RESPIRATION, HUMAN

the process by which oxygen is taken up and carbon dioxide discharged. Adaptations High altitudes Ascent from sea level to high altitude has well-known effects upon respiration. The progressive fall in barometric pressure is accompanied by a fall in the partial pressure of oxygen, both in the ambient air and in the alveolar spaces of the lung; and it is this fall that poses the major respiratory challenge to humans at high altitude. Humans and some mammalian species like cattle adjust to the fall in oxygen pressure through the reversible and non-inheritable process of acclimatization, which, whether undertaken deliberately or not, commences from the time of exposure to high altitudes. Indigenous mountain species like the llama, on the other hand, exhibit an adaptation that is heritable and has a genetic basis. Respiratory acclimatization in humans is achieved through mechanisms that heighten the partial pressure of oxygen at all stages, from the alveolar spaces in the lung to the mitochondria in the cells, where oxygen is needed for the ultimate biochemical expression of respiration. The decline in the ambient partial pressure of oxygen is offset to some extent by greater ventilation, which takes the form of deeper breathing rather than a faster rate at rest. Diffusion of oxygen across the alveolar walls into the blood is facilitated, and in some experimental animal studies the alveolar walls are thinner at altitude than at sea level. The scarcity of oxygen at high altitudes stimulates increased production of hemoglobin and red blood cells, which increases the amount of oxygen transported to the tissues. The extra oxygen is released by increased levels of inorganic phosphates in the red blood cells, such as 2,3-diphosphoglycerate. With a prolonged stay at altitude, the tissues develop more blood vessels, and, as capillary density is increased, the length of the diffusion path along which gases must pass is decreaseda factor augmenting gas exchange. In addition, the size of muscle fibres decreases, which also shortens the diffusion path of oxygen. The initial response of respiration to the fall of oxygen partial pressure in the blood on ascent to high altitude occurs in two small nodules, the carotid bodies, attached to the division of the carotid arteries on either side of the neck. As the oxygen deprivation persists, the carotid bodies enlarge but become less sensitive to the lack of oxygen. The low oxygen partial pressure in the lung is associated with thickening of the small blood vessels in pulmonary alveolar walls and a slight increase in pulmonary blood pressure, thought to enhance oxygen perfusion of the lung apices. Indigenous mountain animals like the llama, alpaca, and vicua in the Andes or the yak in the Himalayas are adapted rather than acclimatized to the low oxygen partial pressures of high altitude. Their hemoglobin has a high oxygen affinity, so that full saturation of the blood with oxygen occurs at a lower partial pressure of oxygen. In contrast to acclimatized humans, these indigenous, adapted mountain species do not have increased levels of hemoglobin or of organic phosphates in the red cells; they do not develop small muscular blood vessels or an increased blood pressure in the lung; and their carotid bodies remain small. Native human highlanders are acclimatized rather than genetically adapted to the reduced oxygen pressure. After living many years at high altitude, some highlanders lose this acclimatization and develop chronic mountain sickness, sometimes called Monge's disease, after the Peruvian physician who first described it. This disease is characterized by greater levels of hemoglobin. In Tibet some infants of Han origin never achieve satisfactory acclimatization on ascent to high altitude. A chemodectoma, or benign tumour, of the carotid bodies may develop in native highlanders in response to chronic exposure to low levels of oxygen. Donald Albert Heath Swimming and diving Fluid is not a natural medium for sustaining human life after the fetal stage; human respiration requires ventilation with air. Nevertheless, all vertebrates, including humans, exhibit a set of responses that may be called a diving reflex, which involves cardiovascular and metabolic adaptations to conserve oxygen during diving into water. Other physiological changes are also observed, either artificially induced (as by hyperventilation) or resulting from pressure changes in the environment at the same time that a diver is breathing from an independent gas supply. Hyperventilation, a form of overbreathing that increases the amount of air entering the pulmonary alveoli, may be used intentionally by swimmers to prolong the time they are able to hold their breath under water. Hyperventilation can be dangerous, and this danger is greatly increased if the swimmer descends to depth, as sometimes happens in snorkeling. The increased ventilation prolongs the duration of the breath-hold by reducing the carbon dioxide pressure in the blood, but it cannot provide an equivalent increase in oxygen. Thus the