2002 Progress Report: Lung Hypoxia as Potential Mechanisms for PM-Induced Health Effects

EPA 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, 2001 through May 31, 2002
RFA: Airborne Particulate Matter (PM) Centers (1999) RFA Text |  Recipients Lists
Research Category: Air Quality and Air Toxics , Particulate Matter , Air

Objective:

Chronic exposure to ambient air particulate matter (PM) leads to an increase in respiratory and cardiovascular diseases. Ambient PM originates from many different anthropogenic and natural sources. Burning of petroleum-based fossil fuel in power plants results in the emission of residual oil fly ash (ROFA). Although it is known that exposure to ROFA produces injury of the airways and lungs, the mechanism of ROFA toxicity is not completely understood. ROFA does not contain significant amounts of organic components, but does contain relatively high quantities of transition metals, predominantly iron (Fe), nickel (Ni), vanadium (V), magnesium (Mg), and calcium (Ca), as well as soluble sulfates. Three metals, Fe, V, and Ni, are present in the largest quantities, and the amount of each can vary depending on the particle source; in some ROFA, Ni content could comprise up to 35 percent of the total metal present.

It recently was shown that water soluble Ni is responsible for the majority of pulmonary injury caused by ROFA. Moreover, the pulmonary inflammation induced by ROFA is reproducible by intratracheal instillation of a mixture of soluble forms of Ni. Twelve days of instillation in rats with nickel chloride (NiCl2), nickel sulfate (NiSO4), or nickel sulfide (Ni3S2) has resulted in in situ inflammatory and fibrotic responses. In addition, acute bronchiolitis was induced in rats by repeated daily inhalation of NiCl2 aerosols over a 5-day period. Chronic exposure of rats to these compounds also has been associated with chronic active inflammation, fibrosis, and alveolar macrophage hyperplasia. This proinflammatory response is likely to be related to a Ni-induced production of cytokines; indeed, secretion of proinflammatory interleukin (IL)-8 has been shown to be up-regulated by Ni exposure.

Recently, we reported that exposure to either soluble or insoluble Ni compounds strongly activated a hypoxia-inducible pathway, including hypoxia-inducible transcription factor (HIF-1) and several hypoxia-inducible genes. It is known that HIF-1 transcription factor plays a role of master regulator of hypoxia-inducible gene expression, and that its induction and activation depends on the cellular level of oxygen and the activity of Fe-containing hydroxylases. These data indicate that hydroxylases serve as oxygen and Fe sensors, and they emphasize the importance of Fe in regulation of hypoxia-inducible gene expression.

Another important PM component is Fe, and some of the pathological effects after inhalation may be due to reactive oxygen species (ROS) produced by Fe-catalyzed reactions. For example, it has been suggested that Fe could induce IL-8 production in A549 cells due to ROS induction. It is clear that Fe and Ni each can produce biological effects. However, there are very few investigations into the effects of co-exposure to these two metals.

Progress Summary:

Progress in Years 1 and 2 of the Project. The effects of Fe and Ni (alone and in combination) on hypoxic stress induction and IL-8 production were investigated in the human lung epithelial 1HAEo- cell line. Exposure to NiSO4 produced hypoxic stress-as measured by induction of hypoxia-inducible NDRG-1/Cap43 protein-and significantly induced IL-8 production by the cells. Similarly, hypoxic stress and IL-8 production were induced by the Fe chelator desferoxamine (DFX), suggesting that Ni may somehow interfere with Fe metabolism. The potential cross-regulatory relationship between these two metals was borne out by a study showing that Ni-induced expression of hypoxic genes and IL-8 production could be antagonized by pretreatment of the cells with Fe. Interestingly, co-exposure with Fe and Ni did not significantly change the uptake of either ferrous (Fe2+) or ferric (Fe3+) forms of iron. However, it was noted that co-exposures caused the cells to attain high intracellular levels of Ni, often at levels that exceeded that of Fe. It is possible that Ni inside the cell may have become substituted for Fe in one of several Fe-containing enzymes/proteins, including dioxygeneses. This substitution, in turn, could lead to inhibition of the activity of the enzymes/proteins and the activation and/or induction of HIF-1 and other transcription factors. Secretion of IL-1ß, IL-6, and TNFalpha by Ni or Fe was not affected; however, treatment of the cells with other PM components or standard particle (such as carbon black and sulfates) was efficient in inducing these cytokines.

Future Activities:

We will continue to advance the objectives of this research project and to investigate the effects of co-exposure to Fe and Ni.

Journal Articles:

No journal articles submitted with this report: View all 3 publications for this subproject

Supplemental Keywords:

air pollution, air pollutants, particulate matter, PM, fine particles, PM2.5, lung hypoxia, PM-induced health effects, health effects, respiratory effects, pulmonary effects, ambient PM, respiratory diseases, cardiovascular diseases, transition metals, iron, Fe, nickel, Ni, vanadium, V, magnesium, Mg, calcium, Ca, soluble sulfates, residual oil fly ash, ROFA, inflammation, fibrosis, alveolar macrophage hyperplasia, HIF-1 transcription factor, hypoxia-inducible gene expression, hypoxic stress, cytokines., RFA, Health, PHYSICAL ASPECTS, Scientific Discipline, Air, ENVIRONMENTAL MANAGEMENT, particulate matter, Environmental Chemistry, Health Risk Assessment, Risk Assessments, Physical Processes, Environmental Monitoring, 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

Relevant Websites:

http://charlotte.med.nyu.edu/epa-pm-center/ Exit

Progress and Final Reports:

Original Abstract
  • 1999
  • 2000
  • 2001 Progress Report
  • 2003 Progress Report
  • 2004
  • Final Report

  • 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