Disease and the Oxygen Cascade - Essay Example

Introduction Oxygen is central to all aerobic forms of life (Treacher, and Leach, 1998). Most diseases have inter-connections with the availabilityand use of oxygen. Conversely, normal functioning of a living cell is not possible without this substance. Normal health, disease, and oxygen are inevitably related. Since oxygen is a gas, the pressure at which it is available is almost as important as its very presence in a given situation. Living cells need oxygen all the time but have no mechanism to store it (Treacher, and Leach, 1998). Most cells, especially those of the human brain, which controls life processes, cannot survive for more than a few minutes without a continuous supply of oxygen at the right pressure. Any disease which affects oxygen supply and access at the cellular level therefore has potentially fatal consequences, even if the disorder is transient. Oxygen does not normally exist in nature by itself, but rather in mixture with other gases (Townsend, and Webster, 2000). Dalton's Law therefore comes in to play at all times, with each gas in a mixture exerting an independent partial pressure (Hopley, and Schalkwyk, 2006). Nitrogen, carbon dioxide, and water vapor are three common gases which generally accompany oxygen during crucial phases of respiration. Living cells may therefore be unable to access oxygen in a state of disease, even though the gas is available in the surroundings. Oxygen availability and demand for this substance are not steady at all times. Physical activity and other physiological processes, including those affected by disease, may cause oxygen demand to peak well over the average level. The partial pressure of oxygen, on the other hand, may fall off steeply, as at high altitudes. Changes in oxygen availability and demand do not necessarily move in tandem. High altitude sickness is a common example of oxygen demand peaking even as its partial pressure falls steeply. Disease may also affect the supply/demand balance of oxygen at the tissue or cellular levels. There is a complicated and inter-related delivery system for oxygen from the atmosphere external to a living being and the mitochondria in cells responsible for oxidative phosphorylation (Lewis, and Fitz-Henry, 2001). Any defect in a tissue, structure, or a system, involved in respiration, circulation, diffusion, or metabolism, can affect the ability to use oxygen for vital processes. This paper defines the series of partial pressures at which oxygen is available at various levels of a living system, and relates the processes involved in the procurement, gaseous exchange, transport, and use of oxygen, to states of disease. Steps in the Oxygen Cascade Most people live at or around sea level. The atmospheric pressure at this level is 760 mmHg and 20.94% of air at this altitude is oxygen (Neligan, 2002). Therefore, the partial pressure of oxygen (PO2) at sea level is 159 mmHg. However, the PO2 at the level mitochondria in cells is as low as 3 mmHg (Neligan, 2002). Where have 156 mmHg gone The vast proportion of oxygen is either diluted or even lost altogether as it travels in to lungs and from the alveoli to blood in the circulatory system. The various stages by which the partial pressure of oxygen falls off are collectively known as the oxygen cascade. Life has evolved to deal with such colossal inefficiencies, and to maintain normal health at the same time. The transfer of oxygen from air to blood in the lungs, the transport of oxygen by blood to organs and to tissues, and the diffusion of oxygen from capillaries to individual cells and to the mitochondria inside them, all take place within specific ranges of partial pressures. However, the balances are delicate, and diseases and other may have serious effects on the oxygen cascade. All diseases which affect the structure and functioning of the lungs, or which affect the capacity of blood to transport oxygen, or which affect circulation of blood to the far reaches of the body, or which affect cellular organization, especially in terms of mitochondrial structures, can have debilitating effects on the oxygen cascade. Cancers, cardiac and blood vessel diseases, deficiencies in the composition of blood, acute trauma, and genetic defects of mitochondria, are the major classes of diseases which impact the oxygen cascade. The oxygen cascade is also affected by muscular weaknesses in the chest wall or diaphragm, by neurological breakdowns in the control of breathing and of respiration, and by unnatural obstructions which may develop at any point of the air passage to the lungs. All blood and oxygen has to pass through the lungs, so any disease affecting these two vital organs will dramatically affect the oxygen cascade. Any disease or defect which affects one stage of the oxygen cascade will also have domino effects on downstream processes (Neligan, 2002). Thus, low