Oxygen, the Breath of Life: Boon and Bane in Human Health, Disease, and Therapy

Oxygen is the 3rd most abundant element in the known universe. Only hydrogen and helium, in that order, are more abundant. The big bang theory of creation asserts that all the elemental oxygen on earth was created late in the life of a dying star. On earth, oxygen is the most abundant element in the lithosphere (land), hydrosphere (water), and atmosphere (air). More precisely, the lithosphere is all the crust or solid, upper portions of the Earth; the hydrosphere includes all the rivers, lakes, seas, and oceans; and the atmosphere is the gas-filled space above and near the earth. Atomic oxygen is chemically and biologically reactive and primarily exists as molecular oxygen (O2, two like atoms combined), or in combination with certain elements (primarily metals). Oxygen forms reactive intermediates and free radicals including peroxide, superoxide and hydroxyl radical. The latter is said to be the most reactive species known in chemistry. Oxygen has a unique arrangement of electrons that is conducive to one-electron transfer reactions that can produce oxygen free radicals and cause biological oxidant stress. However, oxygen is especially suited to serve as the terminal acceptor of electrons in the biological process of electron transfer that is linked via coupled reactions to oxidative phosphorylation that creates adenosine triphosphate (ATP), the universal storage and transfer form of energy for all aerobic life on earth.

Oxygen is especially suited to serve as the terminal acceptor of electrons in the biological process within mitochondria of electron transfer. This process is linked via coupled reactions to oxidative phosphorylation that creates adenosine triphosphate (ATP), the universal storage and transfer form of energy for all aerobic life on earth. However, the unique arrangement of oxygen’s electrons is conducive to one-electron transfer reactions that can produce oxygen free radicals and cause biological oxidant stress. Hans Krebs was the genius who uncovered the complex, biological cycle that we know as the Krebs cycle which revealed the long-hidden secrets of how the energy of consumed food is made available for cellular functions. Oxygen is the only element with the special combination of unique attributes required for cellular bioenergetics, the process of “cold” burning of food molecules to power the cell’s energy needs. A special example of oxygen’s role in “cold burning” is the firefly’s luminescence.

Oxygen was first isolated by Carl Scheele, officially discovered by Joseph Priestly (because he published first), and named by Antoine Lavoisier. Air had historically been known to be required for both animal respiration and for combustion. With the careful laboratory work of Lavoisier, involving weighing and measuring, air was discovered to not be a single element but was found to be composed primarily of two gases, one of which was oxygen in the proportion of about 20%. Priestley published that in a sealed chamber this “pure form of air” (later named oxygen by Lavoisier), was what kept the mouse alive in his experiment. The work of Priestley and Lavoisier disproved and overthrew the Phlogiston Theory which speculated that a substance “phlogiston” was present in air which after combustion became dephlogisticated. The discovery of oxygen as an element and its roles in animal respiration and in combustion, were seminal events in the period of the late 1700s when chemistry transitioned from a largely “black art” (alchemy) to science. Thus, in addition to being essential to life (certain bacteria are exceptions), oxygen had a significant role in the development of modern chemistry.

Evidence supports that all of the molecular oxygen present in Earth’s atmosphere today could have been produced in the last 2,000 years. Photosynthesis by green plants, algae and related phytoplankton are the source of this atmospheric molecular oxygen. Green plants are the “sugar factories of the world” and have intricate microscopic systems within leaves that use sunlight, water, and carbon dioxide to produce carbohydrates and oxygen. Capture of photons from sunlight requires a complex array of pigments that include the green molecule chlorophyll. The photons are captured via absorption by pigments that are organized sequentially in a specific order within leaf structures called chloroplasts. Leaves have a complex, organized macroscopic structure and an even more complex microscopic structure. This organization begins with the shape and structure of the leaf itself. Leaves have an aerodynamic shape that allows them to survive in wind and rain and are oriented to capture sunlight. They have an outer waxy coating which retards water loss but with provisions (stomata) that regulate entrance and efflux of carbon dioxide, oxygen, and water vapor. The biosynthesis of carbohydrate from carbon dioxide requires energy input, and the leaf has intricate mechanisms for capturing sunlight to make chemical bonds in ATP. Great political turmoil recently has arisen over claims that carbon dioxide in the atmosphere is the determining factor in increasing the global temperature by amplifying the “greenhouse” effect. Based on speculation and questionable computer models, man-made (anthropogenic) carbon dioxide is said to be the cause of what initially was called “global warming”, but more recently has been changed to “climate change”. The ability to scientifically measure photosynthesis globally has become relevant for making intelligent decisions about climate change and atmospheric CO2 concentration. There is reason to believe that natural (and/or future artificial) photosynthesis can maintain the balance of atmospheric CO2.

