Pulmonary and Systemic Effects of Inhaled Ultrafine Particles in Senescent Rats with Cardiovascular Disease

EPA Grant Number: R828046
Title: Pulmonary and Systemic Effects of Inhaled Ultrafine Particles in Senescent Rats with Cardiovascular Disease
Investigators: Elder, Alison C.P. , Couderc, Jean-Philippe , Frampton, Mark W. , Oberd√∂rster, G√ľnter , Zareba, Wojciech
Institution: University of Rochester
EPA Project Officer: Hunt, Sherri
Project Period: March 24, 2000 through March 23, 2003 (Extended to September 23, 2003)
Project Amount: $408,859
RFA: Airborne Particulate Matter Health Effects (1999) RFA Text |  Recipients Lists
Research Category: Particulate Matter , Air , Health Effects

Description:

Numerous epidemiological studies report excess morbidity and mortality associated with low levels of particulate air pollution, especially in elderly individuals with cardiopulmonary disease. The investigators hypothesize that inhaled ambient ultrafine particles can induce inflammation and oxidative stress in the lung and systemically in compromised individuals. Priming of lung target cells, as would occur with systemic infection, enhances the injurious effects of particles. The pro-oxidant state of the lung could activate circulating leukocytes and induce changes in blood coagulability, creating cardiovascular stress that can impair heart function in susceptible individuals. Further, the investigators hypothesize that the aged organism cannot cope with oxidant stress as well as the young, resulting in greater or prolonged injury. The following objectives will test these hypotheses in aged, compromised rats using low levels of inhaled ultrafine carbon particles: (1) explore the impact of systemic bacterial toxin-induced stress on pulmonary responses, (2) examine effects on peripheral blood cell oxidant status and coagulability and (3) evaluate effects on cardiac function.

Approach:

Senescent (26 mos) F-344 rats will be exposed to ultrafine carbon particles (99.99% pure; ~20-30 nm; ~100 mg/m3 for 6 hrs) to simulate the nucleation fraction of the ambient fine mode; the deposited dose per unit lung surface area is equivalent to what would result from episodic high ambient ultrafine particle exposures. To prime target cells, endotoxin will be administered via intraperitoneal injection (5 mg/kg) to simulate a mild systemic infection (doses chosen from previous work). Parameters of lung inflammation, tissue injury, BAL and blood cell activation, blood coagulability, and heart rate variability and arrhythmia will be examined immediately, 24, and 48 hrs post-exposure. Comparisons in two other animal models, spontaneously hypertensive (SH) rats and SH rats with heart failure, will be made for the selected time points that produce the most dramatic changes in senescent F-344 rats. Comparisons with larger carbon particles (aggregated ultrafine carbon particles ~250 nm, simulating the accumulation mode) will be made for selected exposure combinations and time points. These studies are complimentary to areas of a currently funded PM Center Program which, among other things, will be exploring the impact of inhaled bacterial toxins on the response to particles. The issue of systemic priming is not addressed in the Center Program; since it is important to characterize the particle responses after priming of lung target cells by both systemic and pulmonary administration of endotoxin, the results from these two programs will be integrated.

Expected Results:

The investigators predict that the extrapulmonary effects of inhaled ultrafine particles will depend on the compartment that is primed by endotoxin (i.e. inhaled or injected) and that the combined stresses of endotoxin and particles will ultimately alter heart function. Further, these effects will be potentiated in SH and SHHF rats with existing cardiovascular disease. Documentation of such effects would point to a mechanism of susceptibility for the aged population with cardiopulmonary disease to the adverse effects of particulate air pollution. Such findings will significantly impact the setting of ambient air quality standards for particulate matter.

Publications and Presentations:

Publications have been submitted on this project: View all 9 publications for this project

Journal Articles:

Journal Articles have been submitted on this project: View all 4 journal articles for this project

Supplemental Keywords:

urban air quality, sensitivity, coagulation, aging, cardiotoxicity., RFA, Health, Scientific Discipline, Air, particulate matter, Toxicology, air toxics, Health Risk Assessment, Risk Assessments, Susceptibility/Sensitive Population/Genetic Susceptibility, Biochemistry, genetic susceptability, Atmospheric Sciences, urban air, sensitive populations, fine particles, human health effects, morbidity, respiration, exposure and effects, cardiovascular vulnerability, exposure, pulmonary disease, animal model, carbon particles, air pollution, chronic health effects, lung inflammation, particulate exposure, bacterial toxin induced stress, cardiopulmonary response, Acute health effects, elderly, PM, cardiotoxicity, mortality, senescent rats, inhaled particles, ultrafine carbon, ultrafine particles, aerosols, air quality, environmental hazard exposures, toxics, animal inhalation study

Progress and Final Reports:

2000 Progress Report
2001 Progress Report
Final Report