Pathogenesis (disease development)
Oxidative or nitrosative stress occurs when cellular antioxidant defenses are too low to compensate for reactive oxygen radicals: As intermediates of metabolism, free radicals are constantly produced in every cell of the human body. The oxygen compounds with unpaired electrons strive to snatch electrons from another atom or molecule. They react with these and form new radicals, which in turn also snatch electrons from other substances, and in a chain reaction there is a constant increase in the number of radicals in the body (= oxidative stress/nitosative stress).
Physiological formation of reactive oxygen species (ROS) and N species (RNS).
- Mitochondrial respiration (a cell requires 1012 molecules of O2 per day).
- In the activation of granulocytes (belong to the white blood cells) and macrophages (phagocytes).
- Fenton reaction – oxidation of organic substrates catalyzed by iron compounds with hydrogen peroxide in acidic medium. Fenton-like reactions can also occur with the participation of other low-valent metal complexes such as Cu(II), Ti(III), Cr(II), or Co(II). The Fenton reaction is considered to be one of the major sources of reactive oxygen species in the cell (= oxidative stress)
- By oxidases such as for example monoaminooxidase, xanthine oxidase, L-aminooxidase, tyrosine hydrolase, flavin oxidase, etc.
- In arachidonic acid metabolism
The nitric oxide radical is formed by NO synthase (NOS) with cleavage from arginine: Arginine + O2 + (NO synthase) → NO. + citrulline.
There are 4 isoenzymes of NO synthase:
- Mitochondrial NO synthase (mtNOS): active in mitochondria (“energy power plants), enhanced NO. synthesis in hypoxia.
- Endothelial NO synthase (eNOS): active in the vascular endothelium (inner wall layer of blood vessels), relaxes the smooth muscle cells of the vessels.
- Inducible NO synthase (iNOS): arises in leukocytes and macrophages, active ubiquitously throughout the organism, forms large amounts of NO. during inflammation, which acts bactericidal (bacteria-killing) or virucidal (virus-killing).
- Neuronal NO synthase (nNOS): arises in glial cells, active in neurons, NO. acts here as a transmitter (transmitter).
Cells maintain homeostasis (steady state) between formation and degradation of reactive oxygen species (ROS) and N species (RNS). Increased concentrations of ROS and RNS lead to structural and functional changes in proteins, lipids, and nucleic acids.
Etiology (causes) of oxidative or nitrosative stress
Biographic Causes
- Genetic burden from parents, grandparents (genetic individuality, meaning genetically determined different endowment, e.g., with scavenger enzyme systems)
- Genetic diseases
- Hemochromatosis (iron storage disease) – genetic disease with autosomal recessive inheritance with increased deposition of iron as a result of increased iron concentration in the blood with tissue damage.
- Genetic diseases
- Age – increasing age
Behavioral causes
- Nutrition
- Malnutrition and undernutrition – including over- and undernutrition.
- Diet low in micronutrients (few cereal products, less than 5 servings of vegetables and fruits (< 400 g/day; 3 servings of vegetables and 2 servings of fruits), few milk and dairy products, less than one to two fish per week, etc) – see prevention with micronutrients
- Pleasure food consumption
- Tobacco (smoking) – the substances inhaled in a single puff from a cigarette form 1015 free radicals in the lungs – a hundred times more than we ourselves have body cells. Detoxification of tar inhaled at the same time creates an additional 1014 free radicals.
- Physical activity
- Extreme physical work
- Competitive and high-performance sports
- UV rays – for example, sunlight, solarium.
Disease-related causes
- Acute and chronic inflammation/infection [Proinflammatory cytokines, e.g., interferon-γ stimulate cellular immune response → leukocytes ↑ and macrophages↑ → nitric oxide radicals (NO. )↑)
- Atherosclerosis (arteriosclerosis; hardening of the arteries]
- Depression
- Hyperglycemia (hyperglycemia) /diabetes mellitus [formation of superoxide anion (O2-. ); posttranslational glycation/advanced glycated end products → formation of further oxidants].
- Hypertension (high blood pressure) [synthesis of oxidants within the endothelial cell]
- Pulmonary diseases such as adult respiratory distress syndrome (ARDS), bronchial asthma, emphysema, chronic obstructive pulmonary disease (COPD).
- Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS).
- Periodontitis
Laboratory diagnoses – laboratory parameters that are considered independent risk factors.
- Malonaldehyde (MDA), 4-hydroxy-2-nonenal (HNE), 2-propenal (acrolein), and oxidized LDL (oxLDL) – indirect indicators of oxidative stress (as end products of lipid peroxidation).
- 8-Hydroxy-2-deoxyguanosine (OHDG) – markers of nucleic acid oxidation.
Drugs
- Antibiotics (e.g. doxycycline) [NO stress].
- Hormonal contraceptives (birth control pills) – significantly increased peroxidation of lipids was recorded in 40- to 48-year-old women using oral contraceptives. This may be an indication of increased cardiovascular risk.
- Cytostatic drugs
X-rays
- Radiatio (radiotherapy) for tumor diseases.
- Ionizing rays
Operations
Environmental pollution – intoxications
