Ambient particulate matter (PM) is increasingly recognized as a significant contributor to human cardiopulmonary morbidity and mortality both in the United States and worldwide. There are strong epidemiologic data that link the daily levels of ambient PM to pulmonary symptoms, rates of infections, school absenteeism, daily use of specific medications, hospitalizations for cardiopulmonary disease, and daily cardiopulmonary mortality rates. Longer term exposure to ambient particulate matter has been associated with an increase in the prevalence of obstructive lung disease and the development of lung cancer. While relatively little is known about the mechanisms by which particulate matter induces disease, it is hypothesized that exposure of epithelial lining cells to ambient particulate matter within the respiratory tract results in the development of reactive oxygen species (ROS) that in turn induce injury and inflammation. We have observed that exposure to well-characterized particulate matter collected from ambient air in Dusseldorf, Germany and Washington, D.C. results in death of alveolar epithelial cells through a mechanism that appears to require iron and the mitochondrial generation of ROS. In this proposal we seek to determine the mechanisms that underlie the generation of reactive oxygen species in response to exposure to particulate matter and the signaling pathways evoked that link the generation of ROS to alveolar epithelial cell death. Specifically, we seek to determine (1) whether iron and ROS generated from the mitochondria are required for particulate matter induced lung epithelial cell death in vitro and in vivo; (2) whether iron and ROS generated in response to particulate matter cause an apoptosis signal-regulating kinase 1 (ASK1) dependent activation of JNK and p38 to induce lung epithelial cell death and (3) whether the activation of p53 acts through the pro-apoptotic Bcl-2 protein PUMA to induce lung epithelial cell death following exposure to particulate matter. These studies combine molecular-genetic approaches to examine the mechanisms of particulate matter induced cell death in vitro and in vivo. Recent estimates suggest that the average loss of life expectancy related to chronic air pollution exposure is between 1.8 and 3.1 years for individuals living in the most polluted American cities. Understanding the mechanisms by which particulate matter induces injury in the lung will help us better design pollution control and response measures that will have a major impact on public health. ? ? ? ? ? ?
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