Project at a Glance
Title: Mechanisms of particulate toxicity: effects on the respiratory system of sensitive animals and asthmatic humans.
Principal Investigator / Author(s): Pinkerton, Kent E
Contractor: UC Davis
Contract Number: 99-315
Research Program Area: Health & Exposure
Topic Areas: Health Effects of Air Pollution, Toxic Air Contaminants
The primary goal of this research project is to test the effects of particulate matter (PM) on allergic airways in the lungs of sensitive animals and human asthmatic subjects. Four experiments were designed in animals, while complementary studies were done in human asthmatic volunteers. The first two animal experiments were to determine whether the Brown Norway (BN) rat can be treated with ovalbumin (OVA) to make it suitable as a model of asthma, and sequentially to measure the physiologic, biochemical and structural effects of BN rats exposed weekly to aerosolized OVA for up to four weeks. The goal of these experiments was to optimize conditions of exposure to aerosolized OVA, while minimizing any changes in the lungs that may potentially mask the effects of subsequent exposure to particles. With knowledge gained from these first two experiments, the third and fourth experiments were designed to use this allergic airway model to allow us to test the effects of short-term exposure to PM on the structure and function of compromised lung airways and parenchyma. Physiologic, biochemical and histopathological parameters were used to assess particle-induced effects in this animal model. The effects of repeated particle exposure on immune factors to potentially alter the allergic response in the lungs were also examined. We found a model of allergic airways could be produced in the BN rat. We found short-term repeated exposure to ammonium nitrate and carbon demonstrated significant effects of particles to alter airway epithelial cells, increase airway inflammation and transiently elevate IL-4 mRNA levels in the lungs, all indicators of an adverse particle effect on the lungs. Human airway biopsies from asthmatic volunteers exposed to particles similar to those used with BN rats were analyzed using in vitro techniques to demonstrate detectable changes in expression for a panel of cytokines due to particulate exposure alone or in combination with ozone. For asthmatic subjects, the most significant changes noted in mRNA levels following PM exposure were increases in IL-1Ŗ and IL-12p35. These findings in both an animal model of allergic airways disease as well as human asthmatics suggest the airway epithelium is an important target of particle-induced effects associated with inflammation and the perturbation of proinflammatory cytokines present in the lungs. We would advocate, based on these findings, a combined approach to test sensitive animals and human asthmatics to similar particles by size and composition can serve to further elucidate the impact as well as the potential mechanisms of action of airborne particles on the respiratory system in individuals with allergic airway disease.
For questions regarding this research project, including available data and progress status, contact: Heather Choi at (916) 322-3893
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