Effect of Diesel Exhaust Particulate Exposures on Endothelial Function in Humans

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Joel Daniel Kaufman, University of Washington
ClinicalTrials.gov Identifier:
NCT00434005
First received: August 25, 2006
Last updated: January 14, 2013
Last verified: January 2013
  Purpose

Objectives: This proposal addresses the overall hypothesis that ambient fine particulate matter exerts cardiovascular health effects via alteration of endothelial homeostasis, through a mechanism mediated by oxidative stress. This project will use a controlled human inhalation exposure to diesel exhaust particulate (DEP) as a model to address the following objectives: 1) Determine whether exposure to inhaled DEP is associated with endothelial dysfunction in a concentration-related manner; 2) Determine whether exposure to inhaled DEP is associated with evidence of systemic oxidative stress; and 3) Determine whether antioxidant supplementation blunts the DEP effect on endothelial function.


Condition Intervention
Healthy
Drug: N-acetylcysteine, ascorbate
Drug: Placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Effect of Diesel Exhaust Particulate Exposures on Endothelial Function in Humans - the Role of Oxidative Stress

Resource links provided by NLM:


Further study details as provided by University of Washington:

Primary Outcome Measures:
  • Brachial artery caliber [ Time Frame: Pre-exposure, immediate post-exposure ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Brachial Artery Flow-Mediated Dilation [ Time Frame: Post-Exposure ] [ Designated as safety issue: No ]
  • Plasma Endothelin-1 [ Time Frame: Post-exposure (adjusted for pre-exposure level) ] [ Designated as safety issue: No ]
  • Serum IL-6 [ Time Frame: Post-exposure (adjusted for pre-exposure level) ] [ Designated as safety issue: No ]

Enrollment: 24
Study Start Date: July 2008
Study Completion Date: August 2010
Primary Completion Date: August 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Diesel Exhaust Drug: N-acetylcysteine, ascorbate
NAC: 600mg twice daily for the day prior to exposure and 1x pre-exposure Ascorbate: 500mg twice daily for 7 days prior to exposure
Drug: Placebo
matched appearance to acetylcysteine and ascorbate intervention
Sham Comparator: Filtered Air Drug: N-acetylcysteine, ascorbate
NAC: 600mg twice daily for the day prior to exposure and 1x pre-exposure Ascorbate: 500mg twice daily for 7 days prior to exposure
Drug: Placebo
matched appearance to acetylcysteine and ascorbate intervention

Detailed Description:

OBJECTIVES Evidence of the cardiovascular health effects of both acute and chronic exposure to ambient fine particulate matter (PM) has continued to accumulate in epidemiologic and experimental studies, without a demonstrated coherent pathophysiologic explanation. At the same time, the role of endothelial homeostasis in the development and triggering of cardiovascular disease has become more clear and compelling. Importantly, oxidative stress has emerged as a potential link between these two developments: Oxidative stress is known to play a role in endothelial dysfunction and is exerted by components of PM, especially of PM from combustion products. Based on this we propose an overall hypothesis: Inhalation of combustion-derived particles impact cardiovascular health by impairing endothelial function, through mechanisms mediated by increased oxidative stress.

Diesel exhaust particulate (DEP), an important contributor to ambient fine PM, has been demonstrated to exert oxidative stress in experimental systems. We propose a series of experiments to explore whether human exposure to DEP results in alteration of endothelial homeostasis and evidence of oxidative stress, and whether an antioxidant regimen can blunt the effects on endothelial function.

The objectives of this proposed research are to address the following specific hypotheses:

  1. Human exposure to inhaled DEP (at concentrations approximating 0, 100, 200 μg PM2.5/m3 [PM less than 2.5 microns in aerodynamic diameter]) results in concentration-related alteration of endothelial homeostasis, as reflected in ultrasonographic measurement of the brachial artery, plasma markers of endothelial homeostasis (endothelin-1, ICAM-1 [intercellular adhesion molecule-1], e-selectin, nitric oxide metabolites nitrate [NO3-] and nitrite [NO2-], IL-6, and TNF-α), and markers of thrombosis associated with endothelial activation or injury (plasminogen activator inhibitor-1 [PAI-1], Von Willebrand's factor [VWF], and D-dimer).
  2. Human exposure to inhaled DEP at 200 µg PM2.5/m3 results in evidence of systemic oxidative stress as assessed by markers in plasma and urine (isoprostane F-2α).
  3. Reduction in oxidant stress by ascorbate and N-acetylcysteine supplementation blunts the effect of inhaled DEP on endothelial function, as determined by ultrasonographic assessment of the brachial artery, plasma markers of endothelial homeostasis, or markers of thrombosis associated with endothelial activation.
  Eligibility

Ages Eligible for Study:   18 Years to 49 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy adults aged 18-49.

Exclusion Criteria:

  • Nonsmokers, no history of hypertension, asthma, diabetes, hypercholesterolemia, or other chronic conditions requiring ongoing medical care. No recent history of antioxidant, vitamin/mineral/botanical, or fatty acid supplementation beyond a daily multi-vitamin.
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00434005

Locations
United States, Washington
Northlake Laboratory
Seattle, Washington, United States, 98105
Sponsors and Collaborators
University of Washington
Investigators
Principal Investigator: Joel D Kaufman, M.D., MPH University of Washington
  More Information

Additional Information:
No publications provided by University of Washington

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Joel Daniel Kaufman, Professor, University of Washington
ClinicalTrials.gov Identifier: NCT00434005     History of Changes
Other Study ID Numbers: 22969-D, R830954, R827355, MO1RR-00037, ES015915, ES013195
Study First Received: August 25, 2006
Last Updated: January 14, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by University of Washington:
Air pollution
diesel
antioxidant
oxidative stress
endothelial
HRV
BAR

Additional relevant MeSH terms:
Acetylcysteine
N-monoacetylcystine
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Expectorants
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Antidotes

ClinicalTrials.gov processed this record on September 30, 2014