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Final Report: Lung Hypoxia as Potential Mechanisms for PM-Induced Health Effects
EPA Grant Number: R827351C010Subproject: 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: Lippmann, Morton
Title: Lung Hypoxia as Potential Mechanisms for PM-Induced Health Effects
Investigators: Cohen, Mitchell , Salnikow, Konstantin
Institution: NYU School of Medicine
EPA Project Officer: Stacey Katz/Gail Robarge,
Project Period: June 1, 1999 through May 31, 2005 (Extended to May 31, 2006)
RFA: Airborne Particulate Matter (PM) Centers (1999)
Research Category: Particulate Matter
Description:
Objective:At-risk individuals with pre-existing hypertensive disease or atherosclerosis, appear to have overtly negative responses to particulate matter (PM). However, mechanisms underlying these effects and which constituents might be causing these outcomes are unclear. Atherosclerosis has been designated a chronic inflammatory process; it has been accepted that circulating levels of IL-6 may reflect the intensity of occult plaque inflammation and vulnerability to rupture. MCP-1 and IL-8 may also play a crucial role in initiating/promoting atherosclerosis. Hypertensive patients are at particular risk of complications related to endothelial damage or abnormal angiogenesis; these processes are correlatable with plasma levels of vascular endothelial growth factor (VEGF). We hypothesized here that select PM constituents (e.g., Al, V, Ni, Mn) act on lung epithelial cells and macrophages to stimulate release of pro-inflammatory cytokines/chemokines that may have a role in initiation or promotion of atherosclerosis. We further hypothesized that the metals contributed to the above noted deleterious responses in patients with pre-existing hypertensive disease/atherosclerosis by: 1) a priori altering the Fe status of these cells that, in turn, 2) results in increased intracellular accumulation of HIF-1α. Due to the latter, lung epithelial cells and macrophages increase their formation/release of proinflammatory cytokines, i.e., IL-6, IL-8, TNF-α, as well as MCP-1 and VEGF, which are then transported to the heart in relatively high (undiluted) concentrations. To validate our hypotheses, lung macrophage and epithelium cell lines were exposed to varying amounts of Fe alone or in combination with Al, V, Mn, or Ni (at levels relevant to those found in ambient urban PM from New York City [NYC]) and levels of each of the above-cited cytokines/chemokines were measured by ELISA, Northern, and Western analyses (the latter to increase the degree of detectability of effects from the treatments). These results could then be used as a baseline of effects for later comparison against the actual formation of these proteins in the lungs of rodents exposed to the “parent” NYC PM2.5 samples.
Summary/Accomplishments (Outputs/Outcomes):The initial studies here examined potential effects of Fe and Ni (alone and in combination) on hypoxic stress induction and IL-8 production in human lung epithelial 1HAEo- cells. Exposure to Ni induced both hypoxic stress and IL-8 production; as similar levels of stress and IL-8 were induced by Fe-chelating desferroxamine (DFX), this suggested that Ni interfered with cell Fe status (much in the manner seen with other PM-associated metals in rat lung macrophages (NR8383 [NR]); Project 8; R827351C008). It is also possible that Ni may have become substituted for Fe in Fe-bearing enzymes/proteins, leading to inhibition of their activity and, subsequently, to activation/induction of HIF-1 transcription factors. To assess if treatment with PM-associated metals led to altered Fe homeostasis that should induce an increased HIF-1α expression that subsequently leads to increases in the presence of MIP-2/IL-8 or VEGF, cultures of 1HAEo- or NR were treated overnight with soluble forms of Ni, V, or Al in combination with a fixed amount of Fe (each at levels that would be present in actual NYC PM2.5). Western analysis of cellular products indicated that increases in the relative amounts of V:Fe caused significant increases in HIF-1α expression (to values similar to those from DFX). Exposure to increasing amounts of Ni also caused increased HIF-1α expression, but less so than with V. Al treatments seemed to have no effect on HIF-1α expression; however, as these exposures caused more cell death and proteolytic damage to materials isolated from viable cells, these measurements may have been biased.
