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Oxygen is essential for survival of multicellular organisms. Although essential for aerobic respiration, it also deals with considerable dangers to life. The reduction of molecular oxygen to water by the mitochondrial electron transport chain converts ADP into ATP. As a result of incomplete reduction, toxic reactive oxygen species (ROS) are formed that can damage different classes of biologic molecules.
All multicellular organisms must maintain oxygen homeostasis. Varieties of defense and regulatory mechanisms have been developed to protect the cell from reduced as well as increased oxygen levels. Interestingly, in the formation of ROS both increases and decreases in cellular O2 levels are resulted.
In this essay, I will expect to describe firstly, oxygen cascade and then some of the adverse effects of hypoxia and hyperoxia and role of ROS in diseases.
The respiratory system is made up of gas-exchanging organs and a pump (1). Gas exchanging organs are lungs and pump is the heart that ventilates the lungs. The pump consists of the chest wall, the respiratory muscles (internal intercostals muscles and external intercostals muscles, the areas in the brain that control the muscles, and the tracts and nerves that connect the brain to the muscles. At rest, normal breathing rate is 12-15 times a minute. About 500 ml of air per breath (6-8 L/min) is inspired and expired. This air mixes with the gas in the alveoli, then, O2 enters the blood in the pulmonary capillaries while CO2 enters the alveoli by simple diffusion. Thus, 250 ml of O2 enters the body per minute.
The rate of diffusion through the alveolar capillary membrane depends on
thickness of the membrane,
surface area of the membrane,
diffusion coefficient of the gas in the substance of the membrane, and
partial pressure difference of the gas between the two sides of the membrane (2).
Oxygen cascade system in the body is made up of lungs and cardiovascular system. Oxygen delivery to a tissue depends on
Amount of oxygen entering the lungs
Pulmonary gas exchange adequacy
Blood flow to the tissue- depends on cardiac output and degree of constriction of the vascular bed in the tissue.
Capacity of the blood to carry oxygen -depends on the amount of dissolved oxygen, amount of Hemoglobin (Hb) in the blood and the affinity of Hb of oxygen.
The dynamics of the reaction of Hb with oxygen make it a suitable carrier (1).
Hb + O2 â†” HbO2 (1)
Combination of the first heme in the Hb with oxygen increases the affinity of the heme for other oxygen. When fully saturated oxygen concentration is 1.39ml per gram of Hb.
Thus, oxygen that diffused from the alveoli into the pulmonary blood is transported to the peripheral tissue capillaries in combination with Hb.
Few amount of oxygen is transported to tissue capillaries in dissolved form of oxygen.
The partial pressure of oxygen (PO2) in the capillaries when the arterial blood reaches the peripheral tissues is still 95mmHg. PO2 in the interstitial that surrounds the tissue is 40mm Hg. Under this pressure difference, oxygen diffuses rapidly from the capillary blood into the tissues.
Metabolic use of oxygen by the cell
It is not the only role of oxygen in cells is to function as an electron acceptor to produce ATP (4). Recent studies have revealed additional roles for oxygen. Oxygen is important to the regulation of membrane transport, intracellular signaling and expression of many genes and the initiation of cell death. The heart is also affected by hypoxia by stimulating the release of Atrial Natriuretic Peptide (ANP) from heart atria (2). Hence, any disturbance in oxygen tension affects many of the regulatory systems in the human body. Sensing of oxygen not only takes place through the carotid body, but also appears to be a property of all tissues. Only a minute level of oxygen pressure is needed in the cells for normal intracellular chemical reactions to occur. Oxygen availability is no longer a limiting factor in the rates of chemical reactions, but the concentration of Adenosin diphosphate (ADP).
Reactive Oxygen Species production by the mitochondrial respiratory chain
Oxygen free radicals together with their metabolites are called reactive oxygen species (ROS) which can encourage direct cell injury, by triggering a cascade of radical reactions promoting the disease process (5) .In eukaryotic cells, the mitochondrial respiratory chain is a major source of ROS. Mitochondrial ROS production is associated with a dysfunction of respiratory chain complexes. Main producers of superoxide anions are complexes I and III of respiratory chain. They are released into the mitochondrial matrix and the intermembrane space.
