Effects of nitrogen dioxide on airway responsiveness in allergic asthma

Abstract: Asthma is one of the most common chronic diseases in the industrialized world and its prevalence is increasing. Clinical symptoms of airway obstruction and bronchial hyper responsiveness can be induced by specific agents, such as allergens and non-specific stimuli, such as cold air and irritants. In order to avoid exacerbation it is important to identify these stimuli and to study how they interact with each other and amplify inflammation in asthma. Nitrogen dioxide (NO2) is one of the major air pollutants and the main source is traffic exhausts outdoors and gas appliances indoors. The major aim of this thesis was to study the effects of ambient levels of NO2 on airway responsiveness to histamine and allergen, in subjects with asthma. Airway hyperresponsiveness is a hallmark of asthma and is associated with clinical symptoms and inflammation. In 19 subjects with mild asthma, airway responsiveness to histamine was measured 30 minutes, 5 hours, 27 hours and 7 days after 30 minutes of exposure to NO2 (500 µg/m3) and to filtered air. Histamine responsiveness increased 5 hours after NO2 exposure, suggesting a delayed enhancing effect of NO2 on airway responsiveness. Exposure to traffic exhausts in the morning rush hours may be followed by exposure to pollen allergen during the pollen season. Eighteen subjects with mild allergic asthma to birch or grass pollen were exposed to NO2 (500 µg/m3) or air in the laboratory followed by a bronchial allergen challenge 5 hours later. Lung function during the evening (peak expiratory flow, PEF) decreased significantly after NO2, compared with the control. No effect was seen on the asthmatic reaction immediately after the challenge. Natural exposure to both NO2 and allergen is usually recurrent and the seasonal, daily, allergen dose is significantly lower than a conventional allergen challenge dose. In order to imitate natural exposure, 16 subjects with allergic asthma to birch or grass pollen were exposed every morning for 4 days to NO2 (500 µg/m3) or air, followed 4 hours later by a small nonsymptomatic dose of allergen. The allergen dose was individually predetermined to 10 % of the conventional challenge dose, measured at the inclusion test. After a single exposure to NO2 and allergen day 1, the early asthmatic reaction was increased compared to air and allergen. During the NO2 week, with 4 days of repeated exposure, both the early and the late reaction measured as fall in the FEV1 (forced expiratory volume in 1 second) after allergen, increased compared with the control. Exposure to NO2 in real life is usually mixed with other pollutants, and in this field study, 20 subjects with mild allergic asthma were exposed for 30 minutes in a car parked in a Stockholm city road tunnel during the morning rush hours in order to assess possible adverse effects. Levels of NO2 and particulate matter (PM10 and PM25) during exposure were monitored. Four hours later, the subjects inhaled a low dose of allergen. The early asthmatic reaction to allergen was increased after tunnel exposure. In the subjects with NO2 exposure >300 µg/m3, both the early and the late reactions and asthma symptoms during the evening increased. In another combined field and laboratory study, we wanted to investigate whether natural exposure to birch pollen allergen during the season influences the bronchial responsiveness to histamine after NO2. Sixteen subjects with asthma and allergy to birch pollen were exposed to 500 µg /m3 NO2 or purified air before and during the pollen season. NO2 exposure did not increase airway responsiveness to histamine during the season. To conclude: the main effect of NO2 observed in these studies of subjects with asthma is an increase in airway responsiveness to allergen and non-specific stimuli. This effect is shown at NO2 and allergen levels which can be encountered in ambient air and the effect may be present several hours after NO2 exposure. The exposure model, with short exposure to ambient levels of NO2 in the laboratory, followed after an interval by inhalation of varying doses of allergen, presents a safe and useful method of studying the effects of NO2 on the airways.