Fresno, CA.

Correspondence to: Joel Kline, MD, FCCP, C33 GH, UIHC, 200 Hawkins Dr, Iowa City, IA 52242; e-mail: joel-kline{at}uiowa.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: The purpose of this study was to examine the effects of NO2, a major component of air pollution, on airway eosinophilic inflammation and bronchial hyperreactivity, using a mouse model of asthma.

Setting and subjects: BALB/c mice (eight mice per experimental group) were studied in a basic research laboratory at the University of Iowa.

Interventions: Using a standard murine model of asthma, BALB/c mice were sensitized to ovalbumin (OVA) by intraperitoneal (IP) injections (days 1 and 7) and were challenged with aerosolized OVA (days 13 and 14). Some mice were exposed to NO2 (2 ppm) in an exposure chamber for 24 h before undergoing OVA aerosol challenge. A control group was exposed to OVA alone.

Measurements and results: The outcomes assessed included airway inflammation, bronchial hyperreactivity to inhaled methacholine, and goblet cell hyperplasia. We found that NO2 exposure modestly increased airway neutrophilia but not airway eosinophilia in OVA-exposed mice. These mice exhibited epithelial damage and loss of epithelial mucin. Surprisingly, nonspecific bronchial hyperreactivity (ie, enhanced pause index) was not increased, although baseline smooth muscle tone was increased (p < 0.05) in the mice exposed to NO2.

Conclusions: These data indicate that relatively short-term (24 h) exposure to NO2 causes epithelial damage, reduced mucin expression, and increased tone of respiratory smooth muscle. Reduced mucin production may be a mechanism of injury following long-term exposure to inhaled NO2. Despite enhancing epithelial damage in OVA-exposed mice, NO2 exposure does not otherwise alter the expression of allergen-induced airway responses.

Key Words: air pollution • environmental tobacco smoke • indoor air quality • mucin


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Epidemiologic studies have demonstrated a strong link between increased concentrations of NO2 in polluted environments and respiratory symptoms, including rhinorrhea, cough, and infections of the lower respiratory tract.12 More recent evidence suggests that exposure to pollutants may also contribute to the development of the sensitization of atopic individuals to aeroallergens.3 Unlike ozone, NO2 is a primary pollutant that is found both indoors and in the outdoor atmosphere. During high-temperature combustion, oxygen reacts with nitrogen to generate oxides of nitrogen, which mainly include nitrogen oxide and NO2. In the outdoors, motor vehicular emissions represent the major source of NO2. While indoor levels can reach up to 4 ppm in power plants, refineries, and ice-skating rinks, outdoor levels usually do not exceed 0.5 ppm.4 Gas stove cooking and environmental tobacco smoke are other sources of indoor household exposure.5

The effects of NO2 exposure on airway disease are beginning to be better appreciated. Animal studies have demonstrated that the terminal bronchiolar epithelium is particularly sensitive to NO2-induced injury after brief exposures (ie, 1 to 6 h), the effects of which include epithelial flattening, loss of cilia and ciliated cells, epithelial cell hyperplasia, damage to surface membranes, and disruption of epithelial tight junctions.67 NO2 also leads to an increased inflammatory cell influx89 and may affect lung defense mechanisms through reduced mucociliary clearance and changes in alveolar macrophages and other immune cells.10 NO2 also may induce an inflammatory cell influx and eosinophil activation in humans.111213