Excessive generation of ROS may lead to the stimulation of the inflammatory process, secretion of chemotactic factors, proteolytic enzymes, growth factors, lipoxygenases, and cycloxygenases, inactivation of antiproteolytic enzymes, and activation of oncogenes and transcription factors.
Within the lungs, many exogenous and endogenous sources in biological reactions lead to ROS generation.
Exogenous sources are tobacco smoke, chemicals, toxic gases dust particles, vapors and ambient air containing toxins.
Oxygen cascade can be related to diseases due to increase O2 cascade or decrease O2 cascade. In addition, it may cause to adjustments in O2cascade. In the univalent reduction of oxygen and the generation of ROS, cellular oxidative phosphorylation is resulted. In the formation of water through the mitochondrial cytochrome oxidase system without the ROS generation, a majority of the univalent reduction of oxygen is resulted. In addition, few other enzymic reactions in the mitochondria may direct to the univalent or divalent reduction of oxygen to produce O2- or H2O2. Sequential reductions of cytochromes, flavoprotein, and ubiquinone by one-electron transfer reactions frequently result in the ROS generation.
Hypoxia is the oxygen deficiency at the tissue level. Hypoxia has been divided into 4 types (1).
Hypoxic hypoxia-In this situation PO2 of the arterial blood is reduced.
Anaemic hypoxia-The arterial PO2 is normal but available Hb amount to carry O2 is reduced.
Ischaemic hypoxia (stagnant hypoxia) -Blood flow to a tissue is low. Therefore adequate O2 is not delivered to tissue despite a normal PO2 and Hb concentration.
Histotoxic hypoxia-The amount of oxygen delivered to a tissue is adequate, but due to the action of toxic agents tissue cells cannot make use of the O2 supplied to them.
Effects on cells
The body shows adaptive reactions for their survival when they are exposed to an environment with reduced oxygen concentration. These reactions increase in respiratory volume, switch from aerobic to anaerobic metabolism, erythropoiesis and angiogenesis (6).Hypoxia causes the production of transcription factors. They are called as hypoxia inducible factors (HIF) (1, 4). For these reactions, cells change the expression of several hypoxia-responsive molecules such as erythropoietin and vascular endothelial growth factor. Hypoxia-inducible factor 1 (HIF-1) was found as a transcriptional factor that binds to Hypoxia-responsible element (HRE) and controls the expression of various hypoxia-responsive molecules. HIF-1 is a key molecule controlling the cellular response to tissue hypoxia (6). HIF-1 is made up of two subunits, HIF-1alpha and HIF-1beta. HIF-1 activity depends mainly on the intracellular HIF-1alpha protein level, which is regulated to be in inverse relation to the oxygen concentration by an oxygen-dependent enzyme, prolyl hydroxylase 2 (PHD2)(1,6). In normally oxygenated tissues, the Î± subunits are rapidly ubiquitinated and destroyed (1). The Î± factors dimerize with the Î², and the dimers activate genes that produce angiogenic factors and erythropoietin in hypoxic cells.
Thus, cells react to tissue hypoxia by sensing the oxygen concentration as the enzyme activity of PHD2, regulating the HIF-1 activity and as a result changing the expression of various hypoxia-responsive molecules (6).
Cellular response regulated by hypoxia-HIF-1 cascade is also involved in pathological situations such as tumor growth, diabetic retinopathy and rheumatoid arthritis. Under these pathological situations, the activation of hypoxia-HIF-1 cascade often leads to accelerate disease progression.
Many cancer cells are hypoxic, and there is possibility of manipulating HIFs to kill cancer cells (1).
Effects on the brain
Structural and functional integrity of brain function depends on a regular oxygen and glucose supply (7, 8). The brain is affected first in hypoxic hypoxia and the other generalized forms of hypoxia (1). It can be life threatening. Hypoxia caused by systemic or local blood circulation abnormalities cannot be tolerated for longer periods because the energy supply to the brain by anaerobic glycolysis is insufficient.
Hypoxia has been effected in central nervous system pathology in some disorders including stroke, head trauma, neoplasia and neurodegenerative disease (7). Complex cellular oxygen sensing systems have developed for tight regulation of oxygen homeostasis in the brain (1). A sudden drop in the inspired PO2 to less than 20 mm Hg causes loss of consciousness in 10-20 seconds and death in 4-5 minutes. Less severe hypoxia causes impaired judgment, drowsiness, dulled pain sensibility, excitement, disorientation, loss of time sense. In addition anorexia, nausea, vomiting, tachycardia, and, when the hypoxia is severe, hypertension. The ventilation rate is increased in proportion to the hypoxia of the carotid chemoreceptor cells.
