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World Allergy Organization
WAO's mission: To be a global resource and advocate in the field of allergy, advancing excellence in clinical care through education, research and training as a world-wide alliance of allergy and clinical immunology societies.

World Allergy Forum: The Epithelium as a Modulator of the Allergic Response

Upper and Lower Airways Response to Pollutants: Altered Epithelial Biology in Allergic Disease

Sundeep Salvi

Airway epithelial cells exist at the interface with the external environment and are therefore among the first cells exposed to inhaled irritants, allergens and noxious stimuli. These cells not only act as a physical barrier, preventing the entry of particles, bacteria, viruses and noxious substances into the airway mucosa, but also play an important role as a metabolically active physicochemical barrier, capable of synthesizing and releasing a large number of inflammatory mediators including eicosanoids, chemokines, pro inflammatory cytokines and hemopoeitic growth factors, all of which are thought to contribute to proliferation, differentiation, activation and chemoattraction of various inflammatory cells in the airway mucosa.

Epidemiological studies have shown a consistent and significant association between exposure to various air pollutants (ozone, nitrogen dioxide and particulate matter) and increases in respiratory morbidity, including allergic diseases, while exposure chamber studies have demonstrated that the underlying biological mechanism appears to be mediated by the induction of oxidative stress and the development of airway inflammation.

About 40-70% of the inhaled ozone is absorbed in the nasal airways, while a substantial amount reaches the terminal airways, where it produces toxic effects on the epithelial cells at the bronchiolar and alveolar level. Human exposure studies to ozone have demonstrated an increased proportion of ciliated epithelial cells in the bronchoalveolar lavage fluid along with increased Substance P immunoreactivity in the airway epithelium, suggesting that ozone causes epithelial damage or fragility and stimulates subepithelial sensory nerves to release Substance P, a potent proinflammatory mediator into the airways. Ozone has been shown to produce an immediate dose dependent increase in the generation of intracellular reactive oxygen species associated with increase in epithelial cell permeability, which could further facilitate entry of inhaled toxins and/or allergens into the airway submucosa with increases in the release of inflammatory cells or their products onto the airway surfaces. Nasal and bronchial epithelial cells obtained from healthy subjects when grown in culture and exposed to ozone produced increased levels of IL1, IL-6, IL-8, TNF and GM-CCF, while nasal epithelial cells from atopic individuals release significantly more IL-8 and GM-CSF than those from healthy subjects, suggesting that epithelial cells from atopic subjects are more sensitive to the effects of ozone.

Repeated low dose exposure to nitrogen dioxide in chamber studies has demonstrated increase in airway hyperresponsiveness and augmentation of allergic responses and viral inflammatory responses. Exposures of confluent cultures of human bronchial epithelial cells to nitrogen dioxide has demonstrated a significant attenuation of ciliary activity, increased cell membrane damage and increased permeability. In addition, exposure to nitrogen dioxide results in significant release of LTC4 and a variety of cytokines, including IL-8, TNF and GM-CSF, while culture studies of nasal epithelial cells obtained from tissues of patients with atopic rhinitis during the pollen season and from tissues of patients with atopic asthma have shown that they release significantly greater quantities of IL-8 and RANTES after exposure to NO2. Exposure to NO2 and ozone has also been shown to significantly decrease electrical resistance from the epithelial cells of patients with atopic rhinitis / asthma, suggesting that epithelial cells from atopic subjects are more susceptible to cell membrane damaging effects of pollutants.

Short-term exposure to diesel exhaust in healthy human volunteers has demonstrated increased production and release of inflammatory mediators and increased influx of neutrophils, lymphocytes and mast cells into the airways, which is mediated by enhanced gene transcription and protein synthesis of IL-8 and Gro- along with upregulation of endothelial and leukocyte adhesion molecule expression. In vitro cell culture studies have demonstrated that diesel exhaust particles produce oxidant response in epithelial cells leading to activation of the transcription factors NF-B and AP-1 followed by enhanced transcription of several proinflammatory molecules. Bronchial epithelial cells from atopic asthmatic individuals, in particular, show further enhanced release of IL-8, GM-CSF and slCAM-1 compared with cells from healthy individuals. Diesel exhaust particles (DEP) can get adsorbed on to pollen particles and this combination further enhances its allergenicity. Nasal instillation of DEP has been shown to augment both total and allergen-specific IgE synthesis in the nasal mucosa in atopic individuals, while it has been suggested that DEP are at least partly responsible for increasing the incidence of allergic diseases.

In summary, various studies have demonstrated that exposure of nasal or bronchial epithelial cells to nitrogen dioxide, ozone and diesel exhaust particles results in synthesis and release of pro-inflammatory mediators, including eicosanoids, cytokines and adhesion molecules. Increased responsiveness of the airways of allergic individuals to the effects of air pollutants may be a consequence of the increased susceptibility and ability of their airway epithelial cells to release significantly increased amounts of specific proinflammatory mediators in response to interaction with inhaled pollutants.

References

  1. 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 1999 Mar;159(3):702-709.
  2. Salvi SS, Frew A, Holgate S. Is diesel exhaust a cause for increasing allergies? Clin Exp Allergy 1999 Jan;29(1):4-8.
  3. Krishna MT, Chauhan AJ, Frew AJ, Holgate ST. Toxicological mechanisms underlying oxidant pollutant-induced airway injury. Rev Environ Health 1998 Jan-Jun;13(1-2):59-71.
  4. Holgate ST, Lackie PM, Davies DE, Roche WR, Walls AF. The bronchial epithelium as a key regulator of airway inflammation and remodelling in asthma. Clin Exp Allergy 1999 Jun;29 Suppl 2:90-95.
  5. Blomberg A, Krishna MT, Helleday R, Soderberg M, Ledin MC, Kelly FJ, Frew AJ, Holgate ST, Sandstrom T. Persistent airway inflammation but accommodated antioxidant and lung function responses after repeated daily exposure to nitrogen dioxide. Am J Respir Crit Care Med 1999

Slide presentation

 

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