Department of Physiology: Respiratory System Physiology-Offline information

Water layer of epithelial cells (figure): Air is filtered both in the trachea and in the bronchi. These airways are lined with ciliated epithelium whose cilia are bathed in a watery saline layer. The saline is produced by epithelial cells when Cl^-secreted into the lumen by apical anion channels draws Na⁺ into the lumen through the paracellular pathway. Movement of solute from the ECF to the lumen creates an osmotic gradient, and water follows the ions into the airways. The CFTR channel, whose malfunction causes cystic fbrosis, is one of the anion channels found on the apical surface of this epithelium.

Partial Pressure: It is essential to recognize that the oxygen bound to hemoglobin does not contribute directly to the PO2 of the blood; only dissolved oxygen does so. Therefore, oxygen diffusion is governed only by the dissolved portion. However, the presence of hemoglobin plays a critical role in determining the total amount of oxygen that will diffuse, as illustrated by a simple example (Figure). Two solutions separated by a semipermeable membrane contain equal quantities of oxygen. The gas pressures in both solutions are equal, and no net diffusion of oxygen occurs. Addition of hemoglobin to compartment B disturbs this equilibrium because much of the oxygen combines with hemoglobin. Despite the fact that the total quantity of oxygen in compartment B is still the same, the number of dissolved oxygen molecules has decreased. Therefore, the PO2 of compartment B is less than that of A, and so there is a net diffusion of oxygen from A to B. At the new equilibrium, the oxygen pressures are once again equal, but almost all the oxygen is in compartment B and has combined with hemoglobin.

Protective Reflexes A group of responses protect the respiratory system from irritant materials. Most familiar are the cough and the sneeze reflexes. Alcohol inhibits the cough reflex, which may partially explain the susceptibility of alcoholics to choking and pneumonia. Another example of a protective reflex is the immediate cessation of respiration that is often triggered when noxious agents are inhaled. Chronic smoking may cause a loss of this reflex.

Summary of factors that stimulate ventilation during exercise

Regulation of respiration (figure): Chemical controls and other factors adjust respiration to keep pace with need. + indicates increased respiration; - indicates decreased respiration; ± means that response may vary with circumstances. For simplicity, the specifc areas of the respiratory centers are not differentiated in this diagram. Many factors have excitatory and inhibitory effects on respiratory neurons that then increase or decrease ventilation accordingly (see figure).
Barbiturates, benzodiazepines, and opioids are all known to cause respiratory depression. Barbiturates and benzodiazepines act by facilitating the effects of gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the central nervous system (CNS), at the α subunit of the GABAA receptor. Opioids act at μ receptors throughout the body, the effects of which can be both excitatory and inhibitory. These drugs depress the response of the medullary respiratory center to hypercapnia (↑ CO2), leading to respiratory depression.

Role of Sensory Receptors in Exercise: As exercise begins, active skeletal muscles consume larger amounts of oxygen and produce larger amounts of carbon dioxide, but arterial concentrations of these gases change very little (at least during mild to moderate exercise). The reason is that feedforward control circuits increase ventilation before the gas concentrations in arterial blood can change. One of these feedforward circuits is the central command associated with the intention to perform exercise; another feedforward signal originates in mechanoreceptors and chemoreceptors in exercising skeletal muscles. Both of these feedforward signals stimulate ventilation. At rest, changes in arterial oxygen and carbon dioxide concentrations regulate ventilation through negative feedback control. During exercise, however, these feedback mechanisms function primarily to prevent hyperventilation that might occur in response to the feedforward signals that increased ventilation during exercise. The increase in ventilation during exercise, which is called exercise hyperpnea, is illustrated in the graph. At the onset of exercise, minute ventilation increases rapidly due to neural signals from the central command and due to feedback from mechanoreceptors and chemoreceptors in the muscle—a phenomenon referred to as the neurogenic response. As exercise progresses, minute ventilation tends to continue increasing, albeit at a much slower rate. Blood-borne signals trigger this more gradual increase, referred to as the humoral response. When exercise terminates, the reverse occurs: Ventilation initially decreases rapidly due to a decrease in neural signals from the central command and feedback from mechanoreceptors and chemoreceptors, but then continues to decrease more slowly until it returns to resting levels.