carbon dioxide that accumulates with exercise takes longer to reach the threshold at which the swimmer is forced to take another breath, but concurrently the oxygen content of the blood falls to unusually low levels. The increased environmental pressure of the water around the breath-holding diver increases the partial pressures of the pulmonary gases. This allows an adequate oxygen partial pressure to be maintained in the setting of reduced oxygen content, and consciousness remains unimpaired. When the accumulated carbon dioxide at last forces the swimmer to return to the surface, however, the progressively diminishing pressure of the water on his ascent reduces the partial pressure of the remaining oxygen. Unconsciousness may then occur in or under the water. Divers who breathe from an apparatus that delivers gas at the same pressure as that of the surrounding water need not return to the surface to breathe and can remain at depth for prolonged periods. But this apparent advantage introduces additional hazards, many of them unique in human physiology. Most of the hazards result from the environmental pressure of water. Two factors are involved. At the depth of a diver, the absolute pressure, which is approximately one additional atmosphere for each 10-metre increment of depth, is one factor. The other factor, acting at any depth, is the vertical hydrostatic pressure gradient across the body. The effects of pressure are seen in many processes at the molecular and cellular level and include the physiological effects of the increased partial pressures of the respiratory gases, the increased density of the respiratory gases, the effect of changes of pressure upon the volumes of the gas-containing spaces in the body, and the consequences of the uptake of respiratory gases into, and their subsequent elimination from, the blood and tissues of the diver, often with the formation of bubbles. The multiple effects of submersion upon respiration are not easily separated from one another or clearly distinguishable from related effects of pressure upon other bodily systems. The increased work of breathing, rather than cardiac or muscular performance, is the limiting factor for hard physical work underwater. Although the increased work of breathing may be largely due to the effects of increased respiratory gas density upon pulmonary function, the use of underwater breathing apparatus adds significant external breathing resistance to the diver's respiratory burden. Arterial carbon dioxide pressure should remain unchanged during changes of ambient pressure, but the impaired alveolar ventilation at depth leads to some carbon dioxide retention (hypercapnia). This may be compounded by an increased inspiratory content of carbon dioxide, especially if the diver uses closed-circuit and semiclosed-circuit rebreathing equipment or wears an inadequately ventilated helmet. Alveolar oxygen levels can also be disturbed in diving. Hypoxia may result from failure of the gas supply and may occur without warning. More commonly, the levels of inspired oxygen are increased. Oxygen in excess can be a poison; at a partial pressure greater than 1.5 bar (surface equivalent value = 150 percent), it may cause the rapid onset of convulsions, and after prolonged exposures at somewhat lower partial pressures it may cause pulmonary oxygen toxicity with reduced vital capacity and later pulmonary edema. In mixed-gas diving, inspired oxygen is therefore maintained at a partial pressure somewhere between 0.2 and 0.5 bar, but at great depths the inhomogeneity of alveolar ventilation and the limitations of gas diffusion appear to require oxygen provision at greater than normal levels. The maximum breathing capacity and the maximum voluntary ventilation of a diver breathing compressed air diminish rapidly with depth, approximately in proportion to the reciprocal of the square root of the increasing gas density. Thus the practice of using an inert gas such as helium as the oxygen diluent at depths where nitrogen becomes narcotic, like an anesthetic, has the additional advantage of providing a breathing gas of lesser density. The use of hydrogen, which in a mixture with less than 4 percent oxygen is noncombustible, provides a greater respiratory advantage for deep diving. At the extreme depths now attainable by humanssome 500 metres in the sea and more than 680 metres in the laboratorydirect effects of pressure upon the respiratory centre may be part of the high-pressure neurological syndrome and may account for some of the anomalies of breathlessness (dyspnea) and respiratory control that occur with exercise at depth. The term carbon dioxide retainer is commonly applied to a diver who fails to eliminate carbon dioxide in the normal manner. An ability to tolerate carbon dioxide may increase the work capacity of a diver at depth but also may predispose him to other consequences that are less desirable. High values of end-tidal carbon dioxide with only moderate exertion may be associated with a diminished tolerance to oxygen neurotoxicity, a condition that, if it occurs