atmospheric pressure at high altitudes, or high pressures in hyperbaric conditions, will affect gaseous exchange in the lungs. Similarly, tissues, organs, and cells will suffer if the cardiac output falls, in lung diseases, in anemia, if blood vessel walls are weakened, or in ischemia. Finally, the entire oxygen cascade will lose utility even it functions normally, if oxidative phosphorylation at the cellular level is impaired. The volume and composition of air entering the lungs, the carrying capacity of blood, the circulatory system, diffusion of oxygen between alveoli and capillaries, and from the latter to cells, and cellular metabolism, are the crucial parts of the oxygen cascade (Treacher, and Leach, 1998). The partial pressure of oxygen when a healthy person inspires dry air ay sea level is 160 mmHg. This drops, largely because of dilution in water and other fluids to 120 mmHg in the alveoli of the lungs. Fluids in blood result in further dilution, so that oxygen in blood is about 100 mmHg. This falls sharply at tissue level to 20 mmHg, and finally to less than 4 mmHg in individual cells (Hopley, and Schalkwyk, 2006). Gradients in the oxygen cascade tend to get steeper as people age. Alveolar ventilation and the amount of oxygen in alveolar air are inversely related. This is expressed as the universal alveolar air equation (Hopley, and Schalkwyk, 2006). The rate of breathing may vary in certain conditions and disease states, so the actual values of the universal alveolar air equation also vary in actual practice. The rate of oxygen consumption affects the partial pressure of oxygen at the level of the alveoli (Lewis, and Fitz-Henry, 2001). The ventilation/perfusion match affects the partial pressure in blood, while the Hemoglobin content affects the same parameter at the cellular level. These are examples of disease states which affect the oxygen cascade. The integrity of the oxygen cascade at all levels is so important for the maintenance of vital parameters that actions to prevent diseases from disturbing the partial pressure levels generally require intensive care and action. Hypoxia may be obvious in an acutely ill patient, but the level of the oxygen cascade which causes such a condition requires careful analysis. Thus, ventilation assistance may not help a patient with hypoxemia. Similarly, hypoxia at the cellular level may not be immediately evident for a person with a disease such as anemia. Prevention of disturbances in the oxygen cascade, early identification of hypoxia or hypoxemia, and timely corrective actions to restore balances are important for maintenance of vital parameters (Treacher, and Leach, 1998). The oxygen cascade has to meet a number of contradictory objectives. It must be energy efficient so that the cardiac and respiratory systems have to do as little work as possible (Treacher, and Leach, 1998). The system has also to match oxygen distribution with metabolic demands made by various organs and tissues; finally, the oxygen must move across capillary/cell membrane boundaries easily so that mitochondria can use the substance effectively. Diseases which affect the oxygen cascade often cause the most significant harm through hypoxia at a particular stage, which in turn also affects downstream processes. Diseases and Disorders which Affect Oxygen Delivery at the Lung/Blood Interface Blood which leaves the lungs on its way to various parts of the body should have a partial pressure of oxygen of around 100 mmHg. This is against normal oxygen content in ambient air of 20.94% (Neligan, 2002). This paper does not consider the many external conditions in which the oxygen content and partial pressure may drop to levels so as to cause hypoxia. However, there are also a number of diseases which affect the oxygen content of blood, as it leaves the lungs on its way to all the cells of the body. Some of these may be due to acute conditions that break the integrity of the air passage, such as trauma, tumors, and excess secretions. Such conditions are relatively benign or can be solved by creating temporary or new passages to the lungs. Chronic diseases cause more serious and lasting effects on the oxygen cascade. . Water vapor dilutes oxygen content in inspired air (Neligan, 2002); this happens in the normal state, and the oxygen cascade provides for it. However, bacterial infections of the respiratory tract and defects in the removal of fluid wastes from blood are examples of diseases which can dilute the oxygen content of moist air as it encounters capillary blood vessels in the lungs, below the normal range. This in turn affects the oxygen content of blood, disturbing the gaseous exchange as it occurs at the junction between the circulatory system and cell borders. Inspired air contains nitrogen apart from oxygen, but a third gas-carbon dioxide-enters the picture as the lungs prepare for gaseous exchange (Neligan, 