Pulmonary Surfactant and Laplace’s Law (figure): The thin film of water that lines the alveoli increases the muscular work required to inflate the lungs because the water’s surface tension decreases the lungs’ compliance, making them harder to stretch. This surface tension creates another problem as well: Hydrogen bonding between adjacent water molecules tends to pull them into a round droplet, which in turn tends to pull the walls of an alveolus inward and make it collapse. What, then, prevents all of the alveoli from collapsing into one large “air bubble”? To understand why the alveoli do not collapse, consider what happens in a soap bubble (see figure): The wall of a soap bubble contains water, which exerts surface tension and thus tends to pull the wall inward. As the bubble shrinks, however, it raises the pressure of the air contained within it, creating a distending pressure that opposes the tendency of the bubble to collapse. The bubble remains at a stable volume, neither collapsing nor expanding, as long as the distending pressure is just large enough to balance the inwardly directed forces created by the surface tension. When the lungs are not expanding or contracting, the volume of an alveolus remains stable for the same reason—the pressure of the air inside it balances the inward forces that would otherwise cause it to collapse. According to Laplace’s law, the air pressure (P ) necessary to prevent the collapse of an alveolus (which is assumed to be spherical) is directly proportional to the surface tension (T ) and inversely proportional to the alveolar radius (r ): P = 2T/r. Here, P is the air pressure gradient across the alveolar wall, given as inside relative to the pressure outside, with outside pressure at zero. Thus, if two alveoli—one larger and one smaller—are subject to the same surface tension, the smaller one will require a greater pressure inside to keep from collapsing. At the end of an inspiration or expiration, air pressure is the same inside all of the alveoli. (If air is not flowing, the pressure of the air must be the same everywhere.) The alveoli are not all the same size, however. This situation poses an interesting problem that is illustrated in the figure, which shows two adjacent alveoli of unequal sizes. Let us assume for the moment that no surfactant is present. If the air pressure is just high enough to prevent the large alveolus from collapsing, then according to Laplace’s law, it cannot be large enough to prevent the smaller alveolus from collapsing. Thus, if the two alveoli were at the same pressure initially, the smaller alveolus should collapse, which will raise the air pressure inside it (P1), making it higher than the pressure in the larger alveolus (P2). Air should then flow down the pressure gradient (from P1 to P2) and, therefore, from the smaller to the larger alveolus, as shown in the left part of the diagram. In real lungs, however, surfactant is present and is actually more highly concentrated in the smaller alveoli. As a consequence, the surface tension in a small alveolus is lower than that in a large alveolus, which reduces the amount of pressure that must exist inside the small alveolus to prevent it from collapsing. For this reason, small and large alveoli can both have stable volumes at the same pressure, as shown in the right part of the diagram.

Graphs (figure) illustrate the Forced Expiratory Volume at 1 second (FEV1) in obstructive and restrictive pulmonary diseases.

Flow-volume curve for expiration (figure).

Brainstem centers of respiratory control (figure).

Chemoreceptor reflexes (figure): The effects of changes in arterial PO₂, PCO₂, and pH on ventilation.

The effects of hypoventilation and hyperventilation on minute ventilation (figure).

Blood flow limits oxygen uptake (figure ). Gas transfer across the alveolar–capillary membrane is affected by pulmonary capillary blood flow. The horizontal axis shows time in the capillary. The average transit time it takes blood to pass through the pulmonary capillaries is 0.75 seconds. The vertical axis indicates gas tension in the pulmonary capillary blood, and the top of the vertical axis indicates gas tension in the alveoli. Individual curves indicate the time it takes for the partial pressure of a specific gas in the pulmonary capillaries to equal the partial pressure in the alveoli. The oxygen transfer is limited primarily by blood flow. Pulmonary capillary PO₂ equilibrates with the alveolar PO₂ in about 0.25 seconds (arrow). The eﬀective thickness of the respiratory membrane increases dramatically if the lungs become waterlogged and edematous, as in pneumonia or left heart failure. Under such conditions, even the 0.75 s that red blood cells spend in transit through the pulmonary capillaries may not be enough for adequate gas exchange, and body tissues suﬀer from oxygen deprivation.

Types and patterns of ventilation (figure)

Lung Volume effect on Pulmonary Vascular & airway Resistance: As lung volume rises (from left panel to right panel, figure), traction distends extra-alveolar vessels, reducing their resistance. In alveolar vessels, on the other hand, increase in lung volume raises resistance as they are compressed by the enlargement of alveoli. Starting from the collapsed state, as a lung is inflated, pulmonary vascular resistance first falls as a result of distension of extra-alveolar vessels, and then rises as the lung is inflated further and alveolar vessels are compressed.