underwater, places the diver at great risk. Nitrogen narcosis is enhanced by the presence of excess carbon dioxide, and the physical properties of carbon dioxide facilitate the nucleation and growth of bubbles on decompression. Independent of the depth of the dive are the effects of the local hydrostatic pressure gradient upon respiration. The supporting effect of the surrounding water pressure upon the soft tissues promotes venous return from vessels no longer solely influenced by gravity; and, whatever the orientation of the diver in the water, this approximates the effects of recumbency upon the cardiovascular and respiratory systems. Also, the uniform distribution of gas pressure within the thorax contrasts with the hydrostatic pressure gradient that exists outside the chest. Intrathoracic pressure may be effectively lower than the pressure of the surrounding water, in which case more blood will be shifted into the thorax, or it may be effectively greater, resulting in less intrathoracic blood volume. The concept of a hydrostatic balance point within the chest, which represents the net effect of the external pressures and the effects of chest buoyancy, has proved useful in designing underwater breathing apparatuses. Intrapulmonary gas expands exponentially during the steady return of a diver toward the surface. Unless vented, the expanding gas may rupture alveolar septa and escape into interstitial spaces. The extra-alveolar gas may cause a burst lung (pneumothorax) or the tracking of gas into the tissues of the chest (mediastinal emphysema), possibly extending into the pericardium or into the neck. More seriously, the escaped alveolar gas may be carried by the blood circulation to the brain (arterial gas embolism). This is a major cause of death among divers. Failure to exhale during ascent causes such accidents and is likely to occur if the diver makes a rapid emergency ascent, even from depths as shallow as two metres. Other possible causes of pulmonary barotrauma include retention of gas by a diseased portion of lung and gas trapping due to dynamic airway collapse during forced expiration at low lung volumes. Decompression sickness may be defined as the illness, following a reduction of pressure, that is caused by the formation of bubbles from gases that were dissolved in the tissues while the diver was at an increased environmental pressure. The causes are related to the inadequacy of the diver's decompression, perhaps failure to follow a correct decompression protocol, or occasionally a diver's idiosyncratic response to an apparently safe decompression procedure. The pathogenesis begins both with the mechanical effects of bubbles and their expansion in the tissues and blood vessels and with the surface effects of the bubbles upon the various components of the blood at the bloodgas interface. The lung plays a significant role in the pathogenesis and natural history of this illness and may contribute to the clinical picture. Shallow, rapid respiration, often associated with a sharp retrosternal pain on deep inspiration, signals the onset of pulmonary decompression sickness, the chokes. Whether occurring alone or as part of a more complex case of decompression sickness, this respiratory pattern constitutes an acute emergency. It usually responds rapidly to treatment by recompression in a compression chamber. David H. Elliott Additional reading The design of the human respiratory system is covered by Peter H. Burri, Joan Gil, and Ewald R. Weibel, Ultrastructure and Morphometry of the Human Lung, in Thomas W. Shields (ed.), General Thoracic Surgery, 2nd ed. (1983), pp. 1842; and two essays in Handbook of Physiology, sect. 3, The Respiratory System, vol. 1, Circulation and Nonrespiratory Functions, ed. by Alfred P. Fishman and Aron B. Fisher (1985); Peter H. Burri, Development and Growth of the Human Lung, pp. 146; and Ewald R. Weibel, Lung Cell Biology, pp. 4791. Peter H. BurriControl of breathing is described in Handbook of Physiology, sect. 3, The Respiratory System, vol. 2, Control of Breathing , 2 vol., ed. by Neil S. Cherniack and John G. Widdicombe (1986); Jack L. Feldman, Neurophysiology of Breathing in Mammals, in Handbook of Physiology, sect. 1, The Nervous System, vol. 4, Intrinsic Regulatory Systems of the Brain, ed. by Floyd E. Bloom (1986), pp. 463524, an overview of the control of breathing; and the following journal articles: Eugene N. Bruce and Neil S. Cherniack, Central Chemoreceptors, Journal of Applied Physiology, 62(2):389402 (Feb. 1987), a short review of advances in understanding the physiological mechanisms that account for the effect of carbon dioxide on breathing; Neil S. Cherniack and Murray D. Altose, Mechanisms of Dyspnea, Clinics in Chest Medicine, 8(2):207214 (June 1987), a brief description of the physiological basis of shortness of breath; Hugo Lagercrantz and Theodore A. Slotkin, The Stress' of Being Born, Scientific American, 254(4):100107 (April 1986), an article on breathing in the infant; Michael E. Long, What Is This Thing Called Sleep?, National Geographic, 172(6):787821 (Dec. 1987), an update on sleep physiology and apnea and on the kinds of research being conducted; and Kingman P. Strohl, Neil S. Cherniack, and Barbara Gothe, Physiologic Basis of Therapy for Sleep Apnea, American Review of Respiratory Disease, 134(6):791802 (June 1986), on abnormal breathing during sleep and how it can be treated. Neil S. CherniackAdaptations of the human respiratory system to high altitude are described in a comprehensive but readable manner in Donald Heath and David Reid Williams, High-Altitude Medicine and Pathology (1989). Donald Albert HeathThe effects of swimming and diving on respiration are detailed in Peter B. Bennett and David H. Elliott (eds.), The Physiology and Medicine of Diving, 3rd ed. (1982); and N.R. Anthonisen, Respiration, in Charles W. Shilling, Catherine B. Carlston, and Rosemary A. Mathias (eds.), The Physician's Guide to Diving Medicine (1984), pp. 7185, part of a chapter on the physiology of diving. David H. Elliott Control of breathing Breathing is an automatic and rhythmic act produced by networks of neurons in the hindbrain (the pons and medulla). The neural networks direct muscles that form the walls of the thorax and abdomen and produce pressure gradients that move air into and out of the lungs. The respiratory rhythm and the length of each phase of respiration are set by reciprocal stimulatory and inhibitory interconnection of these brain-stem neurons. An important characteristic of the human respiratory system is its ability to adjust breathing patterns to changes in both the internal milieu and the external environment. Ventilation increases and decreases in proportion to swings in carbon dioxide production and oxygen consumption caused by changes in metabolic rate. The respiratory system is also able to compensate for disturbances that affect the mechanics of breathing, such as the airway narrowing that occurs in an asthmatic attack. Breathing also undergoes appropriate adjustments when the mechanical advantage of the respiratory muscles is altered by postural changes or by movement. This flexibility in breathing patterns in large part arises from sensors distributed throughout the body that send signals to the respiratory neuronal networks in the brain. Chemoreceptors detect changes in blood oxygen levels and change the acidity of the blood and brain. Mechanoreceptors monitor the expansion of the lung, the size of the airway, the force of respiratory muscle contraction, and the extent of muscle shortening. Although the diaphragm is the major muscle of breathing, its respiratory action is assisted and augmented by a complex assembly of other muscle groups. Intercostal muscles inserting on the ribs, the abdominal muscles, and muscles such as the scalene and sternocleidomastoid that attach both to the ribs and to the cervical spine at the base of the skull also play an important role in the exchange of air between the atmosphere and the lungs. In addition, laryngeal muscles and muscles in the oral and nasal pharynx adjust the resistance of movement of gases through the upper airways during both inspiration and expiration. Although the use of these different muscle groups adds considerably to the flexibility of the breathing act, they also complicate the regulation of breathing. These same muscles are used to perform a number of other functions, such as speaking, chewing and swallowing, and maintaining posture. Perhaps because the respiratory muscles are employed in performing nonrespiratory functions, breathing can be influenced by higher brain centres and even controlled voluntarily to a substantial degree. An outstanding example of voluntary control is the ability to suspend breathing by holding one's breath. Input into the respiratory control system from higher brain centres may help optimize breathing so that not only are metabolic demands satisfied by breathing but ventilation also is accomplished with minimal use of energy. Central organization of respiratory neurons The respiratory rhythm is generated within the pons and medulla. Three main aggregations of neurons are involved: a group consisting mainly of inspiratory neurons in the dorsomedial medulla, a group made up of inspiratory and expiratory neurons in the ventrolateral medulla, and a group in the rostral pons consisting mostly of neurons that discharge in both inspiration and expiration. It is currently thought that the respiratory cycle of inspiration and expiration is generated by synaptic interactions within these groups of neurons. The inspiratory and expiratory medullary neurons are connected to projections from higher brain centres and from chemoreceptors and mechanoreceptors; in turn they drive cranial motor neurons, which govern the activity of muscles in the upper airways and the activity of spinal motor neurons, which supply the diaphragm and other thoracic and abdominal muscles. The inspiratory and expiratory medullary neurons also receive input from nerve cells responsible for cardiovascular and temperature regulation, allowing the activity of these physiological systems to be coordinated