NO2 can potentiate responses to aeroallergens in mildly sensitive asthmatic persons.14 It has been shown that loratadine,1415 an antihistamine, and fluticasone propionate,16 an inhaled steroid, can each block the effects of NO2, suggesting that atopic mechanisms (ie, eosinophil-mediated or mast cell-mediated mechanisms) may be altered by NO2. On the other hand, in vitro studies have not shown that NO2 significantly influences bronchial smooth muscles hyperresponsiveness in wild-type guinea pigs17 or ovalbumin (OVA)-sensitized guinea pigs.1718 The interactions between inhaled aeroallergens and NO2 are not well understood. Thus, in the present study we decided to investigate the effect of relatively short-term exposure (24 h) to NO2 on antigen-induced hyperresponsiveness, mucus production by epithelial cells, and airway inflammation in vivo in a murine model of allergic asthma.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Six to eight-week-old female BALB/c mice (Jackson Laboratory; Bar Harbor, ME) were used for all studies. All animal care and housing requirements of the National Institutes of Health Committee on Care and Use of Laboratory Animals were followed, and all protocols were reviewed and approved by the University of Iowa Animal Care and Use Committee. Eight mice were used for each experimental group.

Exposure Model
Mice were sensitized on days 0 and 7 with 10 µg OVA [Sigma; St. Louis, MO] adsorbed to alum by IP injection. Other mice received saline solution and served as negative controls. Prior to OVA inhalation, some mice were exposed to 2 ppm NO2 for 24 h (day 13). The NO2 concentration in the chamber was maintained at constant levels by the use of an analyzer (NOx analyzer; TSI Incorporated; St Paul, MN). In preliminary studies (data not shown), we examined the effect of a range of concentrations of NO2, and chose 2 ppm as a concentration that reliably induces airway inflammation and is within the range of exposure resulting from indoor air pollution. All mice other than negative controls were challenged with aerosolized OVA (1% solution, nebulized) for 30 min on days 14 and 15, then were killed 48 h later on day 16 (Table 1 ).


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  		Table 1.. Summary of the Mice Sensitization and Challenge Protocols

 
Whole-Lung Lavage
Following euthanasia, the trachea was cannulated and 3 mL saline solution was administered. The washing fluid was collected by gravitational flow. The lavage fluid samples were processed for total and differential cell counts (using Diff-Quik staining of cytospin preparations).

Physiology
Airway hyperactivity was measured on day 16 (immediately prior to death) using a whole-body plethysmograph (Buxco Electronics; Troy, NY) and methacholine-induced airflow obstruction, as previously described.19 Airway resistance is approximated by the enhanced pause (Penh), which is normalized to the Penh following saline solution inhalation for that individual mouse, so that a Penh ratio of 1 implies a Penh value equivalent to that of the baseline, before the methacholine challenge.

Light Microscopy and Morphometry
At the time of death, the lungs of the mice were excised, fixed, and embedded in paraffin. Tissue pathology was studies in 5-µm-thick tissue sections, which were stained with hematoxylin-eosin, while other sections were stained with alcian-blue (pH 2.6) periodic acid-Schiff (AB-PAS) and hematoxylin. The percentage of the area of mucus on the epithelial surface stained with AB-PAS was determined by an image analyzer (SP 500; Olympus; Tokyo, Japan). The area of the respiratory epithelium was outlined, and the image analyzer quantified the area of AB-PAS-stained mucus within this reference area. The percentage of the area of the epithelial surface occupied by stored mucus was calculated over 2 mm of the basal lamina.

Statistical Analysis
Analysis was performed using a one-way analysis of variance or nonparametric Mann-Whitney tests using appropriate software (SPSS; SPSS Inc; Chicago, IL). Values for all measurements were expressed as the mean ± SEM. A p value of < 0.05 was considered to be significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Effects of NO2 Exposure on Airway Inflammation
To examine the effects of NO2 on airway inflammation, we exposed naive mice (ie, controls) and OVA-sensitized BALB/c mice to NO2 (2 ppm for 24 h) or filtered air prior to the inhalation of aerosolized OVA. The inhalation of NO2 significantly induced an influx of neutrophils into the airways of naive mice (control mice, 2.0 + 0.8 x 103 polymorphonuclear (PMN) cells/mL [2.2 + 0.4%]; NO2 inhalation mice, 36.4 + 7.9 x 103 PMN cells/mL [12.5 + 3.0%]; p < 0.05 [eight mice per group]) [Fig 1 ]. In contrast, among OVA-sensitized/exposed mice, NO2 exposure did not significantly alter BAL neutrophilia (OVA mice, 14.9 + 4.1 x 103 PMN cells/mL [3.0 + 0.7%]; OVA + NO2-exposed mice, 9.6 + 4.2 x 103 PMN cells/mL [2.0 + 0.7%]; difference was not significant [eight mice per group]) [Fig 1] or eosinophilia (OVA mice, 389.8 + 57.4 x 103 eosinophils/mL [80.3 + 6.3%]; OVA + NO2-exposed mice, 309.5 + 64.2 x 103 eosinophils/mL [64.5 + 4.8%]; difference not significant [eight mice per group]).