Water is the most abundant molecule in which atomic oxygen is found on earth. Water is composed of two atoms of hydrogen (the simplest of the elements) and one atom of oxygen covalently bonded (four valence electrons are shared). Water covers about 71% of the land mass on earth and by weight water is approximately 0.33% of the atmosphere. It is the only element that is present in the earth-like temperature range as liquid, solid and gas. There is an earth-water cycle, and it nourishes, cleans and sustains the land with transpiration to clouds and condensation as rain, snow, sleet and hail. Our bodies vary in oxygen content, but the average is around 50%; slightly less in women than in men, and more in the skinny than in the obese. Oxygen has physical and chemical properties that are unusual and not predicted, compared to other small, simple compounds. It has maximum density at about 4 degrees Centigrade which causes lakes and ponds to freeze from the top down with interesting consequences. It is a good solvent for many chemicals and it forms the milieu of the cells of our bodies. It forms hydrogen bonds with itself which introduces unexpected structure in collected water molecules. Without it, life as we know it (and what other kind of life might there be?) would not be possible– we even search for it in space and on other worlds as a sign there might be life there.

Since the discovery of oxygen, there have been swings from emphasis on the essential, beneficial nature of oxygen to focus on its damaging effects. Outright speculations and critically-considered hypotheses have ebbed and waned for the therapeutic use of elevated oxygen and practical applications of gas mixtures for deepsea diving and pressurized caissons for construction under water. Oxygen as therapy has been proposed as beneficial or even a panacea. In some hands it was harmful and even deadly. The use of elevated oxygen tensions (as compressed air) began even before oxygen was isolated and identified from air. Oxygen was used as therapy and compressed air was extensively breathed by miners and workers in caissons tunneling under water to construct bridges. These practical, non-therapeutic applications of various breathing mixtures containing oxygen also contributed to scientific understanding of the physiology of oxygen in the human body. Elevated oxygen tensions also were used for U.S. Navy diving operations and laboratory experiments with humans and a variety of life forms. In the early years oxygen therapy was used for a wide variety of diseases, many of which were treated without any established connection to a mechanism of action. Thus, the therapeutic use, laboratory experimentation with, and practical applications of compressed air, gas mixtures at and below one atmosphere pressure, and hyperbaric oxygen has had an interesting, long, and colorful development that included charlatans (probably), adventuresome physicians ahead of their times, visionaries, and practical men of industry.