with respiration. Neurally, inspiration is characterized by an augmenting discharge of medullary neurons that terminates abruptly. After a gap of a few milliseconds, inspiratory activity is restarted, but at a much lower level, and gradually declines until the onset of expiratory neuron activity. Then the cycle begins again. The full development of this pattern depends on the interaction of several types of respiratory neurons: inspiratory, early inspiratory, off-switch, post-inspiratory, and expiratory. Early inspiratory neurons trigger the augmenting discharge of inspiratory neurons. This increase in activity, which produces lung expansion, is caused by self-excitation of the inspiratory neurons and perhaps by the activity of an as yet undiscovered upstream pattern generator. Off-switch neurons in the medulla terminate inspiration, but pontine neurons and input from stretch receptors in the lung help control the length of inspiration. When the vagus nerves are sectioned or pontine centres are destroyed, breathing is characterized by prolonged inspiratory activity that may last for several minutes. This type of breathing, which occasionally occurs in persons with diseases of the brain stem, is called apneustic breathing. Post-inspiratory neurons are responsible for the declining discharge of the inspiratory muscles that occurs at the beginning of expiration. Mechanically, this discharge aids in slowing expiratory flow rates and probably assists the efficiency of gas exchange. It is believed by some that these post-inspiratory neurons have inhibitory effects on both inspiratory and expiratory neurons and therefore play a significant role in determining the length of the respiratory cycle and the different phases of respiration. As the activity of the post-inspiratory neurons subsides, expiratory neurons discharge and inspiratory neurons are strongly inhibited. There may be no peripheral manifestation of expiratory neuron discharge except for the absence of inspiratory muscle activity, although in upright humans the lower expiratory intercostal muscles and the abdominal muscles may be active even during quiet breathing. Moreover, as the demand to breathe increases (for example, with exercise), more expiratory intercostal and abdominal muscles contract. As expiration proceeds, the inhibition of the inspiratory muscles gradually diminishes and inspiratory neurons resume their activity. Gas exchange Respiratory gasesoxygen and carbon dioxidemove between the air and the blood across the respiratory exchange surfaces in the lungs. The structure of the human lung provides an immense internal surface that facilitates gas exchange between the alveoli and the blood in the pulmonary capillaries. The area of the alveolar surface in the adult human is about 100 square metres. Gas exchange across the membranous barrier between the alveoli and capillaries is enhanced by the thin nature of the membrane, about 0.5 micrometre, or 1/100 of the diameter of a human hair. Respiratory gases move between the environment and the respiring tissues by two principal mechanisms, convection and diffusion. Convection, or mass flow, is responsible for movement of air from the environment into the lungs and for movement of blood between the lungs and the tissues. Respiratory gases also move by diffusion across tissue barriers such as membranes. Diffusion is the primary mode of transport of gases between air and blood in the lungs and between blood and respiring tissues in the body. The process of diffusion is driven by the difference in partial pressures of a gas between two locales. In a mixture of gases, the partial pressure of each gas is directly proportional to its concentration. The partial pressure of a gas in fluid is a measure of its tendency to leave the fluid when exposed to a gas or fluid that does not contain that gas. A gas will diffuse from an area of greater partial pressure to an area of lower partial pressure regardless of the distribution of the partial pressures of other gases. There are large changes in the partial pressures of oxygen and carbon dioxide as these gases move between air and the respiring tissues. The partial pressure of carbon dioxide in this pathway is lower than the partial pressure of oxygen, due to differing modes of transport in the blood, but almost equal quantities of the two gases are involved in metabolism and gas exchange. Oxygen and carbon dioxide are transported between tissue cells and the lungs by the blood. The quantity transported is determined both by the rapidity with which the blood circulates and the concentrations of gases in blood. The rapidity of circulation is determined by the output of the heart, which in turn is responsive to overall body requirements. Local flows can be increased selectively, as occurs, for example, in the flow through skeletal muscles during exercise. The performance of the heart and circulatory regulation are, therefore, important determinants of gas transport. Oxygen and carbon dioxide are too poorly soluble in blood to be adequately transported in solution. Specialized