2002). Pulmonary alveoli maintain carbon dioxide content at the same level as in blood entering the lungs, but the carbon content of food affects the amount of carbon dioxide to be excreted. Carbohydrates are highest in carbon content, while fats are amongst the lowest in this respect (Neligan, 2002). It follows that any disease arising from dietary and digestive factors, or which raises the carbon dioxide content of venous blood, can disturb the oxygen cascade in the lungs. Inspiration is integral to the oxygen cascade. Deformations of the rib cage, and defects in the construction and coordination of the muscles of the chest wall and the diaphragm can affect respiration and the functioning of the lungs (Bittar, 2002). Such defects may also develop as a result of accidents and failure of the nervous system. Chemical receptors which regulate respiration are situated in the medulla of the brain and in the circulatory system (Lewis, and Fitz-Henry, 2001). The ones in the central nervous system sense the partial pressure of carbon dioxide, while the ones in the major arteries sense the partial pressure of oxygen. It follows that any diseases which affect the medulla, or which result in damage, blockage, or excision of the carotid artery, can result in stoppage of the breathing process. Hypoxia alone does not act as a stimulus to resume inspiration (Lewis, and Fitz-Henry, 2001). These kinds of disturbances of the oxygen cascade are relatively easy to correct through mechanical ventilation assistance for an affected patient. Frictional resistance to gas movement and the inherent elasticity of tissues oppose the forces created by the movements of the rib cage and diaphragm (Hopley, and Schalkwyk, 2006), and diseases which affect such forces of resistance will also disturb the oxygen cascade. A related aspect is muscular weakness in the chest wall muscles or the diaphragm. Normal operation of the oxygen cascade requires that a certain tidal volume is available to provide oxygen at the level of the alveoli. A disease which causes shallow breathing will result in a drop of oxygen concentration, and a concomitant increase in carbon dioxide concentration at the junctions of bronchioles and capillaries (Townsend, and Webster, 2000). Adequate inspiration is therefore essential for the oxygen cascade to function correctly. Hypoxia which results from hypoventilation can be corrected by administering a higher concentration of oxygen as per the following formula: PAO2 = PIO2 - (PACO2/R), where PIO2 is the partial pressure of inspired oxygen (Townsend, and Webster, 2000). Since the lungs have such an upstream role in the oxygen cascade, it follows that any pathology which affects the structure or functioning of these organs will affect transport of oxygen and oxidative phosphorylation in cells. The system from the nose and mouth to the most internal reaches of the lungs follows about 17 levels of branching, from the trachea to the bronchioles. There are over 100 thousand respiratory bronchioles. The latter have average diameters of about 200 microns. Any disease which affects the normal development of this respiratory tree in a fetus or a child, or which affects the functioning of the bronchioles in adult life, will affect the oxygen cascade. Similarly, chronic obstructive pulmonary disease in adults results in poor ventilation at the level of the bronchioles, leading to hypoxia (Treacher, and Leach, 1998) Surfactant in the lungs plays an important role in the oxygen cascade (Hopley, and Schalkwyk, 2006). The surfactant is made of dipalmitoyl phosphatidyl choline and phosphatidyl glycerol. The surfactant works to neutralize the effect of Laplace's Law, which operates within the branching structure of the bronchioles (Hopley, and Schalkwyk, 2006). Laplace's Law states that the pressure inside a bubble exceeds the pressure outside the bubble by twice the surface tension, divided by the radius. Therefore, smaller bronchioles would collapse entirely were it not for the surfactant. Any infection of chronic condition which affects the production or availability of the surfactant, will therefore lead to a collapse of the finer bronchioles in the respiratory tree. Gas flows within the lungs are both turbulent and laminar (Hopley, and Schalkwyk, 2006). Reynold's number, which is defined as (linear gas velocity) * (diameter) * (density), states that turbulence starts over a product of one thousand. Such conditions prevail at the branches of the respiratory tree, and when the body demands higher rates of oxygenation through rapid and deep breathing. Poiseuille's Law governs laminar air flow in the lungs. The resistance decreases to the fourth power with increase in radius. The structure of the bronchioles is therefore crucial for the oxygen cascade. Gas flows will be affected if finer bronchioles are damaged. The normal oxygen cascade accounts for considerable air loss within