Adaptation to Nitrogen Dioxide: Role of Altered Glycolytic Pathway Enzyme Expression and NF-κB-Dependent Cellular Defenses Against Apoptosis

EPA Grant Number: R825702C003
Subproject: this is subproject number 003 , established and managed by the Center Director under grant R825702
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: Environmental Lung Disease Center (National Jewish Medical and Research Center)
Center Director: Mason, Robert J.
Title: Adaptation to Nitrogen Dioxide: Role of Altered Glycolytic Pathway Enzyme Expression and NF-κB-Dependent Cellular Defenses Against Apoptosis
Investigators: White, Carl W. , Cook, James L.
Institution: National Jewish Medical and Research Center
EPA Project Officer: Chung, Serena
Project Period: February 16, 1998 through February 28, 2003 (Extended to February 28, 2004)
RFA: Environmental Lung Disease Center (National Jewish Medical and Research Center) (1998) RFA Text |  Recipients Lists
Research Category: Targeted Research

Objective:

Mechanisms of cell injury and death caused by toxic oxidant gases such as nitrogen dioxide (NO,) are incompletely understood. The phenomenon of cellular cross-tolerance to gases such as oxygen (hyperoxia) and nitrogen dioxide suggest that development of tolerance to oxidant gas injury is mediated by common mechanisms. Among these adaptive mechanisms may be triggering of signaling pathways, such as protein kinase C and thioredoxin systems, that can activate NF-eB-dependent cellular defenses. In addition to the well known pro- inflammatory responses that result from NF-eB activation, there are also NF-eB-dependent responses that protect cells against a variety of potentially lethal injuries.

Our recent data suggest the importance of the integrity of the injury-induced, NF-eB-dependent cellular response for protection of cells against apoptosis caused by a lethal hyperoxic insult. In addition to their relevance for understanding the basic cellular defenses against oxidant gas injury, these observations also suggest that "cofactors" that function to compromise the NF-eBdependent, cellular response to injury may modulate sensitivity to oxidant lung injury such as that induced by NO2. Certain respiratory virus genes whose expression modifies NF-eB expression and function may be among these cofactors. An example from our studies is the adenoviral El A gene. For example, we have observed a marked increase in the susceptibility of El A-expression cells to apoptosis caused by exposure to 95% oxygen (635 torr).

These data combined with the observation that ElA modulates injury-induced, NF-eB-dependent transcription has led to the following Hypothesis: Nitrogen dioxide-induced, NF-eB-dependent cellular responses involving the cellular glycolytic pathway are important for the adaptive cellular response to oxidant gas injury. In this proposal, we seek to identify candidate adaptive mechanisms that protect cells against nitrogen dioxide injury, to use the ElA gene as a molecular tool to study the role of NF-eB- dependent responses in these adaptive mechanisms and to create an animal model that can be used to test the ir vivo relevance of the NF-eB-dependent response to oxidant lung injury.

Supplemental Keywords:

Health, Scientific Discipline, Toxicology, Environmental Chemistry, Health Risk Assessment, Risk Assessments, Disease & Cumulative Effects, Biochemistry, health effects, Nitrogen dioxide, lung disease, airway disease, pulmonary disease, respiratory problems, enzyme systems, oxidants, human exposure, oxidant gas, cell injury, apoptosis, glycolytic pathway, cofactors, adaptation, biomedical research, human health risk, protein kinase C

Progress and Final Reports:

  • 1998
  • 1999
  • 2000
  • 2001
  • 2002
  • 2003
  • Final

  • Main Center Abstract and Reports:

    R825702    Environmental Lung Disease Center (National Jewish Medical and Research Center)

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R825702C001 SP-A and SP-D in Environmental Lung Disease
    R825702C003 Adaptation to Nitrogen Dioxide: Role of Altered Glycolytic Pathway Enzyme Expression and NF-κB-Dependent Cellular Defenses Against Apoptosis
    R825702C005 Inhalation of Particulate Matter Alters the Allergic Airway Response to Inhaled Allergen
    R825702C006 Particle-Induced Lung Inflammation and Extracellular EC-SOD
    R825702C007 Indoor-Outdoor Relationships of Airborne Particle Count and Endotoxin Concentrations
    R825702C008 The Role of Mitochondrial DNA Mutations in Oxidant-Mediated Lung Injury
    R825702C009 Immunopathogenesis of Hypersensitivity Pneumonitis in the Mouse
    R825702C010 Activation of Natural T Lymphocytes by Diesel Exhaust Particulates Leads to Their Production of Interleukin-4 and TH2 Lymphocyte Differentiation to Allergen
    R825702C011 Latex Antigen Levels During Powdered and Powderless Glove Use
    R825702C012 Adjuvant Effects of Ozone in a Model of Allergen-Induced Airway Inflammation and Hyperresponsiveness
    R825702C013 Acute Exposure to Particulate Air Pollution in Childhood Asthma
    R825702C014 Mechanisms of Ozone Toxicity to the Lung