Oxygen paradoxically exhibits both strongly positive and violently negative effects in biological systems. Irwin Fridovich succinctly characterized this as the “boon and bane” of oxygen. Joe M. McCord in Fridovich’s laboratory, in 1969, had discovered the enzymatic activity of copper-zinc superoxide dismutase that fueled a revolution in research into the mechanism used by the body to defend itself against the toxicity of oxygen. Superoxide dismutase converts the biologically-active oxygen radical, superoxide, into molecular oxygen and hydrogen peroxide and the latter is a substrate for catalase which is abundant in cells and converts hydrogen peroxide into oxygen and water. Oxygen has been shown to be a vital participant in extremely diverse biological functions including phagocytosis, athletic performance, ageing, mitochondrial energetics, and a host of oxidant stress-related and degenerative diseases which are areas of continuing research today. The mechanisms of oxygen toxicity at the cellular level were primarily speculative until near the end of the 1960s when the significance of oxygen “free radicals” became the dominate research theme. The means to examine the mechanisms of oxidative damage to enzymes, membranes and DNA became available and scientists began to probe into intracellular sites and mechanisms of oxygen toxicity. The realization that various electronically “excited” (free radical forms of oxygen) were the culprits that damaged the vital and sometimes delicate machinery of life was brought into sharp focus by the discovery of superoxide dismutase and its exploration by both pure and applied researchers in medicine, chemistry, biochemistry, and molecular biology. There were controversies, primarily about which oxygen radicals were most significant, but this led to realization that a host of factors including the chemistry and biology of the many oxidized species, iron and other transition metals as electron donors, and complex cellular defense mechanisms were essential parts of the new story that began in the late 1960s and is continuing today.

The human body contains coordinated, complex components that work together to efficiently extract oxygen from the air and deliver it to the intracellular sites where it is essential for life. Oxygen’s journey for life begins in the lung where it is transported by a system of branching tubes of decreasing size, the bronchus, bronchioles and bronchi. The lungs are made of a wonderful collection of cells that are organized into a unique, spongy tissue that contains the bronchial tubes with air sacs, the alveoli, at their termini. The interior surface area of the alveoli, collectively, is equal to the area of a tennis court. An intricate system of blood capillaries, arteries, and veins envelops each alveolus and circulates a large supply of blood that arrives deoxygenated and leaves oxygenated. The lung works efficiently by using air pressure and diaphragm muscles to expand and decrease lung volume during breathing. Oxygen is not sufficiently soluble in blood to supply the body’s needs. However, a complex oxygen-carrying molecule, hemoglobin, is packaged into special cells, the red corpuscles where truly magnificent biochemistry reigns. The process works, by analogy, like a subway system to load and unload oxygen and carbon dioxide from alveoli to cells throughout the body. Hemoglobin does double duty and reverses the sequence by loading carbon dioxide from tissues and unloading it in alveoli. The heart supplies the pumping force that moves the red cells which arrive at ever smaller arteries and then to capillaries which intercalate with tissues that must have a continuous supply of oxygen to function. All cells require oxygen to supply the bulk of their energy needs, and some for other purposes, but the brain is especially oxygen hungry and uses approximately 25% of the total resting needs by the body for oxygen. Working muscle is provided with hemoglobin’s cousin, myoglobin, which can store oxygen and release it to contracting muscle cells. Oxygen is nearly perfect for bioenergetics and it also has the right stuff to be efficiently transported.

Parkinson’s, Alzheimer’s, and Huntington’s are degenerative brain diseases with some similarities in symptoms. Oxidative stress has been linked to these diseases, but causation is unproven. Dementia is a central feature but is not diagnostic. Based on historical, clinical descriptions the order of discovery as a disease is: Parkinson’s (1817), Huntington’s (1842) although it probably has been known since the Middle Ages and was called “chorea”, and Alzheimer’s (1906). Alzheimer’s is the most common; Parkinson’s is second; and Huntington’s is the third most common neuronal, degenerative disease. None of these diseases can be cured, and there is generally a long, severe decline in functional ability that is tragic for the individual, the family and friends. Although the causes of these diseases are unknown, there are genetically inherited risks for each. The pathophysiology, brain sites affected, cellular and subcellular mechanisms, and genetics for each disease is complex and oxidant stress has been incriminated for some aspects of these diseases. Parkinson’s results in a progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the metabolism of dopamine itself generates reactive oxygen species. Therapy with the dopamine precursor levo-dopa (dopamine does not pass the blood- brain barrier) does not provide lasting benefits. Speculation that Parkinson’s disease is caused by reactive oxygen species generated from pesticide exposure has not been proven. Discoveries by co-workers in my laboratory pointing to special sensitivity from oxidant stress for certain iron-containing enzymes in amino acid metabolism are promising links to oxidant stress causation. Generation of oxidant stress via aberrant mitochondrial oxidative metabolism is a viable thesis but a cure for these diseases is not in sight and is more likely to result from future discoveries using stem cells and perhaps gene therapy.

