NEW YORK CITY—Poor air quality has long been associated with asthma exacerbation, but new evidence links pollution with new-onset asthma and atopy. At the recent meeting of the American Academy of Allergy, Asthma, & Immunology, researchers described how exposure to ozone and/or diesel exhaust can contribute to the development of these disorders.[1]

Ozone is “a direct oxidant that causes secondary free-radical formation and damages macromolecules, including lipids,” said John R. Balmes, MD, Professor of Medicine at the University of California, San Francisco. Besides the short-term restrictive impairment in lung function that ozone exposure causes in nonasthmatic subjects, “there is also induction of increased airway responsiveness to methacholine or histamine, and increased airway epithelial permeability,” Dr. Balmes noted. In addition, ozone causes acute airway inflammation, as demonstrated by a threefold to fivefold increase in neutrophil counts and elevated levels of biochemical markers: total protein, albumin, and specific cytokines, such as interleukin 6 (IL-6).

Epidemiological studies link high ozone levels with asthma exacerbations, as well as an increase in emergency department visits for asthma. Furthermore, a 27% reduction of peak ozone levels during the 1996 Summer Olympics in Atlanta, achieved by modifying vehicular traffic, was shown to yield a 20% to 40% decrease in asthma health care utilization. Ozone’s association with asthma exacerbations could be attributed to acute induction of airway inflammation and airway hyperresponsiveness or enhanced sensitivity to inhaled aeroallergens with exposure, Dr. Balmes pointed out.

Dr. Balmes further linked ozone with asthma etiology: Among college freshmen who had grown up in southern California, “decreased flow rates at middle and low lung volume (so-called small-airways dysfunction) were found in association with lifetime exposure to ozone, and, in particular, [with] exposure early in life (under age 4).” Comparing his findings with data from animal models, Dr. Balmes noted, “If you expose rhesus monkeys from birth to ozone … [you] get striking abnormalities in airway development: There’s actually loss of some conducting airways” at a stage equivalent to age 3 years in humans. In addition, the monkeys develop enhanced allergen responses and asthma-like symptoms.

David Diaz-Sanchez, PhD, Adjunct Assistant Professor of Medicine at University of California, Los Angeles, described explorations of the effects of DEP on nasal allergic sensitization. He and his colleagues measured immunoglobulin E (IgE) levels in nasal lavage samples taken from human subjects before and after nasal application of DEP, with or without allergen challenge. “The amount of DEP we use is approximately equivalent to 40 hours of exposure in Los Angeles, [but it is] given in a bolus,” Dr. Diaz-Sanchez said.

“DEP, by itself, increases inflammation in the nose: You see an increase in the number of T cells, in the number of total cells, and in the number of neutrophils, but you don’t see an increase in the number of eosinophils” in nonallergic subjects. In contrast, those allergic to short ragweed and challenged with allergen “generate allergic antibody production [IgE] up to 50 times greater when DEP is present than when DEP is absent,” Dr. Diaz-Sanchez noted. “However, you don’t see an increase in ragweed-specific IgG” when DEP is present. At the same time, levels of IL-4, IL-5, IL-6, and IL-13 are elevated, whereas interferon-gamma concentrations are reduced. “It seems that DEP ... increases the TH2 [T-helper 2 cells] environment and decreases the TH1 cytokine environment,” thus enhancing allergic responses at 24 hours, Dr. Diaz-Sanchez remarked.

Interestingly, DEP also affects the immediate response: DEP, but not carbon or other particulates, enhances secretion of histamine.[3] “This correlates to symptom scores,” noted Dr. Diaz-Sanchez. He added, “DEP will reduce to one fifth the amount of allergen required to promote allergic responses.” Thus, DEP clearly can exacerbate allergy.

“But, what we actually wanted to find out is whether you can cause sensitization,” Dr. Diaz-Sanchez explained. To answer this question, he and his colleagues challenged nonallergic subjects with repeated doses of keyhole-limpet hemocyanin (KLH), either in the presence or in the absence of DEP. In response, the subjects produced IgG and IgA, but not IgE. However, when the subjects underwent repeated immunization with KLH plus DEP, they began to also produce IgE, indicating allergic sensitization.[4]

“Chronic exposure to particulate matter will cause reduced pulmonary function, lung volume, and ventilation-diffusion capacity,” said Dr. Diaz-Sanchez, but diesel exhaust may specifically affect lower airways in other ways. Airway reactivity and responses to acetylcholine are increased in animals inhaling DEP.[5] In addition, among nonasthmatic individuals, exposure to diluted diesel exhaust for one hour increased the number of inflammatory cells in the airways as well as the levels of histamine and inflammatory mediators; it also decreased macrophage function.

DEP’s effects are largely chemical, Dr. Diaz-Sanchez said: With phenanthrene, a polyaromatic hydrocarbon that is a component of exhaust, “you can duplicate the results that we see with DEP.” Challenge with ragweed plus phenanthrene leads to enhanced production of IgE specific to ragweed, he pointed out.

DEP’s impact is accentuated in mice with impaired antioxidant responses, suggesting that diesel’s effects involve oxidative stress. Diesel extracts stimulate cultured human bronchial epithelia to release inflammatory cytokines in vitro; however, “if you add N-acetylcysteine … a carbon antioxidant, to the culture, you can block this response,” said Dr. Diaz-Sanchez. “We’re starting to look at whether pretreatment with N-acetylcysteine … can actually block DEP-induced allergic responses in the nose.”

—Mimi Zucker, PhD

References
1. Peden DB, Diaz-Sanchez D, Balmes JR, Kleeberger SR. Air pollution and asthma. Presented at: American Academy of Allergy, Asthma, & Immunology 58th Annual Meeting; March 3, 2002; New York, NY.
2. Michelson PH, Dailey L, Devlin RB, Peden DB. Ozone effects on the immediate-phase response to allergen in the nasal airways of allergic asthmatic subjects. Otolaryngol Head Neck Surg. 1999;120:225-232.
3. Diaz-Sanchez D, Penichet-García M, Saxon A. Diesel exhaust particles directly induce activated mast cells to degranulate and increase histamine levels and symptom severity. J Allergy Clin Immunol. 2000;106:1140-1146.
4. Diaz-Sanchez D, García MP, Wang M, et al. Nasal challenge with diesel exhaust particles can induce sensitization to a neoallergen in the human mucosa. J Allergy Clin Immunol. 1999;104:1183-1188.
5. Nordenhäll C, Pourazar J, Ledin MC, et al. Diesel exhaust enhances airway responsiveness in asthmatic subjects. Eur Respir J. 2001;17:909-915.

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