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  		Figure 1.. Exposure to 2.0 ppm NO2 for 24 h induced significant airway neutrophilia. The exposure of OVA-sensitized/OVA-challenged mice to these levels of NO2 did not significantly alter the number of airway eosinophils or PMN cells. NS = not significant.

 
Effects of NO2 Exposure on Bronchial Hyperreactivity
We also evaluated the effects of inhaled NO2 on the development of methacholine-induced bronchial hyperresponsiveness, as measured by whole-body plethysmography. In accordance with our previous findings, OVA-sensitized/OVA-challenged mice demonstrate marked increases in airway hyperresponsiveness compared to control mice (control mice with Penh recorded after inhalation of 50 mg/mL methacholine [Penh50]/Penh recorded after inhalation of saline solution, 4.84 + 0.47; OVA Penh50, 10.29 + 1.5; p < 0.05 [eight mice per group]). In contrast with the response to antigen exposure, the inhalation of NO2 did not significantly increase bronchial hyperreactivity (NO2 Penh50, 2.97 + 0.45; difference not significant [vs controls]; OVA + NO2 Penh50, 3.28 + 1.01; difference not significant [vs OVA]). However, NO2 exposure increased the absolute (pre-methacholine challenge) Penh among the OVA-exposed mice (OVA Penh, 0.43 + 0.09; OVA + NO2 Penh, 1.03 + 0.33; p < 0.05) but not the naive mice (control Penh, 0.4 + 0.10; NO2 Penh, 0.55 + 0.16; difference not significant), perhaps reflecting structural changes of the airways (Fig 2 ).



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  		Figure 2.. The effect of 2.0 ppm NO2 exposure for 24 h on Penh, a correlate of airway resistance and thus smooth muscle tone. OVA-sensitized/OVA-challenged mice, when exposed to NO2, have significantly increased Penh compared to control mice as well as mice exposed to OVA in the absence of NO2 (p < 0.05).

 
Effects of NO2 Exposure on Airway Epithelia
We next examined the histopathologic changes induced in the airways by NO2 inhalation. One important alteration seen during asthma exacerbations is increased mucus production by the epithelial cells, which was associated with goblet cell hyperplasia/metaplasia.20 As anticipated, OVA-sensitized/challenged mice exhibited significant increases in mucin-positive cells in comparison with control mice (controls, 8.17 + 0.17%; OVA-exposed mice, 18.35 + 1.91%; p < 0.01 [eight mice per group]). Surprisingly, mucin expression was actually reduced following the inhalation of NO2 (NO2-exposed mice, 1.98 + 0.24%; p < 0.01 [vs controls]; OVA + NO2-exposed mice, 3.52 + 1.16%; p < 0.01 [vs OVA-exposed mice]). In contrast, epithelial disruption and denudement were seen to a significantly greater degree in mice exposed to NO2 than in those not exposed (Fig 3 ).



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  		Figure 3.. Lung samples from mice that were exposed to NO2 (2 ppm for 24 h) showed signs of epithelial injury, including epithelial denudation (closed arrows), compared with mice not exposed to NO2. Sensitization to and challenge with OVA induced mucosal hyperplasia and increased mucosal thickness, regardless of NO2 exposure. Top left, A: control mice; top right, B: OVA-sensitized/OVA-challenged mice; bottom left, C: NO2-exposed mice; bottom right, D: NO2 exposure followed by OVA challenge (hematoxylin-eosin, original x40). Open arrows point to peribronchial cellular infiltrate after OVA challenge (top right, B, and bottom right, D).