Oxygen utilization by essential metabolic processes inevitably has the potential to damage or destroy essential cell components by oxidative mechanisms. This negative effect of oxygen is called oxidant stress. Over a lifetime oxidant stress contributes to the decreased functioning observed by aging; it occurs during exercise with both detrimental and adaptive potential; and it is associated with or causative for certain lung and cardiovascular diseases. Oxygen uptake and utilization becomes maximal during athletic performances with high workloads for extended time periods. The associated oxidative stress is positive in outcome via enhanced antioxidant defenses. There is sufficient evidence that the primary source of excess oxidant stress is at the site of oxygen utilization at the inner membrane of mitochondria. Normally, a small fraction of mitochondrial use of oxygen is diverted from the secure transfer, one at a time, of electrons via the cytochrome system to generate water and ATP in a complex, carefully orchestrated process. Four electrons are required to reduce diatomic oxygen completely and partially reduced intermediates, including peroxides, and the free radicals superoxide and hydroxyl radical can form. Oxidative damage occurs, and damaged mitochondria can produce even more free radicals. There are also other biochemical sources and mechanisms that generate oxidative radicals and create oxidant stress. The lung, which is exposed to the highest concentration of oxygen, is especially vulnerable to oxidant stress when hyperoxia is used therapeutically. Lipid membrane damage involving the alveoli, and potentially fibrosis, is a consequence for premature infants and for chronic obstructive pulmonary disease and other lung pathologies in adults. Oxidation of LDL-cholesterol by oxygen free radicals during excess oxidant stress is the initial event in a sequence leading to atherosclerosis and potentially to cardiovascular events and strokes. A natural balance of antioxidant defenses is protective for oxidant stress and is enhanced by antioxidants in the diet and as a positive benefit from exercise. However, there is evidence that, over time, the net effect of oxidant stress contributes to detrimental deteriorations associated with the aging process in the brain and throughout the body.

Oxygen has had a long history; it was the 18th element to be discovered of 118 known elements, of which 28 have been created artificially. Oxygen is essential for all aerobic life on earth and pure oxygen at various partial pressures and mixed with other gases is used as a medicine for conditions where the oxygen supply is inadequate, including for premature infants whose lungs are not completely developed. Oxygen is also used for pathologies where oxygen supply to tissues is compromised. Oxygen is a component in gas mixtures used for deep-water diving for sport, recreation, salvage, exploration and mining. Oxygen is a requirement for manned space flight and commercial air travel. In the future, it is a certainty that all of these uses and requirements will continue. It is almost as sure that things now predictable based on past and current research and things as yet unimagined are destined to happen in the future. For therapy, it is probable that artificial blood that adequately perfuses the body will be routine. For recreation, it is likely that private oxygen chambers will get fancier and be more widely used, as will oxygen as a novelty is “sports” bars. In sports, the use of oxygen in breathing mixtures for deep-sea diving and by free divers will continue although it is difficult to see how current records can be much extended. Artificial gills will never become practical but by mimicking sea mammals, man may become as free as dolphins to explore the deeps. For endurance sports and sprints, oxygen supplementation, particularly for training recovery and its psychological effect, will become common and contribute to new records. Ways to manufacture oxygen cheaply and reliably will make possible undersea habitats that will include underwater cities. As future therapy, antioxidants and other oxidant stress protector molecules will allow expanded therapies for many conditions which are limited by the toxicity of oxygen. The most spectacular advance will be in artificial photosynthesis that will remove carbon dioxide from the atmosphere, provide oxygen and carbon-based fuels and power cells that will far outstrip solar cells.