Analyses of HIF-1α-inducible cyto-/chemokines indicated that Al, Ni, and V each induced VEGF formation in NR cells. Induction levels were all equal-to-greater than that from DFX and the strength of effect was Al ≥ Ni > V. Western analyses of MIP-2 levels were inconclusive due to difficulties in resolving the protein in cell lysates; ELISAs yielded indications that Al had the strongest impact on MIP-2 release. With the 1HAEo- line, ELISAs of supernatants from treated cells suggested that at the higher metal:Fe levels tested, each metal induced IL-8 formation. In contrast, any stimulation of VEGF production appeared to occur with increasing Ni levels only. Critical Western analyses to confirm each noted pattern were impossible due to problems with poor antibody specificities. In their place, mRNA levels of respective HIF-1α-inducible genes were measured to obtain an indication of any induced shift in cyto-/chemokine formation. RT-PCR analyses showed that Al and Ni induced significant levels of VEGF mRNA and that the effect was ratio (i.e., Al:Fe, Ni:Fe)-related; oddly, the effect of V treatment was nominal. Similar results were also noted for IL-6 gene induction. With MCP-1, MIP-2, and TNFα, none of the metals tested had any effect.
The results with the rat macrophage (as compared to the human lung epithelial) line suggest there may be potential species-/cell type-related differences in responses to PM-metal-induced alterations in Fe homeostasis. The data also suggest that the relationship between metal-induced HIF-1α expression and levels of select cyto-/chemokine products may not necessarily be linear. However, this latter finding needs to remain tentative as effects of Al, Ni, and V on several relevant processes in cells need to be refined.
Conclusions:- Select metals within a given sample of PM2.5 can cause altered cellular Fe homeostasis and this effect appears to be governed by the relative content relationships between Fe and at least three co-constituent metals, e.g., Ni, Al, and V.
- Among these metals (that alter Fe homeostasis), Ni and Al (more so than V) also cause changes in the release of select cytokine/chemokine factors that could impact initiation or promotion of atherosclerosis. This effect also is related to relative content relationships between Fe and these metals.
- The observed effects on the inducible release of these factors seem, for now, to be both species- and cell type-dependent.
Technical Report:
Long Version of Final Report (PDF) (4 pp, 98 K, About PDF)
Journal Articles on this Report: 3 Displayed | Download in RIS Format
| Other subproject views: | All 3 publications | 3 publications in selected types | All 3 journal articles |
| Other center views: | All 95 publications | 86 publications in selected types | All 74 journal articles |
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Prophete C, Maciejczyk P, Salnikow K, Gould T, Larson T, Koenig J, Jaques P, Sioutas C, Lippmann M, Cohen M. Effects of select PM-associated metals on alveolar macrophage phosphorylated ERK1 and -2 and iNOS expression during ongoing alteration in iron homeostasis. Journal of Toxicology and Environmental Health, Part A 2006;69(10):935-951. |
R827351 (Final) R827351C008 (Final) R827351C010 (Final) R827352 (Final) R827352C014 (Final) R827355 (Final) R827355C008 (Final) |
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Salnikow K, Davidson T, Zhang Q, Chen LC, Su W, Costa M. The involvement of hypoxia-inducible transcription factor-1-dependent pathway in nickel carcinogenesis. Cancer Research 2003;63(13):3524-3530. |
R827351 (Final) R827351C010 (Final) |
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Salnikow K, Li X, Lippmann M. Effect of nickel and iron co-exposure on human lung cells. Toxicology and Applied Pharmacology 2004;196(2):258-265. |
R827351 (2003) R827351 (Final) R827351C010 (2003) R827351C010 (Final) |
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PM2.5, hypoxia, metals,
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ENVIRONMENTAL MANAGEMENT, Air, Scientific Discipline, Health, RFA, PHYSICAL ASPECTS, Risk Assessment, Risk Assessments, Health Risk Assessment, Physical Processes, Atmospheric Sciences, particulate matter, Environmental Chemistry, Environmental Monitoring, exposure assessment, ambient air quality, chemical characteristics, epidemelogy, airway contractile properties, human health risk, particulates, toxicology, atmospheric particles, acute lung injury, lung hypoxia, pulmonary hypertension, air pollution, environmental risks, ambient air monitoring, atmospheric particulate matter, exposure, atmospheric aerosol particles, airborne particulate matter, human exposure, PM
Relevant Websites:
Long Version of Final Report (PDF) (4 pp, 98 K, About PDF)
http://www.med.nyu.edu/environmental/
http://es.epa.gov/ncer/science/pm/centers.html
Progress and Final Reports:
2001 Progress Report
2002 Progress Report
2003 Progress Report
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