POLLUTION AND ASTHMA: EFFECT ON AIRWAY INFLAMMATION

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Effect of pollutants on asthma.


Epidemiological studies have observed significant associations between asthma morbidity and exposure to several airborne contaminants, both indoors and outdoors. These air contaminants have been referred to in the past as respiratory irritants, implying that they act by irritating airways that are already hyperreactive. However, more recently there are very cogent studies demonstrating that many airborne pollutants should be considered to have more than irritating effects, and can enhance inflammation and other pulmonary immune responses, perhaps by enhancing cytokines and chemokines.

 

Epidemiological and challenge studies.


Pollutants in the ambient air that can potentially affect asthmatics adversely include inhalable particles (including acid aerosols), ozone, sulfur dioxide and nitrogen dioxide. Epidemiologic studies have demonstrated strong associations between ambient inhalable particle concentrations and emergency room visits, hospitalizations (1,2) and symptoms of asthma (3). Such associations have also been described for ozone (4,5). Ambient air is a complex mixture of particles, aerosols and gases. Increases in particle concentration occur in association with increases in acid aerosol and ozone concentrations which together increase respiratory symptoms (6-8). Increased concentrations of the mixture of pollutants have also been associated with increased hospitalizations for asthma (9,10) and increased symptoms (11).

In experimental challenge studies, ozone exposures cause decreases in vital capacity under controlled exposure conditions, but patients with asthma are not more likely to experience these effects than patients without asthma (12), even though epidemiological studies, as noted above, have observed adverse effects of ozone on asthma. At the present time, the mechanism for the adverse pulmonary effects in exposure experiments is unclear. However, a body of work has begun to emerge, as will be cited below, which suggest that exposure to air pollutants may cause effects by acting to induce inflammation and by enhancing inflammation created by the atopic immune response.

 

Pollution as an adjuvant or modulator of inflammation in the airways.


There is now evidence that allergic asthmatics exposed to ozone may experience more adverse effects following exposure to allergen than when allergen exposure occurs without prior exposure to ozone. Molfino et al (13) demonstrated that pre-exposure to ozone increased the specific airway reactivity to grass pollen allergen challenge in grass-allergic asthmatics. While this observation could not be reproduced in the study of Ball et al (14), nor in a later study by the authors themselves (15), it was reproduced by Jorres et al (16), and similar results were obtained with pre-exposure with mixed NO2 and SO2 (16,17), as well as NO2 alone (18,19). Jenkins et al (20) have suggested a reason for the inconsistent results when they demonstrated a threshold effect of pollutants, such that a specific concentration of exposure was required that could not be achieved by longer exposures at lower concentrations However Kehri et al (21) have recently reported increased allergen-induced airway reactivity of subjects with mild allergic asthma after prolonged exposure (7.6 hours) to low doses of ozone (0.16 ppm).

These results suggest that pre-exposure with a number of air pollutants, either alone or in combination, will result in increased bronchial responsiveness to specific allergen in allergic asthmatic patients. It is possible that these results are dependent on the presence of eosinophilic inflammation in the airway prior to exposure to the pollutant, which then enhances this inflammation with increased influx of eosinophils and generation of pro-inflammatory chemokines.

 

Experimental exposure to air pollutants and effect on airway inflammation.


Experimental exposure challenges have focused on the relationship between air pollution and inflammation in the airways, both in atopic and non-atopic individuals with and without asthma. Bascom et al (22) demonstrated in atopic individuals that challenge of the nasal mucosa with specific allergen in the presence of ozone versus air led to an increased influx of neutrophils and eosinophils. This observation was confirmed by Hiltermann et al (23) using a different protocol relating ambient air pollution to nasal lavage results.

Subsequently studies were undertaken to examine inflammatory cells in the lung after ozone challenge in asthmatics versus normals. The results indicated that asthmatic persons may be at risk of developing more severe ozone-induced respiratory tract injury/inflammation, characterized by increased neutrophils, compared to normal persons (24,25). This may explain the increased asthma morbidity associated with ozone pollution episodes observed in epidemiologic studies. More recently, Peden et al (26) have shown that ozone exposure results in increased eosinophilic inflammation in the lower airways of allergic asthmatic subjects. After ozone challenge, these subjects demonstrated an increase in both neutrophils and eosinophils. Vagaggini et al (27) confirmed an increase in neutrophils after exposure of mild asthmatics to ozone compared to air, but failed to demonstrate any increase in eosinophils. However, the patients with asthma were on treatment with inhaled steroid, which may have suppressed the rise in eosinophils, while failing to suppress the neutrophilic response.

In total, these works have suggested very strongly that air pollution can modulate or enhance the airway inflammation associated with allergic and asthmatic diseases.