In addition, Lung volume is an important determinant of airway resistance because the overall cross-sectional area of airways varies with lung volume, causing global changes in airway radius (Figure). At low lung volume, the cross-sectional area is reduced and airway resistance increases. For example, patients with pulmonary fibrosis have low lung compliance and low resting lung volume; high airway resistance contributes to their increased work of breathing.

Distribution of Pulmonary Blood Flow (figure):

Zone 1: Alveolar pressure exceeds arterial and venous pressure; as a result, there is no blood flow in this zone. Present only when alveolar pressure is raised or arterial pressure is reduced.

Zone 2: Arterial pressure exceeds alveolar pressure; alveolar pressure exceeds venous pressure. Blood flow is determined by the difference between arterial and alveolar pressures.

Zone 3: Arterial pressure exceeds venous pressure; venous pressure exceeds alveolar pressure. Flow through zone 3 is dependent on the a-v pressure gradient. The higher hydrostatic pressure in this region results in distention of vessels and, therefore, reduced resistance.

Sleep apnea: An obese man is discovered to have high blood pressure (hypertension) and is sleepy all of the time. His wife reports that he snores very loudly and often sounds like he stops breathing in his sleep. The doctor orders a sleep study, and the diagnosis of obstructive sleep apnea is made. Sleep apnea is characterized by periodic cessation of breathing during sleep. This results in the combination of hypoxemia and hypercapnia (termed asphyxia). In severe cases, this may occur more than 20 times an hour. During a sleep study, these frequent blood oxygen desaturations are documented. Sleep apnea has two general types. Central sleep apnea is primarily due to a decrease in neural output from the respiratory center in the medulla to the phrenic motor nerve to the diaphragm. Obstructive sleep apnea is caused by increased airway resistance because of narrowing or collapse of the upper airways (primarily the pharynx) during inspiration (Figure). Obstructive sleep apnea may occur in as much as 4% of the adult population with a greater frequency in elderly persons and in men. Significant snoring may be an early sign of the eventual development of obstructive sleep apnea. Obesity is clearly a contributing factor because the excess fat in the neck decreases the diameter of the upper airways. A decrease in the activity of the upper airway dilating muscles, particularly during REM sleep, also contributes to airway collapse. Finally, anatomical narrowing and increased compliance of the upper airways contributes to periodic inspiratory obstruction during sleep. Untreated sleep apnea can have many serious consequences, including hypertension of the pulmonary arteries (pulmonary hypertension) and added strain on the right ventricle of the heart. This can lead to heart failure and abnormal heart rhythm, either of which can be fatal. The periodic arousal that occurs during these apneic episodes results in serious disruption of normal sleep patterns and can lead to sleepiness during the day (daytime somnolence). Increased catecholamine release during these frequent arousals can also contribute to the development of high blood pressure. A variety of treatments exist for obstructive sleep apnea. Surgery such as laser-assisted widening of the soft palate and uvula can sometimes be of benefit. Weight loss is often quite helpful. However, the mainstay of therapy is continuous positive airway pressure (CPAP) (Figure). The patient wears a small mask over the nose during sleep, which is attached to a positive-pressuregenerating device. By increasing airway pressure greater than Patm, the collapse of the upper airways during inspiration is prevented. Although the CPAP nasal mask may seem obtrusive, many patients sleep much better with it, and many of the symptoms resolve with this treatment. Our patient was treated with CPAP during the night and also was able to lose a considerable amount of body weight. As a result, his daytime somnolence and hypertension improved over the next year.

Eﬀect of Spinal cord injury on Ventilation: The diaphragm is supplied by the phrenic nerves, which arise from spinal nerves C3– C5, descend along each side of the neck to enter the thorax, and pass to the diaphragm. The intercostal muscles are supplied by the intercostal nerves, which arise from spinal nerves T1–T11 and extend along the spaces between the ribs. Spinal cord injury superior to the origin of the phrenic nerves causes paralysis of the diaphragm and intercostal muscles and results in death unless artificial respiration is provided. A spinal cord injury inferior to the origin of the phrenic nerves causes paralysis of the intercostal muscles. Even though the diaphragm can function maximally, ventilation is drastically reduced because the intercostal muscles no longer prevent the thoracic wall from collapsing inward. Vital capacity is reduced to about 300 mL. If the spinal cord is injured inferior to the origin of the intercostal nerves, both the diaphragm and the intercostal muscles function normally. The importance of the abdominal muscles in breathing can be observed in a person with a spinal cord injury that causes flaccid paralysis of the abdominal muscles. In the upright position, the abdominal organs and diaphragm are not pushed superiorly, and passive recoil of the thorax and lungs is inadequate for normal expiration. An elastic binder around the abdomen can help such patients. When a person is lying down, the weight of the abdominal organs can assist in expiration.