Effects on retina
Retina is the most metabolically active tissue in the human body and, so, the retina is highly sensitive to hypoxia (9). All cells need oxygen for ATP production and even the smallest changes in oxygen tension bring about adjustments in order to maintain oxygen homeostasis in anoxic tissue. The function of the retina is sensitive to oxygen tension. A change in the perfusion pressure of the eye affects the retina although the eye is able to auto regulate its hemodynamic. Systemic hypoxemia due to lung or heart diseases or a vascular disease in the retina can cause retinal hypoxia. All the hypoxia-dependent events in cells appear to share a common denominator, hypoxia-inducible factor (HIF). Oxygen acts the key role in stabilizing HIF-1Î± and its function. When the oxygen tension is normal, HIF-1Î± is rapidly oxidized by hydroxylase enzymes. However, when cells become hypoxic, HIF-1Î± escapes the degradation and accumulates, triggering the activation of a large number of genes, such as vascular endothelial growth factor (VEGF) and erythropoietin. HIF-1Î± has been shown to have, a mediating or contributing role in several oxygen-dependent retinal diseases such as von Hippel-Lindau, proliferative diabetic retinopathy, retinopathy of prematurity and glaucoma. Recent results show that the HIF pathway can be used as a therapeutic target. HIF can be stabilized by inhibiting prolyl hydroxylase or by blocking the VHL: HIF-Î± complex if angiogenesis is the goal, as in retinitis pigmentosa. The down regulation of HIF has a key role if we are to inhibit neovascularization, as in proliferative diabetic retinopathy. HIF is a remarkable example of a single transcription factor that can be regarded as a "master switch" controlling all the oxygen-dependent retinal diseases.
Effects on kidney
Podocytes' function is maintaining the permeability of the glomerular filtration barrier. Studies have found a connection between the development of progressive kidney disease and podocyte failure as seen in gene mutations of podocyte-specific proteins leading to nephrotic syndrome, renal injury and failure (10). The slit diaphragm, which is the intercellular junction between the podocyte foot processes, is made up from different proteins synthesized by podocytes such as podocin, nephrin, CD2-associated protein (CD2AP) and actinin4. The integrity of the slit diaphragm, as regulated by protein expression in podocytes, plays a key role in regulating cytoskeletal dynamics and signaling in and between the podocytes. This is critical for maintaining the selectivity of the glomerular filtration barrier. Acute or chronic hypoxia can damage the podocyte and control slit Diaphragm protein expression. Expression of several proteins expressed in the Slit diaphragm is decreased when podocytes are exposed to hypoxia, along with decreased capability of the podocytes.
Injury to glomerular filtration barrier leads to proteinuria, which is identified as one of the important contributors to progressive renal injury.
Effects on glycogen accumulation
When oxygen becomes limiting, cells reduce mitochondrial respiration and increase ATP production through anaerobic respiration (11). The Hypoxia Inducible Factors (HIFs) play a key role in this metabolic shift by controlling the transcription of key enzymes of glucose metabolism. Oxygen regulates the expression of the muscle glycogen synthase. Hypoxic glycogen synthase induction requires HIF activity and a Hypoxia Response Element within its promoter gene. Glycogen synthase induction correlated with the significant increase in glycogen synthase activity and glycogen accumulation in cells exposed to hypoxia. Significantly, knockdown of either HIF1Î± or glycogen synthase attenuated hypoxia-induced glycogen accumulation, while glycogen synthase over expression was sufficient to mimic this effect. Altogether, these results indicate that glycogen synthase regulation by HIF plays a central role in the hypoxic accumulation of glycogen. Importantly, hypoxia also up regulates the expression of Uridyltryphosphate, glucose-1-phosphate urydylyltransferase and 1,4-Î± glucan branching enzyme , two enzymes involved in the biosynthesis of glycogen (11,12). Therefore, hypoxia regulates almost all the enzymes involved in glycogen metabolism in a coordinated way, leading to its accumulation. Finally, abrogation of glycogen synthesis, by knockdown of glycogen synthase expression, impairs hypoxic preconditioning, suggesting a physiological role for the glycogen accumulated during chronic hypoxia (11).