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
These studies demonstrated, using a murine model, that exposure to 2 ppm NO2 for 24 h induces airway neutrophilia in naive mice but did not alter the cellular inflammatory response to inhaled allergen in OVA-sensitized animals. The inhalation of NO2, in this model, increased the Penh (a measure of airway resistance) of OVA-sensitized/challenged mice but did not increase bronchial hyperresponsiveness to inhaled methacholine. Most notably, a morphometric evaluation of the airways demonstrated that epithelial disruption was enhanced by the inhalation of NO2, both in naive and allergic mice. In addition, mucus expression was reduced in the NO2-exposed animals. These findings are consistent with the known toxic effects of NO2 on the airway. Epithelial disruption and denudement are common in inflamed airways, and air pollution can symptomatically exacerbate atopic asthma.21 These epithelial changes, often seen before the onset of airway repair and remodeling, are acute responses to airway injury.

We speculate that the increased Penh values seen in NO2-exposed mice were linked to the structural changes in their airway epithelia. Although some investigators2223 have criticized the use of whole-body plethysmography to assess airway hyperresponsiveness, we have found that this measure correlates well with airway inflammation.192425 In the current study, we think that the Penh measure reflects alterations that may occur throughout the air passages, integrating changes that extend from the nasal passageway through the lower airways.

NO2, like sulfur dioxide and ozone, is a major component of air pollution. The threshold value for both the primary and secondary national Ambient Air Quality Standard for NO2 is 0.053 ppm (measured as an annual arithmetic mean concentration). Six-day integrated indoor and outdoor concentrations of NO2 were measured in two communities in Southern California using passive samplers. The average indoor and outdoor NO2 concentrations were 0.028 and 0.020 ppm, respectively.26 Other studies of indoor air pollution have demonstrated average levels as high as 0.05 to 0.08 ppm, with higher levels associated with gas cooking and environmental tobacco smoke.52728 Although the level of NO2 to which mice were exposed in the current study were significantly greater than those found in most indoor environments, it is important to realize that our data reflect a relatively short-term (ie, 24 h) exposure to NO2 and may substantially underestimate the effect of long-term or life-long exposures to polluted air.

It has been shown that exposures of 2 to 5 ppm NO2 in healthy subjects increases the number of inflammatory cells found in BAL fluid.11 Wang and coworkers1629 studied the effects of NO2 inhalation in subjects with seasonal allergic rhinitis and found that NO2 exposure increased allergen-induced eosinophilic cationic protein, mast cell tryptase, myeloperoxidase, and interleukin-8. Another study showed that, in asthmatic subjects, short-term exposure to NO2 from single episodes of gas cooking was associated with immediate airflow limitation. Continued exposure from repeated episodes of gas cooking by asthmatic women was associated with a greater use of rescue bronchodilators.30 Blomberg et al31 showed that the inhalation of 2 ppm NO2 for 6 h caused significant decrements in FEV1 and FVC after the first exposure, but these effects were attenuated following repeated exposures.

In contrast with clinical studies, in vitro studies on smooth muscles have not supported the existence of a direct role of NO2 in inducing bronchospasm. Neither human nor murine bronchial smooth muscle demonstrates altered contractility following exposure to NO2.1718 In this current study, we have presented data supporting those in vitro studies by demonstrating that short-term exposure to NO2 does not significantly alter airway hyperreactivity. Blomberg et al31 showed that repeated exposure to NO2 results in the attenuation of the changes in FEV1 and FVC that develop after an initial exposure in healthy, adult nonsmokers. This attenuation of lung function response after repeated or prolonged exposure to NO2 is consistent with the response patterns seen after repeated daily exposures to other environmental pollutants, such as ozone and carbon monoxide.3233 The inability to induce hyperreactivity may be attributed to counterregulatory mechanisms, which might include replenishment of lost antioxidants in the epithelial lining fluid or the up-regulation of other defense elements. Like carbon monoxide, NO2 can reduce bronchial hyperreactivity by the generation of bronchodilating substances such as cyclic guanosine monophosphate.3334 One important determinant of bronchial reactivity is the resting state of the airways.35 An increase in resting bronchomotor tone, either by the direct action of spasmogens or by the autonomic nervous system, may potentiate a subsequent constrictor stimulus. In this study, we found that NO2 significantly increased baseline airway smooth muscle time, as measured by baseline Penh.