Infant respiratory distress syndrome: Infants, especially those with a gestation age of less than 7 months. This condition occurs because surfactant (see figure) is not produced in is common in premature adequate quantities until approximately 7 months of development. Thereafter, the amount produced increases as the fetus matures. Pregnant women who are likely to deliver prematurely can be given cortisol, which crosses the placenta into the fetus and stimulates surfactant synthesis. If a newborn produces insufficient surfactant, the lungs tend to collapse. Thus, the muscles of respiration must exert a great deal of energy to keep the lungs inflated, and even then ventilation is inadequate. Without specialized treatment, most babies with this disease die soon after birth as a result of inadequate ventilation of the lungs and fatigued respiratory muscles. Infants with infant respiratory distress syndrome are treated with pressurized air, which delivers oxygen-rich air to the lungs. The pressure helps keep the alveoli inflated. In addition, surfactant administered with the pressurized air can reduce surface tension in the alveoli. Surfactant can be obtained from cow, pig, and human lungs; from human amniotic fluid; or from genetically modified bacteria. Synthetic surfactant is also available.

Photic sneeze reflex: About 17–25% of people have a photic sneeze reflex, which is stimulated by exposure to bright light, such as the sun. The sneeze reflex may be connected to the pupillary reflex, which causes the pupils to constrict in response to bright light. Researchers speculate that the complicated “wiring” of the pupillary and sneeze reflexes are intermixed in some people, so that, when bright light activates a pupillary reflex, it also activates a sneeze reflex. Sometimes the photic sneeze reflex is fancifully called ACHOO, which stands for autosomal dominant compelling helio-ophthalmic outburst. As the name suggests, the reflex is inherited as an autosomal dominant trait. A person needs to inherit only one copy of the gene to have a photic sneeze reflex.

Pulmonary edema: The accumulation of excess fluid in the lungs—is a fairly common, yet dangerous, disorder. This condition is marked by signs of respiratory distress (including tachypnea, or rapid, shallow breathing) and by low oxygen levels in the tissues (hypoxia), which may be evident as a bluish coloration (cyanosis) of the skin and mucous membranes. Pulmonary edema occurs in two stages: interstitial edema, in which excess fluid accumulates in the interstitial spaces in lung tissue, and alveolar edema, in which fluid accumulates in the alveoli. In severe cases, fluid may even move into the airways, in which case the affected person may cough up a frothy foam. Pulmonary edema interferes with breathing in two ways: (1) by increasing the distance over which gases must diffuse to move between alveolar air and capillary blood, which impedes gas exchange, and (2) by interfering with the action of pulmonary surfactant, which causes a decrease in lung compliance and thus an increase in the work of breathing. Pulmonary edema is similar to systemic edema. The most common cause of pulmonary edema is increased hydrostatic pressure in the pulmonary capillaries. Left heart failure can cause a backup of blood in the pulmonary circulation, which increases the pressure in the pulmonary veins. As pressure builds up in the pulmonary capillaries, fluid is pushed out of the capillaries and into the interstitial space of the lungs. Treatment of pulmonary edema is critical because it is a life-threatening situation. The symptoms of pulmonary edema are treated by administering oxygen and diuretics (medications that increase fluid output by the kidneys). However, the cause of the pulmonary edema must be determined and treated appropriately once the symptoms are stabilized.