Oxygen toxicity occurs when the partial pressure of alveolar O2 is more than that which is breathed under normal conditions. With continuous exposure to supraphysiologic concentrations of O2, hyperoxia develops (13, 14). Under hyperoxic conditions, a large influx of reactive O2 species (ROS) is produced. In intracellular and extracellular biological systems, the mass effect of ROS increasing, caused by O2 overexposure, disrupts the balance between oxidants and antioxidants, and this disruption of homeostasis can result in damage to cells and tissues.
Role of ROS in diseases
ROS involve in the biological reactions of environmental molecules and toxicants both directly and indirectly (5). Cell membrane damage is a common occurrence in all types of cellular injury. In ROS-induced cellular injury, due to direct interaction of ROS or by the formation of peroxides and their terminal products damage to membranes of the cell and organelles are occurred. If not controlled, this self-spreading reaction can result in extensive damage of cellular membranes. Damage to cell membranes creates in profound ionic alterations within the cells and organelles. In ROS-induced cellular damage, the primary changes that occur are usually restricted to the cell membranes and membranes of the organelles. Because of the differences in their membrane lipids, Lysosomal membranes are usually considered resistant to ROS-induced lipid peroxidation. ROS are involved in the entering of inflammatory cells into the lung through the expression of chemo attractant proteins called chemokines. Macrophage inflammatory protein is chemo tactic to monocytes, lymphocytes, basophils, neutrophils, and eosinophils Induction of MIP-la by the activated alveolar macrophages is initiated by ROS. ROS can activate the nuclear transcriptional regulatory factor. This factor can bind to develop sequences of the promoter genes of interleukins and enhance the expression of genes to produce more cytokines. The enhanced cytokine production results in a cascade of biological reactions encouraging the disease process. ROS also play a significant role in the regulation of gene transcription and signal transduction pathways. Because reactive stress has been revealed to change intracellular Ca (II) homeostatasis, cellular redox state may adjust more than just these transcription factors. Such an effect may make worse free radical reactions, activate endonudease, and contribute to cell death. ROS also affect the synthesis of NO. They play a key role in the inflammation response process when macrophages are activated by a proinflammatory stimulus.
Oxygen derived species such as superoxide radical, hydrogen peroxide, singlet oxygen and hydroxyl radical are well known to be cytotoxic and have been implicated in the etiology of a wide array of human diseases, including cancer (14). Various carcinogens may also partly exert their effect by generating reactive oxygen species (ROS) during their metabolism. Oxidative damage to cellular DNA can lead to mutations therefore; play an important role in the initiation and progression of multistage carcinogenesis. The changes in DNA such as base modification, rearrangement of DNA sequence, miscoding of DNA lesion, gene duplication and the activation of oncogenes may be involved in the initiation of various cancers. Elevated levels of ROS and down regulation of ROS scavengers and antioxidant enzymes are associated with various human diseases including various cancers. ROS are also implicated in diabetes and neurodegenerative diseases. ROS influences central cellular processes such as proliferation, apoptosis, senescence that are implicated in the development of cancer. Understanding the role of ROS as key mediators in signaling cascades may provide various opportunities for pharmacological intervention.
Role of ROS in Immune System
ROS are severely involved in both parts of the immunological defense system, the innate and the acquired systems (14). When expose to environmental pathogens ROS are synthesized as a part of the oxidative burst in activated phagocytes, which are in the local inflammatory environment. It manifests one of the first lines of defense mounted against the invading pathogens. Although rapid, this innate immunity is usually partially effective. Acquired immunity will be commenced when pathogen-derived antigenic peptides are presented to the T lymphocytes. Pathogen-derived antigenic peptides are the result of phagocytosis and digestion by activated phagocytes. Because excess ROS continue to be locally synthesized by the activated phagocytes, ROS are involved in the acquired immune response, as a result develop the intracellular signal transduction cascades within the T lymphocytes, and thereby decrease their activation threshold.