the lungs. This loss is about one-third of the tidal volume which enters a healthy lung (Hopley, and Schalkwyk, 2006). This oxygen loss increases if any disease affects the anatomy of lungs, increasing the dead space. Similarly, infections or pathologies which affect the perfusion of bronchioles, will also impact the oxygen cascade. The anatomical dead space can be measured by using a rapid nitrogen analyzer following inspiration of pure oxygen (Hopley, and Schalkwyk, 2006). This procedure will indicate if the dead space in a lung has increased due to disease. Since all parts of the lungs are not equally ventilated, the normal operation of the oxygen shunt depends upon hypoxic pulmonary vasoconstriction (Townsend, and Webster, 2000). Sepsis and inflammation are some of the medical conditions in which blood is sent to poorly ventilated parts of the lung, resulting in disturbances of the oxygen cascade at this stage. High arterial pressures and trauma are other conditions in which hypoxic pulmonary vasoconstriction processes are disturbed, affecting the oxygen cascade as a whole (Townsend, and Webster, 2000). Bronchospasms, edema, and pneumonia, are some of the serious and common lung diseases which affect the oxygen cascade, leaving blood with inadequate oxygen content for the tissues and cells. Diseases of alveolar structure and the pulmonary endothelium also affect gaseous exchange between alveoli and capillaries (Bittar, 2002). Diseases which change the structure, thickness, and elasticity of bronchiole walls result in diffusion impairment (Townsend, and Webster, 2000). Diffusion impairment may also be due to low cardiac output, leading to reduced contact time of blood and air at the bronchiole/capillary junction. Diffusion impairment affects the transfer of oxygen to blood, but since carbon dioxide is more soluble than oxygen, its elimination remains relatively unaffected. Most cases of diffusion impairment can be treated on emergency bases by delivery of pure oxygen (Townsend, and Webster, 2000). The clinical manifestations of diffusion impairment are the same as in the case increases in the true shunt due to congenital heart defects. The normal true shunt is due to admixture of venous and arterial blood around the fine bronchioles or because some blood flows through the lungs without adequate time for full oxygenation (Townsend, and Webster, 2000). Any dramatic increase in the true shunt because of anatomical defects in the heart will disturb the oxygen cascade, and this condition will not respond to even pure oxygen administration. Defects of ventilation perfusion, diffusion, the lateral shunt, and the output of the heart all affect the transfer of oxygen from bronchioles to the blood vessel system (Neligan, 2002). Edema, chronic obstructive pulmonary disease, pulmonary embolisms, interstitial disease, and long periods of lying supine, are all disease conditions which affect the oxygen cascade because of defects in diffusion and perfusion (Townsend, and Webster, 2000). Fick's Law, which states that gas exchange across a membrane is directly proportional to the surface area of the membrane, and inversely proportional to the thickness of the membrane, applies to diseases which reduce the effective surface area of bronchioles, or which affect the structure and thickness of bronchiole walls (Hopley, and Schalkwyk, 2006). Graham's Law also implies that the oxygen cascade is more affected by membrane diseases than carbon dioxide elimination, since oxygen is heavier and less soluble than gases lost in expiration. Finally, even anemia can affect the oxygen cascade at the level of the lungs, since oxygen has to travel further before it can find hemoglobin with which to react (Hopley, and Schalkwyk, 2006). Disease Effects of Oxygen Transport to Mitochondria The preceding section of this paper has tried to establish how a variety of diseases can affect the oxygen cascade as atmospheric air travels in to and within the lungs. Any significant drop below 100 mmHg in the partial pressure of oxygen as it leaves the lungs to oxygenate the various parts of the body, will affect tissue and cell oxidative phosphorylation. However, it is not as though the oxygen cascade is safe if all goes well in the lungs: diseases may also impact oxygenation after blood has left the lungs. Circulatory defects, deficiencies in the structure and composition of various blood components, and abnormal conditions in the micro-environment of blood capillaries and cell membranes, are all further obstacles for proper execution of the oxygen cascade (Treacher, and Leach, 1998). Most oxygen in carried in blood attached to hemoglobin, while a small portion remains in solution. Henry's Law, which states that the number of molecules of gas dissolved in solution is proportional to the partial pressure of the gas, determines the dissolved oxygen content. Thus, any disease which affects