EPA Science Inventory

Nitric Oxide and Superoxide Mediate Diesel Particle Effects in Cytokine-Treated Mice and Murine Lung Epithelial Cells ─ Implications for Susceptibility to Traffic-Related Air Pollution

Citation:

Manzo, N., A. LaGier, R. Slade, A. Ledbetter, J. Richards, AND J. Dye. Nitric Oxide and Superoxide Mediate Diesel Particle Effects in Cytokine-Treated Mice and Murine Lung Epithelial Cells ─ Implications for Susceptibility to Traffic-Related Air Pollution. Particle and Fibre Toxicology. BioMed Central Ltd, London, Uk, 9:43, (2012).

Description:

Abstract Background: Epidemiologic studies associate childhood exposure to traffic-related air pollution with increased respiratory infections and asthmatic and allergic symptoms. The strongest associations between traffic exposure and negative health impacts are observed in individuals with respiratory inflammation. We hypothesized that interactions between nitric oxide (NO), increased during lung inflammatory responses, and reactive oxidative species (ROS), increased as a consequence of traffic exposure ─ played a key role in the increased susceptibility of these at-risk populations to traffic emissions. Methods: Diesel ex¬haust particles (DEP) were used as surrogates for traffic particles. Murine lung epithelial (LA-4) cells and BALB/c mice were treated with a cytokine mixture (cytomix: TNFalpha, IL-1beta, and IFNgamma) to induce a generic inflammatory state. Cells were ex¬posed to saline or DEP (25µg/cm2) and examined for differential effects on redox balance and cytotoxicity. Likewise, mice undergoing nose-only inhalation exposure to air or DEP (2mg/m3 x 4h/d x 2d) were assessed for differential effects on lung inflammation, injury, antioxidant levels, and phagocyte ROS production. Results: Cytomix treatment significantly increased LA-4 cell NO production though iNOS activation. Cytomix+DEP-exposed cells incurred the greatest intracellular ROS production, with commensurate cytotoxicity, as these cells were unable to maintain redox balance. By contrast, saline+DEP-exposed cells were able to mount effective antioxidant responses. DEP effects were mediated by: (1) increased ROS including superoxide anion (O2˙-), related to increased xanthine dehydro¬genase expression and reduced cytosolic superoxide dismutase activity; and (2) increased peroxynitrite generation related to interaction of O2˙with cytokine-induced, NO. Effects were partially reduced by SOD supplementation or by blocking iNOS induction. In mice, cytomix+DEP-exposure resulted in greater ROS production in lung phagocytes. Phagocyte and epithelial effects were, by and large, prevented by treatment with FeTMPyP, which accelerates peroxynitrite catalysis. Conclusions: During inflammation, due to interactions of NO and O2˙, DEP-exposure was associated with nitrosative stress in surface epithelial cells and resident lung phagocytes. As these cell types work in concert to provide protection against inhaled pathogens and allergens, dysfunction would predispose to development of respiratory infection and allergy. Results provide a mechanism by which individuals with pre-existing respiratory inflammation are at increased risk for exposure to traffic-dominated urban air pollution.

Purpose/Objective:

This manuscript shows how interactions between nitric oxide (NO), increased during lung inflammatory responses, and reactive oxidative species (ROS), increased as a consequence of traffic particle exposure, interact to induce lung injury and inflammation in at risk populations.

URLs/Downloads:

EPHD-12-100-ABSTRACT.PDF   (PDF,NA pp, 426.521 KB,  about PDF)

Record Details:

Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Start Date: 11/12/2012
Completion Date: 11/12/2012
Record Last Revised: 06/20/2013
Record Created: 05/26/2013
Record Released: 05/26/2013
OMB Category: Other
Record ID: 255934

Organization:

U.S. ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF RESEARCH AND DEVELOPMENT

NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB

ENVIRONMENTAL PUBLIC HEALTH DIVISION

CARDIOPULMONARY AND IMMUNOTOXICOLOGY BRANCH