Oxidative stress and free radicals in COPD – implications and relevance for treatment

Figures & data

Table 1 Free radicals (ROS, RNS) as contributors to oxidative stress

Name	Formula	Characteristics
Hyperoxide/superoxide	^•O2^−	Highly unstable, signaling function, synaptic plasticity
Hydrogen peroxide	H2O2	Cell toxicity, signaling function, generation of other ROS
Hydroxyl radical	^•OH	Free radical, highly unstable, very reactive agent
Alkoxyl radical	RO^•	Free radical, reaction product of lipids
Peroxyl radical	ROO^•	Free radical, reaction product of lipids
Hypochlorite anion	OCl^−	Reactive oxygen species, reactive chlorine species, enzymatically generated by myeloperoxidase
Singlet oxygen	^1O2	Induced/excited oxygen molecule, radical and nonradical form
Ozone	O3	Environmental toxin
Nitric oxide	^•NO	Environmental toxin, endogenous signal molecule
Peroxynitrite	ONOO^−	Highly reactive reaction intermediate of ^•O2 and ^•NO
Nitrogen dioxide	^•NO2	Highly reactive radical, environmental toxin
Nitrogen oxides	NOx	Environmental toxins, including NO and ^•NO2, derived from the combustion process

Abbreviations: RNS, reactive nitrogen species; ROS, reactive oxygen species.

Table 2 ROS-related hallmarks impacting COPD

Mechanism	Outcome
Imbalance of proteases/antiproteases	Inactivation of antiprotease shield (α1AT, SLPI) Activation of metalloproteinases
Molecular mechanisms • Upregulation of gene transcription (NF-κB, AP-1) • Increase of cellular cytokine production in the lung • Signal transduction	Increased gene expression of inflammatory mediators and cytokines (IL-1, TNFα, IL-8, GM-CSF, iNOS) Steroid resistance Airway remodeling
Nuclear histone acetylation/deacetylation balance Remodeling of DNA/chromatin	Chronic inflammation Decreased histone deacetylase 2

Abbreviations: COPD, chronic obstructive pulmonary disease; iNOS, inducible nitric oxide synthase isoenzymes; ROS, reactive oxygen species; SLPI, secretory leukocyte protease inhibitor; α₁AT, alpha-1-antitrypsin; IL-1, interleukin 1; TNF-α, tumor necrosis factor alpha; IL-8, interleukin-8; GM-CSF, granulocyte macrophage colony-stimulating factor.

Figure 1 Generating reactive oxygen and nitrogen species and defending against them.

Notes: Homeostasis of pro- and antioxidative processes is a prerequisite for normal growth and metabolism. Increased as well as suppressed formation of reactive species may be harmful. An elevated formation of reactive species may lead to random cellular damage causing aging and disease, but also to specific signaling pathways. Adapted by permission from Macmillan Publishers Ltd: NATURE. Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of aging. Nature. 2000;408(6809):239–247,²⁶ copyright 2000. Available from: http://www.nature.com/nature/index.html.
Abbreviations: CAT, catalases; GPx, peroxidases; NADPH, ; RNS, reactive nitrogen species; SOD, superoxide dismutases.

Table 3 Environmental (exogenous) and endogenous causes of oxidative stress

Inflammation (activated macrophages and neutrophils)

Tobacco smoke (active and passive exposition)

Hyperoxia (long term oxygenation therapy)

Hypoxia (hypobaric and normobaric hypoxia)

Environmental air pollutants (particulate matter, occupational dusts, traffic exhaust)

Depletion of antioxidant screen (chronic smoking)

Reoxygenation (ischemia/reperfusion)

Mitochondrial electron transport (respiratory chain)

Oxidative enzymes (lipoxygenases, cyclooxygenases, cytochrome P450) Ionizing radiation

Table 4 Aims of successful antioxidative treatment intervention in COPD

Neutralization of systemic and local oxidative burden

Concomitant decrease of biomarkers (MPO, NO)

Improvement of endogenous antioxidant defense

Defense against FR generation

Inhibition of inflammatory gene expression

Repression of airway inflammation

Amplification of nonenzymatic antioxidant concentrations (dietary measures, pharmacological intervention)

Inhibition of the development of systemic disease

Ameliorating lung-function decline

Decrease of the exacerbation rate

Decrease of respiratory symptoms

Restoration of steroid responsiveness

Overcoming mucus hypersecretion

Slowing skeletal muscle dysfunction and atrophy

Intracellular targeted antioxidants

Combined effects of antioxidants

High bioavailability and low toxicity

Abbreviations: COPD, chronic obstructive pulmonary disease; FR, free radical; MPO, myeloperoxidase; NO, nitrogen monoxide.

Table 5 Agents with antioxidative potential

Thiols and novel thiol compounds	Carbocysteine
Nrf2 activators	Erdosteine
	Fudosteine
	Glutathione esters
	N-acetyl-L-cysteine
	N-acystelyn
	N-isobutyryl-cysteine
	Procysteine
	Thioredoxin
	Sulforaphane
	Imidazolide
Dietary polyphenols, flavonoids	Acai
Nutraceuticals (natural compounds)	Flavonols
	Flavones
	Lycopene
	Resveratrol (red wine extract)
	Sulforaphane
	Turmeric (curcumin)
	Quercetin (green tea)
	Vitamin D
	Polyunsaturated fatty acids
	Omega-3 fatty acids
Radical scavengers, other antioxidants	Apocynin
	Edaravone
	Ergothioneine
	Hydrogen sulfide
	Catechin (green tea)
	Lazaroids
	Myeloperoxidase inhibitors (thioxanthine)
	Glutaredoxin
	Nitrone spin traps
	Peroxiredoxins
	Porphyrins
	Hydrogen sulfide (H2S)
Synthetic molecules, specific spin traps	α-phenyl-N-tert-butyl nitrone (EcSOD/SOD3 mimetics)
Catalytic oxidants	Porphyrins (AEOL 10150, 10113)
	Superoxide dismutase mimetics
	Lipid peroxidation blockers
	Protein carbonylation blockers (Edaravone, lazaroids/tirilazad)
	Tocotrienols
Antioxidant vitamins	Vitamins C, E, provitamin A
Redox modulators, redox sensor inhibitors	Manganese-metalloporphyrins
	Selenium compounds
Antioxidant enzyme mimetics	Ebselen
iNOS inhibitors	Manganese-metalloporphyrins

Abbreviations: EcSOD, extracellular superoxide dismutase; iNOS, inducible nitric oxide synthase isoenzymes; Nrf2, NF-E2-related factor 2.

FinkelTHolbrookNJOxidants, oxidative stress and the biology of ageingNature2000408680923924711089981

 PubMed Web of Science ®Google Scholar