the partial pressure of oxygen in pulmonary blood vessels will reduce the oxygen content in plasma (Townsend, and Webster, 2000). Anemia is the most prominent disease in which the hemoglobin content of blood becomes abnormal. Each molecule of hemoglobin attaches to 4 molecules of oxygen, but each of the associations is different in terms of durability (Townsend, and Webster, 2000). Some forms of hemoglobin cannot combine with oxygen at all, so if a person for genetic reasons has a deficiency in the right types of hemoglobin, then the oxygen cascade will degrade further as blood travels from the lungs to the furthest reaches of the body, regardless of the oxygen content of blood in the pulmonary region. There is a trade-off in managing critically ill patients, between substituting low hemoglobin with additional oxygen supplies, and increasing blood viscosity through higher red blood corpuscles (Treacher, and Leach, 1998) Cardiac function affects oxygen delivery to tissues regardless of the oxygen content of blood. A cardiac output of 5 liters a minutes, translates normally to 1 liter per minute of oxygen availability at the tissue level (Townsend, and Webster, 2000). Oxygen demand from tissues varies with physiological and physical activity levels. Thus heart diseases which reduce output rates may seriously impair the oxygen availability for cells, even in a resting state. The body does have an oxygen store to last for a few minutes, but this is scarcely adequate for chronic drop in cardiac output. Drop in cardiac output is not the only circulatory contribution to hypoxia at the tissue level. This may also happen because fine capillaries are lost or because blood vessels and branches are blocked. Hypertension, high saturated fat content in blood, and uncontrolled or poorly managed diabetes, are some of the prominent diseases which affect the capability of the circulatory system to deliver adequately oxygenated blood at proper rates to all parts of the body. Tissue hypoxia due to faulty or inadequate angiogenesis is also a factor of malignant tumors (Wilson, 2003). Stromal and neoplastic cells have enormous oxygen demands which even a fully functional oxygen cascade system cannot meet. Some cancers are known to cause defects in micro-vessel structures in the circulatory system. Tissue hypoxia is therefore a characteristic of tumors regardless of normal blood oxygenation. Further, artificial inhibition of angiogenesis has potential applications in the management of tumors by inducing apoptosis of malignancy (Wilson, 2003). Effects of Mitochondrial Disorders and Defects Mitochondria have genetic material distinct from the rest of the body (Sengers, and Trijbels, 2003). This is made entirely from maternal genes without any chromosomal contribution from a male parent. This may be the reason for mitochondrial irregularities which prevent proper oxidative phosphorylation in cells, even if the entire oxygen cascade functions normally. The clinical manifestations of mitochondrial irregularities are varied and difficult to establish in clinical settings. Nevertheless, it is noteworthy that vital life processes may be affected even if the entire oxygen cascade acts in concert. Conclusions The oxygen cascade is a complex process with a number of stages. Capture of oxygen from external air, transporting it through blood to all cells of the body, coping with peak oxygen demands in response to activity, and the cellular process of oxidative phosphorylation, principally involve nerves, blood vessels, muscles, mitochondria, the heart, and the lungs. Any disease of these tissues, structures, and organs disturbs the oxygen cascade with downstream effects. Cancers, diabetes, neuropathy, trauma, muscle degeneration, cardiac, lung, and circulatory diseases, as well as sepsis and inflammation are some prominent and common medical conditions which affect the normal functioning of the oxygen cascade. Hypoxia can be confusing from the medical care stand point, especially in acute conditions, because the clinical manifestations are the same regardless of the stage, site, and nature of the disturbance in the oxygen cascade. Aggressive fluid loading may adversely affect gas exchange in the lungs or around cells. Oxygen administration and mechanical ventilation assistance may therefore be unhelpful or even counter-productive in some cases of hypoxia. Early and accurate diagnosis is therefore central to management. Hypoxemia and hypoxia in the cellular environment may arise due to certain diseases such as anemia, due to hardening and partial blockage of blood vessels, or because of congenital defects in mitochondria: these may remain without obvious or direct symptoms for extended periods of time. Comprehensive monitoring of downstream phases of the oxygen cascade is therefore an important component of preventive care. 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