Understanding exercise: Recruiting Respiratory Reserve Capacities: When the body is resting, the heart pumps 5 liters of blood per minute to both the systemic and pulmonary circuits, called the cardiac output. This 5-liter amount fills only about one-third of the pulmonary capillary capacity. Thus only one of every three capillaries is conducting blood at any given time, and more capillaries in the base of the lungs are carrying blood than in the apex. Alveoli near capillaries that are not conducting blood are collectively referred to as the physiological dead space because, like the air found in the anatomical dead space, air in these alveoli does not participate in gas exchange. As cardiac output increases during exercise, more of the capillaries begin carrying blood continuously, and perfusion becomes more uniform throughout the lungs. Thus the physiological dead space constitutes one type of pulmonary reserve capacity that can be accessed during exercise. Once cardiac output exceeds three times the resting value, all of the reserve capillaries have been recruited; pulmonary pressure then rises modestly, and blood flows faster within individual capillaries. As a consequence, the amount of time each red blood cell spends exchanging gas with an alveolus is reduced. Transit time along the length of an alveolar capillary at rest is about 1 second, but a red blood cell can fully exchange oxygen and carbon dioxide in one-third of that time. Thus two-thirds of the time for red blood cells to travel through a pulmonary capillary constitutes a second type of pulmonary reserve capacity. In combination, these two reserve mechanisms ensure that the pulmonary circuit can accommodate up to a sixfold increase in cardiac output during exercise, with no reduction in red blood cell oxygenation or carbon dioxide release.

Hypoxia-Induced Pulmonary Hypertension: Hypoxia has opposite effects on the pulmonary and systemic circulations. Hypoxia relaxes vascular smooth muscle in systemic vessels and elicits vasoconstriction in the pulmonary vasculature. Hypoxic pulmonary vasoconstriction is the major mechanism regulating the matching of regional blood flow to regional ventilation in the lungs. With regional hypoxia, the matching mechanism automatically adjusts regional pulmonary capillary blood flow in response to alveolar hypoxia and prevents blood from perfusing poorly ventilated regions in the lungs. Regional hypoxic vasoconstriction occurs without any change in pulmonary arterial pressure. However, when hypoxia affects all parts of the lung (generalized hypoxia), it causes pulmonary hypertension because all of the pulmonary vessels constrict. Hypoxia-induced pulmonary hypertension affects individuals who live at a high altitude (8,000 to 12,000 feet) and those with chronic obstructive pulmonary disease (COPD), especially patients with emphysema. With chronic hypoxia-induced pulmonary hypertension, the pulmonary artery undergoes major remodeling during several days. An increase in wall thickness results from hypertrophy and hyperplasia of vascular smooth muscle and an increase in connective tissue. These structural changes occur in both large and small arteries. Also, there is abnormal extension of smooth muscle into peripheral pulmonary vessels where muscularization is not normally present; this is especially pronounced in precapillary segments. These changes lead to a marked increase in pulmonary vascular resistance. With severe, chronic hypoxia-induced pulmonary hypertension, the obliteration of small pulmonary arteries and arterioles, as well as pulmonary edema, eventually occur. The latter is caused, in part, by the hypoxia-induced vasoconstriction of pulmonary veins, which results in a significant increase in pulmonary capillary hydrostatic pressure. A striking feature of the vascular remodeling is that both the pulmonary artery and the pulmonary vein con strict with hypoxia; however, only the arterial side under goes major remodeling. The postcapillary segments and veins are spared the structural changes seen with hypoxia. Because of the hypoxia-induced vasoconstriction and vascular remodeling, pulmonary arterial pressure increases. Pulmonary hypertension eventually causes right heart hypertrophy and failure, the major cause of death in COPD patients.

Pulse oximeter (figure): Is a device that clips on a fingertip or pinna and noninvasively measures the oxyhemoglobin saturation. Because it is noninvasive and fast, it is commonly used in hospitals for many purposes when not all of the information that can be obtained from blood gas machines is needed. The pulse oximeter has two light-emitting diodes (LEDs): one emits red light (with a wavelength of 600–750 nm), and
the other emits infrared light (of 850–1,000 nm). Oxyhemoglobin absorbs relatively more infrared light, allowing more of the red light to pass through the tissue to a sensor, whereas deoxyhemoglobin absorbs more of the red and passes more of the infrared light. From this information, the device determines the percent oxyhemoglobin saturation.

