Grantee Research Project Results
Final Report: Effects of Inhaled Ultrafine Particles on Asthma
EPA Grant Number: R826785Title: Effects of Inhaled Ultrafine Particles on Asthma
Investigators:
Institution: Lovelace Biomedical & Environmental Research Institute
EPA Project Officer: Chung, Serena
Project Period: October 1, 1998 through September 30, 2001 (Extended to September 30, 2002)
Project Amount: $545,147
RFA: Health Effects of Particulate Matter and Associated Air Pollutants (1998) RFA Text | Recipients Lists
Research Category: Human Health , Air , Particulate Matter
Objective:
The original objective of this research project was to test two hypotheses. Inhaled ultrafine particles trigger asthma attacks: (1) directly by stimulating the release of allergic-response cytokines in the lung of asthmatics, or (2) indirectly by decreasing the concentrations of inhaled allergen necessary to cause asthma attacks. Mice sensitized to produce allergic immune responses in their lungs to inhaled ovalbumin (OVA) were exposed to either ultrafine (~0.03 µm) carbon-black particles or diesel exhaust (~ 0.03 µm total particulate matter). Timing of the OVA aerosol challenge was varied to either before or after ultrafine particle exposure to determine whether the presence of allergic inflammation during particle exposure was required to elicit a response due to ultrafine particle exposure. Ultrafine carbon particle concentrations also were spiked at various times during the exposure to determine whether transient increases led to further ultrafine particle exposure effects. Following exposure physiologic (airway hyperresponsiveness [AHR]), pathologic (airway inflammation), and immunologic (total and allergen specific IgE, IgG levels, and cytokine [IL-2, 4, 5 and IFN] levels) features of the allergic/asthmatic phenotype were measured.
Summary/Accomplishments (Outputs/Outcomes):
The potential effects of inhaled ultrafine carbon particles on allergic immune responses to inhaled allergens were explored in a mouse model of allergic airways disease. Mice were sensitized to OVA by repeated intraperitoneal injection. Mice were then exposed to OVA (10 minutes) either 24 hours before ultrafine particle exposure or immediately after particle exposure. Ultrafine carbon particles were generated using an electric spark discharge generator with graphite electrodes. Target concentrations were 50 µg/m3 for 6 hours with some groups receiving a 1-hour spike in concentration up to 200 µg/m3 at different times during the exposure. Ultrafine particle exposure (50 µg/m3) alone led to an increase in AHR as measured by Penh 24 hours following the end of exposure. The addition of a 1-hour spike (200 µg/m3) in the ultrafine particle concentration did not further increase AHR. Particle exposure 24 hours after an inhalation OVA challenge led to an increase in Penh for all particle exposure groups. When the inhalation OVA challenge immediately followed the particle exposure, only those animals exposed to particles that included a 1-hour spike the last hour of exposure had an increased Penh response. Animals that were challenged by inhalation exposure to OVA developed increased numbers of eosinophils, neutrophils, and lymphocytes in their bronchoalveolar lavage fluids (BALF). However, exposure to ultrafine particles alone or in combination with OVA challenge did not lead to a further increase in BALF inflammatory cell numbers. There were no significant differences in the levels of IL-2, 4, and 5, following exposure to ultrafine particles. Following OVA challenge, IFN levels tended to be lower in air-exposed animals. Interestingly, regardless of OVA challenge, IFN levels tended to decrease as the timing of the 1-hour ultrafine particle exposure spike (200 µg/m3) shifted towards the end on the 6-hour ultrafine particle exposure period. OVA challenge tended to increase serum total and OVA-specific IgE levels in air-exposed animals. Ultrafine particle exposure did not significantly alter serum antibody levels. It is concluded from these studies that acute ultrafine particle exposure minimally enhances AHR, but does not enhance other pathologic or immunologic features of the asthmatic phenotype in this animal model.
Based on the minimal effect that ultrafine carbon particle exposure had on exacerbating the asthmatic phenotype, we sought to examine whether a more complex ultrafine particle exposure (e.g., diesel exhaust) would have a different effect. Using the same OVA-sensitized mouse model, animals were challenged with an OVA aerosol 24 hours prior to diesel exposure. Diesel exhaust was generated from a 2000 model Cummins ISB Turbo diesel 5.9 L engine operated on the U.S. Environmental Protection Agency (EPA) Engine Dynomometer Schedule for Heavy Duty Diesel Engines. Diesel exposure concentrations were approximately 40 and 1,000 µg/m3 total particulate matter for 6 hours per day on three consecutive days. Exposure to the highest concentration of diesel exhaust (1,000 µg/m3) led to a small but significant increase in AHR as measured by Penh. Exposure at the lower concentration of diesel (~40 µg/m3) exhaust did not increase AHR above air-exposed animals. There appeared to be a dose-dependant increase in the total number of inflammatory cells in the BAL. However, there was only a statistically significant increase in the number of BAL eosinophils at the 1,000 µg/m3 diesel exposure level. Exposure to diesel exhaust had no effect on the levels of IL-2, 4, 5, and IFN in BALF. Although statistical significance between exposure groups was absent, there appears to be a dose-dependent increase in serum total and OVA-specific IgE. No significant changes were observed in serum IgG1 and IgG2a levels. These results suggest that at relatively high experimental exposure conditions, diesel exhaust can increase the level of AHR and allergic inflammation in an animal model of allergic airway disease. However, at lower exposure concentrations, diesel exhaust does not enhance the allergic response in this animal model.
The research findings support the following conclusions: (1) at relatively low experimental exposure concentrations, ultrafine particles induce small changes in AHR but do not otherwise increase allergic airway responses in mice; (2) the presence or absence of allergic inflammation in the lung does not lead to enhanced ultrafine particle effects; (3) exposure to high levels of diesel exhaust enhance allergic inflammation, and AHR in allergic mice, however, lower levels do not.
Journal Articles:
No journal articles submitted with this report: View all 5 publications for this projectSupplemental Keywords:
sensitive populations, ambient air, air, exposure, risk, heal effects, human health, dose-response, animal, cellular, children, susceptibility, allergens, particulate matter, acute health effects, air pollution, air toxics, airborne pollutants, airway disease, allergic airway, asthma, asthmatic phenotype, diesel, exhaust, inhalation, laboratory animals, antibody, cytokine, airway, lungs., RFA, Scientific Discipline, Health, Air, Toxicology, particulate matter, Environmental Chemistry, Allergens/Asthma, Atmospheric Sciences, ambient air quality, asthma, cytokine production, particulates, lungs, fine particles, human health effects, inhalability, cytokines, carbon, pulmonary disease, allergic airway, exposure, carbon black, airway inflammation, chronic health effects, human exposure, lung inflammation, airborne pollutants, inhalation, Acute health effects, allergens, respiratoryProgress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.