Oxidative Stress
Learning Objectives
Students will be able to:
- Define oxidative stress and explain its role in disease
- Identify major reactive oxygen species and their sources
- Describe antioxidant defense mechanisms
- Explain how particle exposure disrupts redox balance
- Connect oxidative damage to DNA mutations, lipid peroxidation, and protein oxidation
The Big Question
"What is oxidative stress, and why is it considered a unifying mechanism linking air pollution to so many different diseases?"
What is Oxidative Stress?
Oxidative stress occurs when the production of reactive oxygen species (ROS) exceeds the capacity of antioxidant defense systems:
Oxidative Stress = ROS Production > Antioxidant Capacity
This imbalance leads to oxidative damage to cellular components: lipids, proteins, and DNA.
Reactive Oxygen Species (ROS)
| Species | Formula | Half-life | Reactivity |
|---|---|---|---|
| Superoxide anion | O2- | ~1 ms | Moderate |
| Hydrogen peroxide | H2O2 | Stable | Low (but can cross membranes) |
| Hydroxyl radical | OH | ~10-9 s | Extremely high |
| Singlet oxygen | 1O2 | ~1 us | High |
| Peroxynitrite | ONOO- | ~1 s | High (reactive nitrogen species) |
How Particles Generate ROS
Direct Mechanisms
- Surface reactions: Metal ions (Fe, Cu) on particle surfaces catalyze Fenton reactions
- Quinone redox cycling: Organic compounds cycle between oxidized/reduced states
- PAH photochemistry: Polycyclic aromatic hydrocarbons generate ROS with light
Indirect Mechanisms
- Inflammatory cells: Activated macrophages and neutrophils produce ROS
- Mitochondrial dysfunction: Damaged mitochondria leak electrons
- NADPH oxidase: Enzyme activation in phagocytes
The Fenton Reaction
Transition metals on particle surfaces catalyze the conversion of hydrogen peroxide to the highly reactive hydroxyl radical:
Fe2+ + H2O2 → Fe3+ + OH + OH-
This is why iron content of particles is often correlated with oxidative potential and toxicity.
Antioxidant Defense Systems
Enzymatic Antioxidants
- SOD: Superoxide dismutase converts O2- to H2O2
- Catalase: Converts H2O2 to H2O + O2
- GPx: Glutathione peroxidase reduces peroxides
- GR: Glutathione reductase regenerates GSH
Non-Enzymatic Antioxidants
- Glutathione (GSH): Major intracellular antioxidant
- Vitamin C: Water-soluble, plasma antioxidant
- Vitamin E: Lipid-soluble, protects membranes
- Uric acid: Plasma antioxidant
Oxidative Damage to Biomolecules
Lipid Peroxidation
- Attacks membrane fatty acids
- Chain reaction propagates
- Produces MDA, 4-HNE
- Membrane dysfunction
Protein Oxidation
- Carbonyl formation
- Disulfide cross-links
- Enzyme inactivation
- Protein aggregation
DNA Damage
- 8-oxo-guanine formation
- Strand breaks
- Base modifications
- Mutation potential
The Hierarchical Oxidative Stress Model
Progressive Response to Oxidative Stress
| Level | Response | Outcome |
|---|---|---|
| Tier 1 (Low) | Nrf2 activation, antioxidant gene expression | Protective, adaptive |
| Tier 2 (Moderate) | NF-kB activation, inflammation | Potentially damaging |
| Tier 3 (High) | Mitochondrial damage, apoptosis/necrosis | Cell death, tissue damage |
Reference: Li et al. (2008). Hierarchical oxidative stress model. Environmental Health Perspectives.
Activity: Redox Balance Analysis
Oxidative Stress Calculation
- Research task: Look up typical glutathione (GSH) levels in healthy lung lining fluid vs. smokers or high PM exposure groups
- Calculate GSH/GSSG ratio: The ratio of reduced to oxidized glutathione indicates redox status. What ratio indicates oxidative stress?
- Create a diagram: Show the balance between ROS production and antioxidant defenses, indicating what happens when each side dominates
- Discussion: Why might antioxidant supplements not simply "fix" oxidative stress from air pollution?
Key Takeaway
Oxidative stress represents the imbalance between reactive oxygen species production and antioxidant defenses. Particles generate ROS through both direct surface chemistry and indirect inflammatory pathways. The resulting oxidative damage to lipids, proteins, and DNA underlies many of the health effects of air pollution. This mechanism helps explain how inhaled particles can cause effects far beyond the respiratory system, as oxidative stress triggers inflammation and cellular dysfunction throughout the body.