Decompression Sickness As the diver ascends to sea level, the amount of nitrogen dissolved in the plasma decreases as a result of the progressive decrease in the P_N2. If the diver surfaces slowly, a large amount of nitrogen can diffuse through the alveoli and be eliminated in the expired breath. If decompression occurs too rapidly, however, bubbles of nitrogen gas (N₂) can form in the tissue fluids and enter the blood. This process is analogous to the formation of carbon dioxide bubbles in a champagne bottle when the cork is removed. The bubbles of N₂ gas in the blood can block small blood channels, producing muscle and joint pain as well as more serious damage. These effects are known as decompression sickness, commonly called “the bends.” Airplanes that fly long distances at high altitudes (30,000 to 40,000 ft) have pressurized cabins so that the passengers and crew do not experience the very low atmospheric pressures of these altitudes. If a cabin were to become rapidly depressurized at high altitude, much less nitrogen could remain dissolved at the greatly lowered pressure. People in this situation, like the divers that ascend too rapidly, would thus experience decompression sickness.

Hyperbaric oxygen therapy (HBOT), in which a patient breathes 100% oxygen at 2 to 3 atmospheres pressure, does not increase the amount of oxygen carried by hemoglobin, because this is already nearly maximum (with 97% oxyhemoglobin saturation) when breathing sea level air. However, it does significantly increase the oxygen carried by plasma—from 0.3 ml O₂/100 ml blood at sea level to up to 6 ml O₂/100 ml blood for 100% oxygen at 3 atmospheres pressure. This is useful in the treatment of decompression sickness from scuba diving that results when air bubbles form in the tissues and travel in the blood as air emboli, because (from Boyle’s law) raising the pressure decreases the size of the bubbles. HBOT also helps to kill anaerobic bacteria and is used to treat gas gangrene, which is caused by certain bacteria that produce gas and tissue necrosis that may require amputation of the affected limb. Additionally, hyperbaric oxygen helps to treat carbon monoxide poisoning, severe traumatic injuries (such as crush injuries), certain inflammations, and other conditions.

Sudden infant death syndrome (SIDS): Is the sudden death of an infant under one year old that cannot be otherwise explained. Sometimes called crib death, it most often strikes infants between the ages of two and four months. The cause of SIDS is unknown, but evidence suggests it may be due to a failure of the central or peripheral chemoreceptors to detect a rise in carbon dioxide. The incidence of SIDS has been falling significantly since the American Academy of Pediatrics recommended that parents put infants to sleep on their backs rather than on their stomachs, and that infants sleep on a firm surface. However, SIDS still remains the leading cause of death in infants younger than one year.

Maximal O₂ consumption (max VO₂): The determination of best single predictor maximal O₂ of consumption a person’s work capacity is the, or max VO₂, which is the maximum volume of O₂ the person is capable of using per minute to oxidize nutrient molecules for energy production. Max VO₂ is measured by having the person engage in exercise, usually on a treadmill or bicycle ergometer (a stationary bicycle with variable resistance). The workload is incrementally increased until the person becomes exhausted. Expired air samples collected during the last minutes of exercise, when O₂ consumption is at a maximum because the person is working as hard as possible, are analyzed for the percentage of O₂ and CO₂ they contain. Furthermore, the volume of air expired is measured. Equations are then used to determine the amount of O₂ consumed, taking into account the percentages of O₂ and CO₂ in the inspired air, the total volume of air expired, and the percentages of O₂ and CO₂ in the exhaled air. Maximal O₂ consumption depends on three systems. The respiratory system is essential for ventilation and exchange of O₂ and CO₂ between air and blood in the lungs. The circulatory system is required to deliver O₂ to the working muscles. Finally, the muscles must have the oxidative enzymes available to use the O₂ once it has been delivered. Regular aerobic exercise can improve max VO₂ by making the heart and respiratory system more efficient, thereby delivering more O₂ to the working muscles. Exercised muscles themselves become better equipped to use O₂ once it is delivered. The number of functional capillaries increases, as do the number and size of mitochondria, which contain the oxidative enzymes. Maximal O₂ consumption is measured in liters per minute and then converted into milliliters per kilogram of body weight per minute so that large and small people can be compared. As would be expected, athletes have the highest values for maximal O₂ consumption. The max VO₂ for male cross-country skiers has been recorded to be as high as 94 mL O₂/kg/min. Distance runners maximally consume between 65 and 85 mL O₂/kg/min, and football players have max VO₂ values between 45 and 65 mL O₂/kg/min, depending on the position they play. Sedentary young men maximally consume between 25 and 45 mL O₂/kg/min. Female values for max VO₂ are 20% to 25% lower than for males when expressed as mL/kg/min of total body weight. The difference in max VO₂ between females and males is only 8% to 10% when expressed as mL/kg/min of lean body weight, however, because females generally have a higher percentage of body fat (the female sex hormone estrogen promotes fat deposition). Available norms are used to classify people as being low, fair, average, good, or excellent in aerobic capacity for their age group. Exercise physiologists use max VO₂ measurements to prescribe or adjust training regimens to help people achieve their optimal level of aerobic conditioning.

