Role of Neprilysin in Airway Inflammation Induced by Diesel Exhaust Emissions

EPA Grant Number: R834677C159
Subproject: this is subproject number 159 , established and managed by the Center Director under grant R834677
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: Health Effects Institute (2010 — 2015)
Center Director: Greenbaum, Daniel S.
Title: Role of Neprilysin in Airway Inflammation Induced by Diesel Exhaust Emissions
Investigators: Wong, Simon S.
Institution: University of Arizona , Health Effects Institute (HEI)
EPA Project Officer: Hunt, Sherri
Project Period: April 1, 2010 through March 31, 2015
RFA: Health Effects Institute (2010) RFA Text |  Recipients Lists
Research Category: Health Effects , Air Quality and Air Toxics , Air

Objective:

Neprilysin, also known as neutral endopeptidase (NEP), is an enzyme that degrades multiple peptides that affect airway blood vessels. The expression of NEP on the surface of cells varies in a number of airway injury conditions and in several types of cancers. The investigators objective is to study whether exposure to diesel exhaust affected the airway expression or function of NEP. Some prior studies had shown that exposure of humans and laboratory animals to diesel exhaust particles (DEP) or whole diesel exhaust emissions (DEE) affected the airways. Dr. Wong and colleagues hypothesize that components of diesel exhaust downregulate the function or expression of NEP in the airways and that this may lead to dis orders in airway function. They also hypothesize that in conditions in which NEP expression was decreased, responses to diesel exhaust would be increased.

Approach:

The investigators will evaluate airway inflammatory responses and NEP expression and activity in the fluid and cells obtained from bronchoalveolar lavage and the lung tissue of mice genetically deficient in NEP (Nep-knockout mice) or wild-type mice (control). The mice will be instilled with 10 or 100 μg resuspended DEP, and their BAL fluid will be analyzed 7 days later; the investigators will use National Institute of Standards and Technology SRM 2975 particles, which were originally generated by a diesel-powered industrial forklift. The investigators  will also measure airway inflammatory responses and NEP activity in the induced sputum of 11 healthy human volunteers (ages 19–33 yr) 1 hour after exposure to DEE in a staged mining environment. A base line measurement of NEP activity will be taken at least 1 week before volunteers will be exposed to DEE.

Expected Results:

The investigators intend to evaluate airway inflammatory responses and expression of the enzyme neprilysin in response to diesel exhaust particle exposure. Dr. Wong and colleagues anticipate that their research will reveal that components of diesel exhaust decrease neprilysin levels in airways, leading to airway function disorders and heightened responses to diesel exhaust.

Supplemental Keywords:

Health Effects, Air Toxics, particulate matter, mobile-source emissions, motor vehicle exhaust, diesel exhaust, airway inflammation

Relevant Websites:

http://pubs.healtheffects.org/getfile.php?u=652 Exit


Main Center Abstract and Reports:

R834677    Health Effects Institute (2010 — 2015)

Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R834677C149 Development and Application of a Sensitive Method to Determine Concentrations of Acrolein and Other Carbonyls in Ambient Air
R834677C150 Mutagenicity of Stereochemical Configurations of 1,3-Butadiene Epoxy Metabolites in Human Cells
R834677C151 Biologic Effects of Inhaled Diesel Exhaust in Young and Old Mice: A Pilot Project
R834677C152 Evaluating Heterogeneity in Indoor and Outdoor Air Pollution Using Land-Use Regression and Constrained Factor Analysis
R834677C153 Improved Source Apportionment and Speciation of Low-Volume Particulate Matter Samples
R834677C155 The Impact of the Congestion Charging Scheme on Air Quality in London
R834677C156 Concentrations of Air Toxics in Motor Vehicle-Dominated Environments
R834677C158 Air Toxics Exposure from Vehicle Emissions at a U.S. Border Crossing: Buffalo Peace Bridge Study
R834677C159 Role of Neprilysin in Airway Inflammation Induced by Diesel Exhaust Emissions
R834677C160 Personal and Ambient Exposures to Air Toxics in Camden, New Jersey
R834677C162 Assessing the Impact of a Wood Stove Replacement Program on Air Quality and Children’s Health
R834677C163 The London Low Emission Zone Baseline Study
R834677C165 Effects of Controlled Exposure to Diesel Exhaust in Allergic Asthmatic Individuals
R834677C168 Evaluating the Effects of Title IV of the 1990 Clean Air Act Amendments on Air Quality
R834677C172 Potential Air Toxics Hot Spots in Truck Terminals and Cabs
R834677C173 Detection and Characterization of Nanoparticles from Motor Vehicles
R834677C174 Cardiorespiratory Biomarker Responses in Healthy Young Adults to Drastic Air Quality Changes Surrounding the 2008 Beijing Olympics