Oxidative Tissue Damage Flashcards
Oxidative Phosphorylation
reduction of O2 to water to produce ATP
Cytochrome P450 pathway
metabolism of endogenous hormones and exogenous drugs/toxins
Anti-microbial killing in phagocytes
NADPH oxidase, myeloperoxidase
Importance of Oxygen
most abundant element on planet (47%), Ideal electron acceptor for biological catalysis
O2 high redox potential can let it form ROS
Superoxide anion, hydrogen peroxide, hydroxyl radical (goes through these three radicals on the way to reduction to water)
Endogenous source of ROS
oxidative phosphorylation, NADPH oxidases, peroxisomes, xanthine oxidase, free metals
Environmental source of ROS
Cigarette smoke, radiation, drugs/pesticides, pollutants, ozone
Mitochondrial electron leak
largest source of electron leak is ubiquinone; mito produce enzymes to fix leak (SOD I, II, III - take superoxide and metabolize it to hydrogen peroxide)
Oxidative Stress
imbalance between oxidants and antioxidant defenses in favor of oxidants, leading to disruption of redox control/signaling and to cell and molecular damage
Nitrostative Stress
RNS, products of NO syntheses, RNS interact with ROS to produce strong oxidants
Oxidative tissue damage definition
chemical disruption of cellular/tissue structure and function by the oxidation of specific macromolecules
Free Radical definition
a chemically-reactive atom or molecule with an unpaired or free electron
Prevention of Oxidative Injury
control tissue pO2 to limit molecular oxidations; maintain basal and inducible anti-oxidant defense systems; sequester reactive transition metals (Fe, Cu) in unreactive forms
Antioxidant Defenses
anti-oxidant enzymes; small molecule anti-oxidant defense; damage repair and disposal enzymes; transition metal sequestration
Regulation of antioxidant enzymes
most anti-oxidant enzyme systems are both constitutive and inducible; increased expression relies on redox-sensitive kinases, phosphates, or TFs
Antioxidant Enzymes…
content varies from tissue to tissue, but localizes to sites of ROS generation
How do small molecule and dietary anti-oxidants work?
3 critical factors
- bioavailability for reaction
- local concentration of anti-oxidant molecule
- kinetics of reaction
Ascorbate Reaction
ascorbate donates an electron to quench a radical, resultant ascorbic radical is stabilized through resonance, additional oxidation then reduction
Pulmonary Oxygen Toxicity
After exposure to 100% O2, there is an immediate increase in cellular ROS production; can lead to inflammation and destruction of lung; can cause fibrosis; intermittent exposure to high oxygen can promote tolerance of the toxic effect of high O2 by inducing anti-oxidant enzymes
Ischemia-Reperfusion Injury
Oxidative tissue damage occurs primarily during the repercussion or re-oxygenation phase; during O2 deprivation, the stores of ATP, ADP, and AMP are depleted; causes xanthine to be converted to uric acid which produces hydrogen peroxide and superoxide; can react with metals to produce hydroxyl radicals which damage membranes
Acute Inflammatory Response
Enzymes found in leukocytes (bleach and other chlorinating species) can leak from leukocytes and cause oxidative tissue damage during inflammation
Cigarette smoking
smoke from tobacco contains more than 4,000 bioactive compounds; principal cause of COPD and lung cancer; depletes anti-oxidants by chronic stimulation of ROS/RNS production