References:

  1. Pope CA III. Respiratory hospital admissions associated with PM10 pollution in Utah, Salt Lake, and Cache Valleys. Arch Environ Health 46:90-97, 1991.
  2. Lipsett M, Hurley S, Ostro B. Air pollution and emergency room visits for asthma in Santa Clara County, California. Environ Health Perspect 1997;105:216-222.
  3. Pope CA III, Dockery DW, Spengler JD, Raizenne MA. Respiratory health and PM10 pollution. A daily time series analysis. Am Rev Respir Dis 144:668-674, 1991.
  4. Stieb DM, Burnett RT, Beveridge RC, Brook JR. Association between ozone and asthma emergency department visits in Saint John, New Brunswick, Canada. Environ Health Perspect 1996;104:1354-1360.
  5. Cody RP, Weisel CP, Birnbaum G, Lioy PJ The effect of ozone associated with summertime photochemical smog on the frequency of asthma visits to hospital emergency departments. Environ Res 1992;58:184-194
  6. Pope CA III, Dockery DW. Acute health effects of PM10 pollution on symptomatic and asymptomatic children. Am Rev Respir Dis.1992 145:1123-1128.
  7. Thurston GD, Lippmann M, Scott MB, Fine JM. Summertime haze air pollution and children with asthma. Am J Respir Crit Care Med 1997;155:654-660.
  8. Gielen MH, van der Zee SC, van Wijnen JH, van Steen CJ, Brunekreef B. Acute effects of summer air pollution on respiratory health of asthmatic children. Am J Respir Crit Care Med 1997;155:2105-2108.
  9. Thurston GD, Ito K, Hayes CG, Bates DV, Lippmann M. Respiratory.hospital admissions and summertime haze air pollution in Toronto, Ontario: consideration of the role of acid aerosols. Environ Res 1994;65:271-290
  10. Thurston GD, Ito K, Kinney PL, Lippmann M A multi-year study of air pollution and respiratory hospital admissions in three New York State metropolitan areas: results for 1988 and 1989 summers.J Expo Anal Environ Epidemiol 1992;2:429-450
  11. 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 1996;154:300-307.
  12. Lippmann M. Health effects of ozone. A critical review. JAPCA 1989;39:672-95.
  13. 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 1991 Jul 27;338(8761):199-203
  14. Ball BA, Folinsbee LJ, Peden DB, Kehrl HR. Allergen bronchoprovocation of patients with mild allergic asthma after ozone exposure. J Allergy Clin Immunol 1996 Sep;98(3):563-572.
  15. Hanania NA, Tarlo SM, Silverman F, Urch B, Senathirajah N, Zamel N, Corey P. Effect of exposure to low levels of ozone on the response to inhaled allergen in allergic asthmatic patients. Chest 1998; 114:752-6. 16.
  16. 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 1996 Jan;153(1):56-64.
  17. Rusznak C, Devalia JL, Davies RJ. Airway response of asthmatic subjects to inhaled allergen after exposure to pollutants. Thorax 1996;51:1105-1108.
  18. Devalia JL, Rusznak C, Herdman MJ, Trigg CJ, Tarraf H, Davies RJ. Effect of nitrogen dioxide and sulphur dioxide on airway response of mild asthmatic patients to allergen inhalation. Lancet 1994 Dec 17;344(8938):1668-1671.
  19. Tunnicliffe WS, Burge PS, Ayres JG. Effect of domestic concentrations of nitrogen dioxide on airway responses to inhaled allergen in asthmatic patients. Lancet 1994 Dec 24;344(8939-8940):1733-1736.
  20. Jenkins HS, Devalia JL, Mister RL, Bevan AM, Rusznak C, Davies RJ. The Effect of Exposure to Ozone and Nitrogen Dioxide on the Airway Response of Atopic Asthmatics to Inhaled Allergen. Dose- and time-dependent effects. Am J Respir Crit Care Med 1999;160:33-39
  21. Kehri 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 1999;104:1198-1204.
  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 1990 Sep;142(3):594-601.
  23. Hiltermann TJ, de Bruijne CR, Stolk J, Zwinderman AH, Spieksma FT, Roemer W, Steerenberg PA, Fischer PH, van Bree L, Hiemstra PS. Effects of photochemical air pollution and allergen exposure on upper respiratory tract inflammation in asthmatics. Am J Respir Crit Care Med 1997 Dec;156(6):1765-1772.
  24. 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 1996 Jul;154(1):24-29.
  25. Aris RM, Christian D, Hearne PQ, Kerr K, Finkbeiner WE, Balmes JR. Ozone-induced airway inflammation in human subjects as determined by airway lavage and biopsy. Am Rev Respir Dis 1993 Nov;148(5):1363-1372.
  26. Peden DB, Boehlecke B, Horstman D, Devlin R. prolonged acute exposure to 0.16 ppm ozone induce eosinophilic airway inflammation in asthmatic subjects with allergies. J Allergy Clin Immunol 1997; 100: 802-
  27. Vagaggini B, Carnevali S, Macchioni P, Taccola M, Fornai E, Bacci E, Bartoli ML, Cianchetti S, Dente FL, Di Franco A, Giannini D, Paggiaro PL. Airway inflammatory response to ozone in subjects with different asthma severity. Eur Respir J 1999;13:274-80.
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