Mechanisms of Age-dependent Ozone Induced Airway Dysfunction

EPA Grant Number: R827447
Title: Mechanisms of Age-dependent Ozone Induced Airway Dysfunction
Investigators: Shore, Stephanie
Current Investigators: Shore, Stephanie , Johnston, Richard , Laporte, Johanne , Murthy, G.G. Krishna , Want, Matt
Institution: Harvard University
EPA Project Officer: Hahn, Intaek
Project Period: July 1, 1999 through June 30, 2002 (Extended to July 31, 2003)
Project Amount: $852,937
RFA: Children's Vulnerability to Toxic Substances in the Environment (1999) RFA Text |  Recipients Lists
Research Category: Children's Health , Health Effects , Human Health , Health


Acute exposure to ozone (O3) causes airway hyper-responsiveness (AHR). However, the mechanistic basis for O3 induced AHR has not been established. O3 may be a particularly important respiratory hazard for children. Despite the importance of AHR as one of the defining features of asthma, no studies of age related differences in O3 induced AHR have been reported. Hence, the purpose of this proposal is to examine age related changes in O3 induced AHR in mice and to determine the mechanistic basis for observed changes. We hypothesize that O3 induced TNFa formation is required for AHR, and that O3 causes more pronounced AHR in young than adult mice due to a more pronounced inflammatory response, resulting in part from an increased dose of O3 in the younger animals despite inhalation of the same concentration, and in part from age related differences in TNFa formation.


In aim 1, we will measure, in mice aged 2 weeks through 26 weeks, the concentration and time related effects of O3 on AHR using whole body plethysmography and conventional mechanics, and on histologic and biochemical indices of airway injury and inflammation. In each mouse used for these studies, we will also measure ventilation (VE) during O3 exposure in order to assess the actual O3 dose. In aim 2, we will test the hypothesis that O3 induced translocation of the nuclear transcription factor AP-1 and subsequent production of TNFa leads to AHR, In mice of various ages, we will measure effects of O3 on AP-1 translocation by gel shift assay, TNFa mRNA by Northern blotting, TNFa release by enzyme immunoassay, and we will assess O3 induced AHR in mice rendered mice unresponsive to TNFa either by genetic deletion of TNFa receptors, or by administration of a soluble TNFa receptor - IgG chimera.

Expected Results:

Our preliminary data indicate that we can expect to see more pronounced O3- induced AHR in young versus older mice. We also expect that adult mice will have lower specific VE and will reduce VE during O3 exposure, whereas younger mice will not, resulting in a greater inhaled dose of O3 in the younger animals. If our hypothesis is correct, we would expect to see no difference in AHR-O3 dose-response curves between animals of different ages even though we see a leftward shift in the AHR-O3 concentration-response curves in the younger animals. In addition, we expect to generate data indicating an important role for the cytokine TNFa in O3 induced AHR. The data will be important in establishing guidelines for ambient O3 concentrations in a susceptible population, children, and in making informed decisions about interventional type studies in children.

Publications and Presentations:

Publications have been submitted on this project: View all 5 publications for this project

Journal Articles:

Journal Articles have been submitted on this project: View all 4 journal articles for this project

Supplemental Keywords:

air, sensitive populations, dose-response, health effects, biology, pathology., RFA, Health, Scientific Discipline, PHYSICAL ASPECTS, Air, air toxics, Health Risk Assessment, Risk Assessments, Susceptibility/Sensitive Population/Genetic Susceptibility, Biochemistry, Physical Processes, Children's Health, Molecular Biology/Genetics, tropospheric ozone, genetic susceptability, asthma, lung injury, ozone induced inflammation, sensitive populations, exposure and effects, stratospheric ozone, exposure, age-related differences, airway disease, dose response model, respiratory problems, ozone, air pollution, enzyme systems, ozone induced airway dysfunction, children, human exposure, assessment of exposure, children's vulnerablity, inhalation, age dependent response, biomedical research, acute exposure, environmental hazard exposures

Progress and Final Reports:

  • 2000 Progress Report
  • 2001 Progress Report
  • 2002
  • 2003
  • Final Report