2001 Progress Report: Lung Hypoxia as Potential Mechanisms for PM-Induced Health EffectsEPA Grant Number: R827351C010
Subproject: this is subproject number 010 , established and managed by the Center Director under grant R827351
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: EPA NYU PM Center: Health Risks of PM Components
Center Director: N/A
Title: Lung Hypoxia as Potential Mechanisms for PM-Induced Health Effects
Investigators: Salnikow, Konstantin
Current Investigators: Cohen, Mitchell , Salnikow, Konstantin
Institution: New York University School of Medicine
EPA Project Officer: Chung, Serena
Project Period: June 1, 1999 through May 31, 2005 (Extended to May 31, 2006)
Project Period Covered by this Report: June 1, 2000 through May 31, 2001
RFA: Airborne Particulate Matter (PM) Centers (1999) RFA Text | Recipients Lists
Research Category: Air Quality and Air Toxics , Particulate Matter , Air
The objective of this research project is to test the hypothesis that PM2.5 exposure induces hypoxic events, pulmonary hypertension, and proinflammatory and apoptotic responses in lung cells. Several epidemiologic studies have demonstrated a link between exposure to ambient particulate matter (PM) and adverse respiratory effects. Based on radiologic studies of the lungs of children residing in urban regions where PM levels often are well above acceptable levels, there is evidence that chronic exposure to PM has led to respiratory tract damage in these otherwise clinically healthy individuals. Other studies of nonsmokers suggest a link between long-term exposure to PM and the increased development of obstructive airway disease. Some investigators have suggested that these changes arising from chronic exposure to PM are because of the repeated induction of inflammatory events in the lungs. Furthermore, the ongoing PM exposures potentiate a cycle of overproduction of proinflammatory cytokines and agents involved in lung tissue repair or fibrosis. Pulmonary hypertension could be another pathologic change in the PM-exposed lungs. This disease may arise from increased production of potent vasoconstrictor endothelin that will restrict lung blood flow and lead to a state of hypoxia. The purpose of this study is to examine whether exposure to PM results in activation of the hypoxia-inducible signaling pathway. A determination as to whether or not PM (in this case, as PM2.5) exposure can induce hypoxic changes in vitro in lung cells would permit subsequent follow-up investigations in the mouse lung to be performed. This might help to delineate the mechanisms by which the above-noted changes in lung structure of PM-exposed children and adults might have evolved.
To test the hypothesis that PM2.5 exposure induces hypoxic events, pulmonary hypertension, proinflammatory and apoptotic responses in lung cells, we are studying the expression of hypoxia-inducible and proinflammatory proteins (VEGF, Cap43, endothelin, IL-1, and PAI-1), the induction of c-Jun, the activation SAPK/JNK kinase, and AP-1 transcription factor in rat and human bronchoepithelial and endothelial cells in vitro. The same parameters will be studied in rat lungs exposed to PM2.5 in vivo.
Concentrated ambient PM is the most realistic surrogate for particulate air pollution for use in controlled exposures. They mostly are composed of inorganic ions, metals, black carbon, and organic materials. To identify the biologically active components of PM, and particularly the role of PM-associated transition metals, we have done a series of experiments comparing the effects of concentrated ambient PM, laboratory-generated ultrafine carbon and polystyrene particles, as well as particles containing nickel and chromium only. The preliminary results have been done on human lung A549 cells, in which we were able to show that hypoxia-inducible pathway in these cells was activated only by nickel containing particles. The activation was monitored by the induction of hypoxia-inducible proteins (Cap43 and IL-1), as well as by the induction of SAPK kinase. Currently, experiments involving human BEAS-2 cells, in which we are testing all the above-mentioned endpoints, are underway.
Future activities are to perform studies examining the effects of concentrated ambient PM, laboratory-generated ultrafine carbon, and polystyrene particles, as well as metal combinations on the hypoxia-inducible pathway in human BEAS-2 and rat CL149 bronchoepithelial cells.
Journal Articles:No journal articles submitted with this report: View all 3 publications for this subproject
Supplemental Keywords:particulate matter, PM, adverse respiratory effects, chronic exposure, lungs, PM-exposed lungs, proinflammatory cytokines, ambient PM., RFA, Health, Scientific Discipline, PHYSICAL ASPECTS, Air, ENVIRONMENTAL MANAGEMENT, particulate matter, Environmental Chemistry, Health Risk Assessment, Risk Assessments, Environmental Monitoring, Physical Processes, Atmospheric Sciences, Risk Assessment, ambient air quality, atmospheric particulate matter, particulates, atmospheric particles, chemical characteristics, toxicology, ambient air monitoring, acute lung injury, airborne particulate matter, environmental risks, exposure, epidemelogy, lung hypoxia, air pollution, aerosol composition, atmospheric aerosol particles, pulmonary hypertension, human exposure, PM, airway contractile properties, exposure assessment
Progress and Final Reports:Original Abstract
Main Center Abstract and Reports:R827351 EPA NYU PM Center: Health Risks of PM Components
Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R827351C001 Exposure Characterization Error
R827351C002 X-ray CT-based Assessment of Variations in Human Airway Geometry: Implications for Evaluation of Particle Deposition and Dose to Different Populations
R827351C003 Asthma Susceptibility to PM2.5
R827351C004 Health Effects of Ambient Air PM in Controlled Human Exposures
R827351C005 Physicochemical Parameters of Combustion Generated Atmospheres as Determinants of PM Toxicity
R827351C006 Effects of Particle-Associated Irritants on the Cardiovascular System
R827351C007 Role of PM-Associated Transition Metals in Exacerbating Infectious Pneumoniae in Exposed Rats
R827351C008 Immunomodulation by PM: Role of Metal Composition and Pulmonary Phagocyte Iron Status
R827351C009 Health Risks of Particulate Matter Components: Center Service Core
R827351C010 Lung Hypoxia as Potential Mechanisms for PM-Induced Health Effects
R827351C011 Urban PM2.5 Surface Chemistry and Interactions with Bronchoalveolar Lavage Fluid (BALF)
R827351C012 Subchronic PM2.5 Exposure Study at the NYU PM Center
R827351C013 Long Term Health Effects of Concentrated Ambient PM2.5
R827351C014 PM Components and NYC Respiratory and Cardiovascular Morbidity
R827351C015 Development of a Real-Time Monitoring System for Acidity and Soluble Components in Airborne Particulate Matter
R827351C016 Automated Real-Time Ambient Fine PM Monitoring System