Mucins are polydispersed and highly glycosylated molecules, and are the principal determinant of the viscoelastic properties of mucus.36 Excessive mucus production by hyperplastic goblet cells has been reported in patients with acute and chronic asthma.37 Allergic asthma is characterized by airway hyperresponsiveness to a variety of specific and nonspecific stimuli, chronic pulmonary eosinophilia, elevated serum IgE levels, and excessive airway mucus production.38 Mucus hypersecretion is also an important part of the sequelae induced by a number of toxic insults to the lung such as inhaled irritants, neutrophil products, or viral and bacterial infections.394041 The production of mucus, although at times used as a proxy for airway injury and "remodeling," may actually serve as a defense against inhaled harmful agents. Reduced levels of mucus expression may thus be a mechanism of, as well as a marker for, airway injury. The reduced amounts of airway mucin observed in this study after the inhalation of NO2 might be due to a loss of production secondary to the noxious effects of this common environmental pollutant.

We conclude that short-term exposure to NO2 induces neutrophilic airway inflammation, epithelial damage, and increased baseline airway smooth muscle tone in naive mice. Although enhancing epithelial disruption, this exposure did not significantly alter the influx of inflammatory cells or bronchial hyperresponsiveness in a murine model of atopic asthma.


   Footnotes
 
Abbreviations: AB-PAS = alcian blue periodic acid-Schiff stain; IP = intraperitoneal; OVA = ovalbumin; Penh = enhanced pause; Penh50 = enhanced pause recorded after inhalation of 50 mg/mL methacholine; PMN = polymorphonuclear

This study was supported by the University of Iowa Environmental Health Science Research Center (grant ES50605) and National Heart, Lung, and Blood Institute grant RO1 HL59324.

Received for publication August 6, 2003. Accepted for publication February 4, 2004.


   References
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 Abstract
 Introduction
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 References
 

