Effect of Diesel Exhaust Particulate Exposures on Endothelial Function in Humans
Condition: Healthy
Study type: Interventional

Summary: 
      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.
    

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.
    

Intervention name(s): N-acetylcysteine, ascorbate; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): NAC: 600mg twice daily for the day prior to exposure and 1x pre-exposure Ascorbate: 500mg twice daily for 7 days prior to exposure; matched appearance to acetylcysteine and ascorbate intervention
Intervention MeSH terms: Acetylcysteine; N-monoacetylcystine
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Air pollution; diesel; antioxidant; oxidative stress; endothelial; HRV; BAR