Airborne Particulate Matter-Induced Lung Inflammation

EPA Grant Number: R826782
Title: Airborne Particulate Matter-Induced Lung Inflammation
Investigators: Morandi, Maria T. , Holian, Andrij , Parsley, Edwin
Institution: The University of Texas at Houston
Current Institution: The University of Texas at Houston , University of Montana
EPA Project Officer: Hunt, Sherri
Project Period: October 1, 1998 through September 30, 2001 (Extended to September 30, 2002)
Project Amount: $674,288
RFA: Health Effects of Particulate Matter and Associated Air Pollutants (1998) RFA Text |  Recipients Lists
Research Category: Air Quality and Air Toxics , Air , Health Effects , Particulate Matter

Description:

Recent epidemiological studies have reported a statistically significant association between short-term increases in airborne respirable particulate matter (PM) and increased mortality and morbidity from respiratory and cardiovascular disease. Although toxic effects of airborne PM have been demonstrated with a variety of animal models and, to a more limited extent, with human subjects, the mechanism(s) that would explain the reported associations between exposure to PM and adverse health effects remains to be elucidated. Given the results of the epidemiology studies and some of the toxicology data, this mechanism(s) probably involves exacerbation of pre-existing cardiovascular and pulmonary chronic diseases. The very large number of individuals exposed to respirable PM and the lack of an accepted mechanistic hypothesis to explain the reported adverse health effects emphasizes the importance of the current proposed study. We propose that one of the important targets of PM-induced inflammation is the alveolar macrophage (AM). The purpose of this study is to test the hypothesis that fine PM (PM2.5) induce apoptosis of what is termed an immune suppresser population of AM that allows the remaining immune active AM population to more easily activate T helper cells resulting in activation of cytokine cascades and development of lung inflammation. We further propose that these effects would be more pronounced in individuals with chronic lung disease.

Approach:

There are four major goals of this research. Goal 1: To characterize PM2.5-induced apoptosis and phenotype shifts in human AM in vitro and AM apoptosis and T helper cell activation in murine models in vivo. Goal 2: To characterize the influence of age in murine models on the bioactivity of PM2.5. Goal 3: To characterize the effects of PM2.5 on AM apoptosis and phenotype shifts in human AM isolated from patients with chronic lung disease. Goal 4: To characterize the bioactive chemical components of PM2.5 that affect apoptosis and phenotype shifts in human AM and T helper cell activation in murine models. To accomplish these goals PM2.5 will be collected on polyester membrane filters until a sufficient mass (is accumulated for groups of in vitro and in vivo studies. Sites for collection will be representative of industrial, motor vehicle, residential and background sources around Houston as well as sites in El Paso, TX. It is anticipated that approximately 30 separate filter pools will be collected during each year of the study. Particles will be collected in a 12 hr daytime (photochemically derived PM) and nighttime formate at each site. PM collected on filters from same site sampling will be pooled for chemical analysis and biological studies. The PM will be analyzed for metals and organic components. Additional positive and negative control particles will include NIST particles 1648 and 1649, crystalline silica, titanium dioxide and ROFA particles (provided by the EPA). Studies in Goal 1 will be in vitro studies to assess the ability of the PM to cause apoptosis and necrosis of human AM, shifts in AM phenotypes, and stimulation of antigen presenting cell activity. Similar studies (apoptosis and antigen presenting activity) will be conducted in vivo by giving the particles intratracheally to C57Bl/6 and Balb/c mice and will also include measurements of Th1 and Th2 cytokines in the lung lavage fluid. Lung inflammation caused by the various PM will be assessed by differential analysis of lavaged AM and histological examination of perfusion fixed lung sections. Studies in Goal 2 will be in vivo studies with mice using optimal endpoints determined from Goal 1 and will examine very young mice and aged mice obtained from the National Institute of Aging. Studies in Goal 3 will utilize AM obtained from patients with chronic obstructive lung disease, asthma and chronic interstitial lung disease and focus on whether PM are more effective in causing apoptosis, shifts in macrophage phenotypes and stimulation of immune responses in cells from these sensitive subpopulations. Studies in Goal 4 will fractionate PM into water soluble and organic soluble components and test these on human AM in vitro and mice in vivo to determine where the biologically active component of PM is located.

Expected Results:

We anticipate demonstrating that PM will cause a dose-dependent induction of apoptosis in human AM in vitro that will preferentially deplete the suppresser AM population. The remaining population of human AM will be able to more effectively stimulate T helper cells. Similar results are expected in vivo with murine models. Further, we anticipate that AM from young and old mice will be more susceptible to injury than cells from young adult mice. It is also expected that AM obtained from patients with chronic lung disease will demonstrate an even greater shifts of AM phenotypes than cells from healthy subjects. In addition, we propose that we will be able to correlate the potency of PM some component(s) or property of PM.

Publications and Presentations:

Publications have been submitted on this project: View all 5 publications for this project

Journal Articles:

Journal Articles have been submitted on this project: View all 2 journal articles for this project

Supplemental Keywords:

One of the major limitations in understanding the health risks associated with PM exposure (as defined by the NRC report on PM) is the lack of a well-defined toxic mechanism and uncertainty in what characteristics of PM are important in determining the toxic effects of PM. This project will address a testable hypothesis that could account for morbidity and mortality effects of PM and address the characteristics of PM that account for the toxic effects of PM. Therefore, the results from this study will be very useful for developing mechanistic-based risk assessment strategies for particulate exposure on human health., RFA, Health, Scientific Discipline, Air, Geographic Area, particulate matter, Toxicology, Health Risk Assessment, State, Risk Assessments, Susceptibility/Sensitive Population/Genetic Susceptibility, genetic susceptability, indoor air, Atmospheric Sciences, Biology, Immunology, EPA Region, sensitive populations, particulates, health risks, human health effects, inhalability, morbidity, Texas, airway disease, cardiovascular vulnerability, exposure, pulmonary disease, air pollution, pre-existing conditions, human exposure, cardiopulmonary response, mortality studies, lung inflammation, Region 6, coronary artery disease, Acute health effects, indoor air quality, mortality, environmental hazard exposures, toxics

Relevant Websites:

ambient air, indoor air, sensitive populations, environmental chemistry, biology, analytical, Texas, TX, EPA Region 6,

Progress and Final Reports:

Final Report