  1. Koo, LC, Ho, JH, Ho, CY, et al (1990) Personal exposure to nitrogen dioxide and its association with respiratory illness in Hong Kong. Am Rev Respir Dis 141,1119-1126[ISI][Medline]
  2. Evans, RG, Webb, K, Homan, S, et al Cross-sectional and longitudinal changes in pulmonary function associated with automobile pollution among bridge and tunnel officers. Am J Ind Med 1988;14,25-36[Medline]
  3. Eggleston, PA, Rosenstreich, D, Lynn, H, et al Relationship of indoor allergen exposure to skin test sensitivity in inner-city children with asthma. J Allergy Clin Immunol 1998;102,563-570[CrossRef][ISI][Medline]
  4. Peden, DB, Boehlecke, B, Horstman, D, et al Prolonged acute exposure to 0.16 ppm ozone induces eosinophilic airway inflammation in asthmatic subjects with allergies. J Allergy Clin Immunol 1997;100,802-808[CrossRef][Medline]
  5. Cyrys, J, Heinrich, J, Richter, K, et al Sources and concentrations of indoor nitrogen dioxide in Hamburg (west Germany) and Erfurt (east Germany). Sci Total Environ 2000;250,51-62[CrossRef][Medline]
  6. Evans, MJ, Stephens, RJ, Cabral, LJ, et al Cell renewal in the lungs of rats exposed to low levels of NO2. Arch Environ Health 1972;24,180-188[ISI][Medline]
  7. Stephens, RJ, Freeman, G, Evans, MJ Early response of lungs to low levels of nitrogen dioxide: light and electron microscopy. Arch Environ Health 1972;24,160-179[ISI][Medline]
  8. Glasgow, JE, Pietra, GG, Abrams, WR, et al Neutrophil recruitment and degranulation during induction of emphysema in the rat by nitrogen dioxide. Am Rev Respir Dis 1987;135,1129-1136[Medline]
  9. DeNicola, DB, Rebar, AH, Henderson, RF Early damage indicators in the lung: V. Biochemical and cytological response to NO2 inhalation. Toxicol Appl Pharmacol 1981;60,301-312[CrossRef][ISI][Medline]
  10. Morrow, PE Toxicological data on NOx: an overview. J Toxicol Environ Health 1984;13,205-227[ISI][Medline]
  11. Sandstrom, T, Stjernberg, N, Eklund, A, et al Inflammatory cell response in bronchoalveolar lavage fluid after nitrogen dioxide exposure of healthy subjects: a dose-response study. Eur Respir J 1991;4,332-339[Abstract]
  12. Frampton, MW, Finkelstein, JN, Roberts, NJ, Jr, et al Effects of nitrogen dioxide exposure on bronchoalveolar lavage proteins in humans. Am J Respir Cell Mol Biol 1989;1,499-505
  13. Frampton, MW, Smeglin, AM, Roberts, NJ, Jr, et al Nitrogen dioxide exposure in vivo and human alveolar macrophage inactivation of influenza virus in vitro. Environ Res 1989;48,179-192[Medline]
  14. Peden, DB Mechanisms of pollution-induced airway disease: in vivostudies. Allergy 1997;52,37-44[Medline]
  15. Bayram, H, Devalia, JL, Khair, OA, et al Effect of loratadine on nitrogen dioxide-induced changes in electrical resistance and release of inflammatory mediators from cultured human bronchial epithelial cells. J Allergy Clin Immunol 1999;104,93-99[Medline]
  16. Wang, JH, Devalia, JL, Duddle, JM, et al Effect of six-hour exposure to nitrogen dioxide on early-phase nasal response to allergen challenge in patients with a history of seasonal allergic rhinitis. J Allergy Clin Immunol 1995;96,669-676[CrossRef][ISI][Medline]
  17. Chitano, P, Lucchini, RE, Coser, E, et al In vitro exposure of guinea pig main bronchi to 2.5 ppm of nitrogen dioxide does not alter airway smooth muscle response. Respir Med 1995;89,323-328[Medline]
  18. Chitano, P, Coser, E, Lucchini, RE, et al In vitro exposure to nitrogen dioxide (NO2) does not alter bronchial smooth muscle responsiveness in ovalbumin-sensitized guinea-pigs. Pulm Pharmacol 1994;7,251-257[Medline]
  19. Kline, JN, Kitagaki, K, Businga, TR, et al Treatment of established asthma in a murine model using CpG oligodeoxynucleotides. Am J Physiol Lung Cell Mol Physiol 2002;283,L170-L179[Abstract/Free Full Text]