systems for each gas have evolved to increase the quantities of those gases that can be transported in blood. These systems are present mainly in the red cells, which make up 40 to 50 percent of the blood volume in most mammals. Plasma, the cell-free, liquid portion of blood, plays little role in oxygen exchange but is essential to carbon dioxide exchange. Transport of oxygen Oxygen is poorly soluble in plasma, so that less than 2 percent of oxygen is transported dissolved in plasma. The vast majority of oxygen is bound to hemoglobin, a protein contained within red cells. Hemoglobin is composed of four iron-containing ring structures (hemes) chemically bonded to a large protein (globin). Each iron atom can bind and then release an oxygen molecule. Enough hemoglobin is present in normal human blood to permit transport of about 0.2 millilitre of oxygen per millilitre of blood. The quantity of oxygen bound to hemoglobin is dependent on the partial pressure of oxygen in the lung to which blood is exposed. The curve representing the content of oxygen in blood at various partial pressures of oxygen, called the oxygen-dissociation curve, is a characteristic S-shape because binding of oxygen to one iron atom influences the ability of oxygen to bind to other iron sites. In alveoli at sea level, the partial pressure of oxygen is sufficient to bind oxygen to essentially all available iron sites on the hemoglobin molecule. Not all of the oxygen transported in the blood is transferred to the tissue cells. The amount of oxygen extracted by the cells depends on their rate of energy expenditure. At rest, venous blood returning to the lungs still contains 70 to 75 percent of the oxygen that was present in arterial blood; this reserve is available to meet increased oxygen demands. During extreme exercise the quantity of oxygen remaining in venous blood decreases to 10 to 25 percent. At the steepest part of the oxygen-dissociation curve (the portion between 10 and 40 millimetres of mercury partial pressure), a relatively small decline in the partial pressure of oxygen in the blood is associated with a relatively large release of bound oxygen. Hemoglobin binds not only to oxygen but to other substances such as hydrogen ions (which determine the acidity, or pH, of the blood), carbon dioxide, and 2,3-diphosphoglycerate (2,3-DPG; a salt in the red blood cells that plays a role in liberating oxygen from hemoglobin in the peripheral circulation). These substances do not bind to hemoglobin at the oxygen-binding sites; however, with the binding of oxygen, changes in the structure of the hemoglobin molecule occur that affect its ability to bind other gases or substances. Conversely, binding of these substances to hemoglobin affects the affinity of hemoglobin for oxygen. (Affinity denotes the tendency of molecules of different species to bind to one another.) Increases in hydrogen ions, carbon dioxide, or 2,3-DPG decrease the affinity of hemoglobin for oxygen, and the oxygen-dissociation curve shifts to the right. Because of this decreased affinity, an increased partial pressure of oxygen is required to bind a given amount of oxygen to hemoglobin. A rightward shift of the curve is thought to be of benefit in releasing oxygen to the tissues when needs are great in relation to oxygen delivery, as occurs with anemia or extreme exercise. Reductions in normal concentrations of hydrogen ions, carbon dioxide, and 2,3-DPG result in an increased affinity of hemoglobin for oxygen, and the curve is shifted to the left. This displacement increases oxygen binding to hemoglobin at any given partial pressure of oxygen and is thought to be beneficial if the availability of oxygen is reduced, as occurs at extreme altitude. Temperature changes affect the oxygen-dissociation curve similarly. An increase in temperature shifts the curve to the right (decreased affinity; enhanced release of oxygen); a decrease in temperature shifts the curve to the left (increased affinity). The range of body temperature usually encountered in humans is relatively narrow, so that temperature-associated changes in oxygen affinity have little physiological importance. Interplay of respiration, circulation, and metabolism The interplay of respiration, circulation, and metabolism is the key to the functioning of the respiratory system as a whole. Cells set the demand for oxygen uptake and carbon dioxide discharge, that is, for gas exchange in the lungs. The circulation of the blood links the sites of oxygen utilization and uptake. The proper functioning of the respiratory system depends on both the ability of the system to make functional adjustments to varying needs and the design features of the sequence of structures involved, which set the limit for respiration. The main purpose of respiration is to provide oxygen to the cells at a rate adequate to satisfy their metabolic needs. This involves transport of oxygen from the lung to the tissues by means of the circulation of blood. In antiquity and the medieval period, the heart was regarded as a furnace where the fire of life