Role of ROS in sickle cell disease
Sickle cell disease is an inherited disorder of Hb synthesis (15). It is related with significant morbidity and death because of periodic occlusion of vessels: pain crises and multiorgan damage. The microvascular responses to the beginning, development and resolution of vaso-occlusive events are consistent with an inflammatory phenotype as suggested by activation of multiple cell types, an oxidatively stressed environment and endothelial cell dysfunction (16). Reduced anti-oxidant defenses in Sickle Cell Disease patients are related with activation of enzymatic (NADPH oxidase, xanthine oxidase) and non-enzymatic (sickle haemoglobin auto-oxidation) sources of ROS. The resultant oxidative stress creates inhibition or activation of endothelial cells of arteries and veins, resulting in impaired vasomotor function and blood cell-endothelial cell adhesion. Changes in substrate and cofactor availability for endothelial cell nitric oxide synthase may cause reactive oxygen- and nitrogen-induced events that lead to Sickle Cell Disease-induced vasculopathy. The emerging role of reactive oxygen and nitrogen species in the pathogenesis of Sickle Cell Disease provides a platform for the development of new agents to treat this painful and fatal disease.
Role of ROS in oxidative DNA damage and cancer
As a major cause of cancer, damage to DNA by ROS has been found. Reactive Oxygen Species can damage DNA and the cell division with unpaired or misrepaired damage leads to mutations (17). The majority of mutations induced by ROS involve in modification of guanine, causing G (Guanine) â†’T (Thiamine) transversions. If it involves to critical genes such as oncogenes or tumor suppressor genes, initiation or progression can result. In addition, ROS can act at several steps in multistage carcinogenesis. It is now revealed that ROS are involved both in the initiation and in progression of cancer.
Mutations caused by oxidative DNA damage include a range of specifically oxidized purines and pyrimidines, single strand breaks, alkali labile sites and instability formed directly or by repair processes. It has been difficult to set up the frequency and specificity of mutations by individual oxygen radical induced lesions because of variety of DNA modifications produced by ROS. Some of these modified bases have been revealed that they possess mutagenic properties. So, if not repaired they can cause carcinogenesis. Although all the four bases are modified by ROS, mutations are usually involved with modification of Guanine Cytosine base pairs, while that of Adenine Thiamine base pair rarely cause mutations. Increased levels of modified bases in cancerous tissue may be due to the production of large amount of H2O2. It is found to be characteristic of human tumor cells. Presence of oxidative DNA modifications in cancer tissue further helps to initiation of cancer in humans by ROS.
Role of ROS in type 2 Diabetes
Normally, the pancreatic Î²-cells adapt their insulin secretion to the differences in blood glucose concentration sensed by their glucose sensor, glucokinase (18). The rate of insulin-dependent glucose consumption by glycolysis in the Î²-cells will increased during hyperglycemia (12). Then mitochondrial Electron Transport Chain (ETC) promotes ATP generation, which will then be released to the cytosol. Under high ATP:ADP ratio, plasma membrane of the Î²-cells will be depolarized, and the potassium-ATP channels will be closed allowing the opening of voltage-sensitive Ca2+ channels. Increased intracellular Ca2+ is the activator of exocytosis and insulin releasing from the secretory granules (14).
Accumulation of ROS in the mitochondria is associated with mitochondrial dysfunction. This was revealed an age-related process. The Î²-cells will be predominantly vulnerable to ROS damage with advanced age, based on their low expression of the antioxidant protective enzymes, which will permit for the increase of damaging effect of ROS.
Diabetic complications are also related to a state of oxidative stress. Diabetic retinopathy, being a major cause of blindness, oxidative stress acts a significant role in its pathogenesis (9). The pigment-epithelium-derived factor, a small-secreted glycoprotein that was shown to exert protective effect on the retina based on its antioxidant mechanisms in addition to other properties as the neurotrophic, antivasopermeability, antiangiogenic, ant fibrosis and anti-inflammatory properties.
It is the primary mediator of a cascade of heart damaging events, initialing from ROS formation and leading to myocardial ischemia, inflammation and death of myocytes.
Mammalian life and the biological processes that maintain cellular integrity depend on a continuous supply of oxygen to continue aerobic metabolism. Reduced oxygen delivery and failure of cellular use of oxygen occur in various conditions and if not identified result in organ dysfunction and death. It affects to almost all the systems in the body. Therefore, avoidance, early recognition, and correction of hypoxia are essential.
Hyperoxia is a condition of excess delivery of O2 in tissues. When the partial pressure of alveolar O2 is more than that which is breathed under normal situation, oxygen toxicity occurs. Hyperoxia may cause pathological conditions producing a large influx of reactive O2 species.