  20. Blyth, DI, Pedrick, MS, Savage, TJ, et al Induction, duration, and resolution of airway goblet cell hyperplasia in a murine model of atopic asthma: effect of concurrent infection with respiratory syncytial virus and response to dexamethasone. Am J Respir Cell Mol Biol 1998;19,38-54[Abstract/Free Full Text]
  21. Koenig, JQ Air pollution and asthma. J Allergy Clin Immunol 1999;104,717-722[CrossRef][ISI][Medline]
  22. Hantos, Z, Brusasco, V Assessment of respiratory mechanics in small animals: the simpler the better? J Appl Physiol 2002;93,1196-1197[Free Full Text]
  23. Mitzner, W, Tankersley, C, Lundblad, LK, et al Interpreting Penh in mice. J Appl Physiol 2003;94,828-832[Free Full Text]
  24. Kline, JN, Jagielo, PJ, Watt, JL, et al Bronchial hyperreactivity is associated with enhanced grain dust-induced airflow obstruction. J Appl Physiol 2000;89,1172-1178[Abstract/Free Full Text]
  25. Kline, JN, Waldschmidt, TJ, Businga, TR, et al Modulation of airway inflammation by CpG oligodeoxynucleotides in a murine model of asthma. J Immunol 1998;160,2555-2559[Abstract/Free Full Text]
  26. Lee, K, Xue, J, Geyh, AS, et al Nitrous Acid, nitrogen dioxide, and ozone concentrations in residential environments. Environ Health Perspect 2002;110,145-150
  27. Brugge, D, Vallarino, J, Ascolillo, L, et al Comparison of multiple environmental factors for asthmatic children in public housing. Indoor Air 2003;13,18-27[Medline]
  28. Rojas-Bracho, L, Suh, HH, Oyola, P, et al Measurements of children’s exposures to particles and nitrogen dioxide in Santiago, Chile. Sci Total Environ 2002;287,249-264[Medline]
  29. Wang, JH, Duddle, J, Devalia, JL, et al Nitrogen dioxide increases eosinophil activation in the early-phase response to nasal allergen provocation. Int Arch Allergy Immunol 1995;107,103-105[CrossRef][ISI][Medline]
  30. Ng, TP, Seet, CS, Tan, WC, et al Nitrogen dioxide exposure from domestic gas cooking and airway response in asthmatic women. Thorax 2001;56,596-601[Abstract/Free Full Text]
  31. Blomberg, A, Krishna, MT, Helleday, R, et al Persistent airway inflammation but accommodated antioxidant and lung function responses after repeated daily exposure to nitrogen dioxide. Am J Respir Crit Care Med 1999;159,536-543[Abstract/Free Full Text]
  32. Folinsbee, LJ, Horstman, DH, Kehrl, HR, et al Respiratory responses to repeated prolonged exposure to 0.12 ppm ozone. Am J Respir Crit Care Med 1994;149,98-105[Abstract]
  33. Cardell, LO, Lou, YP, Takeyama, K, et al Carbon monoxide, a cyclic GMP-related messenger, involved in hypoxic bronchodilation in vivo. Pulm Pharmacol Ther 1998;11,309-315[CrossRef][ISI][Medline]
  34. Kobayashi, T, Hamano, Y, Domeki, H Effect of acute nitrogen dioxide exposure on the free amino acids of rat serum. Toxicol Lett 1980;6,157-161[Medline]
  35. Benson, MK Bronchial hyperreactivity. Br J Dis Chest 1975;69,227-239[ISI][Medline]
  36. Sheehan, JK, Thornton, DJ, Somerville, M, et al Mucin structure: the structure and heterogeneity of respiratory mucus glycoproteins. Am Rev Respir Dis 1991;144,S4-S9[ISI][Medline]
  37. Ordonez, CL, Khashayar, R, Wong, HH, et al Mild and moderate asthma is associated with airway goblet cell hyperplasia and abnormalities in mucin gene expression. Am J Respir Crit Care Med 2001;163,517-523[Abstract/Free Full Text]
  38. Beasley, R, Roche, WR, Roberts, JA, et al Cellular events in the bronchi in mild asthma and after bronchial provocation. Am Rev Respir Dis 1989;139,806-817[ISI][Medline]
  39. Samet, JM, Cheng, PW The role of airway mucus in pulmonary toxicology. Environ Health Perspect 1994;102(suppl),89-103
  40. Ukai, K, Sakakura, Y Newcastle disease viral infection in chicken nasal turbinate and maxillary sinus. Acta Otolaryngol 1992;112,710-716[Medline]
  41. Breuer, R, Christensen, TG, Lucey, EC, et al Quantitative study of secretory cell metaplasia induced by human neutrophil elastase in the large bronchi of hamsters. J Lab Clin Med 1985;105,635-640[ISI][Medline]



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