kept the blood boiling. Modern cell biology has unveiled the truth behind the metaphor. Each cell maintains a set of furnaces, the mitochondria, where, through the oxidation of foodstuffs such as glucose, the energetic needs of the cells are supplied. The precise object of respiration therefore is the supply of oxygen to the mitochondria. Cell metabolism depends on energy derived from high-energy phosphates such as adenosine triphosphate (ATP), whose third phosphate bond can release a quantum of energy to fuel many cell processes, such as the contraction of muscle fibre proteins or the synthesis of protein molecules. In the process, ATP is degraded to adenosine diphosphate (ADP), a molecule with only two phosphate bonds. To recharge the molecule by adding the third phosphate group requires energy derived from the breakdown of foodstuffs, or substrates. Two pathways are available: (1) anaerobic glycolysis, or fermentation, which operates in the absence of oxygen; and (2) aerobic metabolism, which requires oxygen and involves the mitochondria. The anaerobic pathway leads to acid waste products and is wasteful of resources: The breakdown of one molecule of glucose generates only two molecules of ATP. In contrast, aerobic metabolism has a higher yield (36 molecules of ATP per molecule of glucose) and results in clean wasteswater and carbon dioxide, which are easily eliminated from the body and are recycled by plants in the process of photosynthesis. For any sustained high-level cell activity, the aerobic metabolic pathway is therefore preferable. Since oxidative phosphorylation occurs only in mitochondria, and since each cell must produce its own ATP (it cannot be imported), the number of mitochondria in a cell reflects its capacity for aerobic metabolism, or its need for oxygen. The supply of oxygen to the mitochondria at an adequate rate is a critical function of the respiratory system, because the cells maintain only a limited store of high-energy phosphates and of oxygen, whereas they usually have a reasonable supply of substrates in stock. If oxygen supply is interrupted for a few minutes, many cells, or even the organism, will die. Oxygen is collected from environmental air, transferred to blood in the lungs, and transported by blood flow to the periphery of the cells where it is discharged to reach the mitochondria by diffusion. The transfer of oxygen to the mitochondria involves several structures and different modes of transports. It begins with ventilation of the lung, which is achieved by convection or mass flow of air through an ingeniously branched system of airways; in the most peripheral airways ventilation of alveoli is completed by diffusion of oxygen through the air to the alveolar surface. The transfer of oxygen from alveolar air into the capillary blood occurs by diffusion across the tissue barrier; it is driven by the oxygen partial pressure difference between alveolar air and capillary blood and depends on the thickness (about 0.5 micrometre) and the surface area of the barrier (about 130 square metres in humans). Convective transport by the blood depends on the blood flow rate (cardiac output) and on the oxygen capacity of the blood, which is determined by its content of hemoglobin in the red blood cells. The last step is the diffusive discharge of oxygen from the capillaries into the tissue and cells, which is driven by the oxygen partial pressure difference and depends on the quantity of capillary blood in the tissue. In this process the blood plays a central role and affects all transport steps: oxygen uptake in the lung, transport by blood flow, and discharge to the cells. Blood also serves as carrier for both respiratory gases: oxygen, which is bound to hemoglobin in the red blood cells, and carbon dioxide, which is carried by both plasma and red blood cells and which also serves as a buffer for acid-base balance in blood and tissues. Metabolism, or, more accurately the metabolic rate of the cells, sets the demand for oxygen. At rest, a human consumes about 250 millilitres of oxygen each minute. With exercise this rate can be increased more than 10-fold in a normal healthy individual, but a highly trained athlete may achieve a more than 20-fold increase. As more and more muscle cells become engaged in doing work, the demand for ATP and oxygen increases linearly with work rate. This is accompanied by an increased cardiac output, essentially due to a higher heart rate, and by increased ventilation of the lungs; as a consequence, the oxygen partial pressure difference across the airblood barrier increases and oxygen transfer by diffusion is augmented. These dynamic adjustments to the muscles' needs occur up to a limit that is twice as high in the athlete as in the untrained individual. This range of possible oxidative metabolism from rest to maximal exercise is called the aerobic scope. The upper limit to oxygen consumption is not conferred by the ability of muscles to do work, but rather by the limited ability of the respiratory system to provide or utilize oxygen at a higher rate. Muscle can do more work, but beyond the aerobic scope they must revert to anaerobic metabolism, with the result that waste products, mainly lactic acid, accumulate and limit the duration of work. The limit to oxidative metabolism is therefore set by some features of the respiratory system, from the lung to the mitochondria. Knowing precisely what sets the limit is important for understanding respiration as a key vital process, but it is not straightforward, because of the complexity of the system. Much has been learned from comparative physiology and morphology, based on observations that oxygen consumption rates differ significantly among species. For example, the athletic species in nature, such as dogs or horses, have an aerobic scope more than twofold greater than that of other animals of the same size; this is called adaptive variation. Then, oxygen consumption per unit body mass increases as animals become smaller, so that a mouse consumes six times as much oxygen per gram of body mass as a cow, a feature called allometric variation. Furthermore, the aerobic scope can be increased by training in an individual, but this induced variation achieves at best a 50 percent difference between the untrained and the trained state, well below interspecies differences. Within the aerobic scope the adjustments are due to functional variation. For example, cardiac output is augmented by increasing heart rate. Mounting evidence indicates that the limit to oxidative metabolism is related to structural design features of the system. The total amount of mitochondria in skeletal muscle is strictly proportional to maximal oxygen consumption, in all types of variation. In training, the mitochondria increase in proportion to the augmented aerobic scope. Mitochondria set the demand for oxygen, and they seem able to consume up to five millilitres of oxygen per minute and gram of mitochondria. If energy (ATP) needs to be produced at a higher rate, the muscle cells make more mitochondria. It is thus possible that oxygen consumption is limited at the periphery, at the last step of aerobic metabolism. But it is also possible that more central parts of the respiratory system may set the limit to oxygen transport, mainly the heart, whose capacity to pump blood reaches a limit, both in terms of rate and of the size of the ventricles, which determines the volume of blood that can be pumped with each stroke. The issue of peripheral versus central limitation is still under debate. It appears, however, that the lung as a gas-exchanging organ has sufficient redundancy that it does not limit aerobic metabolism at the site of oxygen uptake. But, whereas the mitochondria, the blood, the blood vessels, and the heart can increase in number, rate, or volume to augment their capacity when energy needs increase, such as in training, the lung lacks this capacity to adapt. If this proves true, the lung may well constitute the ultimate limit for the respiratory system, beyond which oxidative metabolism cannot be increased by training. Ewald R. Weibel The mechanics of breathing Air moves in and out of the lungs in response to differences in pressure. When the air pressure within the alveolar spaces falls below atmospheric pressure, air enters the lungs (inspiration), provided the larynx is open; when the air pressure within the alveoli exceeds atmospheric pressure, air is blown from the lungs (expiration). The flow of air is rapid or slow in proportion to the magnitude of the pressure difference. Because atmospheric pressure remains relatively constant, flow is determined by how much above or below atmospheric pressure the pressure within the lungs rises or falls. Alveolar pressure fluctuations are caused by expansion and contraction of the lungs resulting from tensing and relaxing of the muscles of the chest and abdomen. Each small increment of expansion transiently increases the space enclosing lung air. There is, therefore, less air per unit of volume in the lungs and pressure falls. A difference in air pressure between atmosphere and lungs is created, and air flows in until equilibrium with atmospheric pressure is restored at a higher lung volume. When the muscles of inspiration relax, the volume of chest and lungs decreases, lung air becomes transiently compressed, its pressure rises above atmospheric pressure, and flow into the atmosphere results until pressure equilibrium is reached at the original lung volume. This, then, is the sequence of events during each normal respiratory cycle: lung volume change leading to pressure difference, resulting in flow of air into or out of the lung and establishment of a new lung volume. The lungchest system The forces that normally cause changes in volume of the chest and lungs stem not only from muscle contraction but from the elastic properties of both the lung and the chest. A lung is similar to a balloon in that it resists stretch, tending to collapse almost totally unless held inflated by a pressure difference between its inside and outside. This tendency of the lung to collapse or pull away from the chest is measurable