Peripheral Chemoreceptors: When specialized glomus cells {glomus, a ball-shaped mass} (figure) in the carotid and aortic bodies are activated by a decrease in PO₂ or pH or by an increase in PCO₂, they trigger a reﬂex increase in ventilation. Under most normal circumstances, oxygen is not an important factor in modulating ventilation because arterial PO₂must fall to less than 60 mm Hg before ventilation is stimulated. This large decrease in PO₂ is equivalent to ascending to an altitude of 3000 m. However, any condition that reduces plasma pH or increases PCO₂ will activate the carotid and aortic glomus cells and increase ventilation. The details of glomus cell function remain to be worked out, but the basic mechanism by which these chemoreceptors respond to low oxygen is similar to the mechanism you learned for insulin release by pancreatic beta cells or taste transduction in taste buds. In all three examples, a stimulus inactivates K ⁺ channels, causing the receptor cell to depolarize. Depolarization opens voltage-gated Ca²⁺channels, and Ca²⁺entry causes exocytosis of neurotransmitters (ATP or ACh) onto the sensory neuron. In the carotid and aortic bodies, neurotransmitters initiate action potentials in sensory neurons leading to the brain stem respiratory networks, signaling them to increase ventilation. Because the peripheral chemoreceptors respond only to dramatic changes in arterial PO₂, arterial oxygen concentrations do not play a role in the everyday regulation of ventilation. However, unusual physiological conditions, such as ascending to high altitude, and pathological conditions, such as chronic obstructive pulmonary disease (COPD), can reduce arterial PO₂ to levels that are low enough to activate the peripheral chemoreceptors.

Is stiﬂing a sneeze harmful? Scientists have found that air travels at 100 miles an hour during a sneeze. This is enough force to propel sneeze droplets up to 12 ft away from the person sneezing. If a sneeze is stiﬂed, the air is forced into the eustachian tube and middle ear, potentially causing damage to the middle ear.

What happens when “the wind gets knocked out of you”? The “wind may get knocked out of you” following a blow to the upper abdomen in the area of the stomach. There is a network of nerves in that region called the solar plexus. Trauma to this area can cause the diaphragm to experience a sudden, involuntary, and painful contraction called a spasm. It’s not possible to breathe while the diaphragm experiences this spasm—hence, the feeling of being breathless. The pain and inability to breathe stop once the diaphragm relaxes.

Psychological Hyperventilation: People who hyperventilate during psychological stress are sometimes told to breathe into a paper bag so that they rebreathe their expired air, enriched with CO₂. This procedure helps to raise their blood PCO₂ back up to the normal range. This is needed because hypocapnia causes cerebral vasoconstriction, reducing brain perfusion and producing ischemia. The cerebral ischemia causes dizziness and can lead to an acidotic condition in the brain, which, through stimulation of the medullary chemoreceptors, causes further hyperventilation. Breathing into a paper bag can thus relieve the hypocapnia and stop the hyperventilation.

As the body ages: As we advance in age, the respiratory muscles weaken and the chest wall becomes more rigid due to a stiffening of the costal cartilages and ribs. the tissues of the respiratory tract become less elastic and more rigid. This includes the alveolar sacs, resulting in a decrease in the lung capacity. This decrease can amount to almost 35% when individuals reach their 70s. The levels of oxygen gas being carried by the blood also decrease as we age, and gas exchange across the respiratory membranes of the alveoli decreases. In spite of these changes, older adults are capable of light exercise regimens and are encouraged to do so in order to maintain their muscle tone, strength, and endurance. The ciliary action of the epithelium lining the respiratory tract decreases with age, resulting in a buildup of mucus inside the respiratory passageways. This is why older adults become much more susceptible to bronchitis, pneumonia, emphysema, and other respiratory infections.Many factors interact to reduce the efficiency of the respiratory system in elderly individuals. Here are three examples:

1. With age, elastic tissue deteriorates throughout the body. These changes reduce the compliance of the lungs and lower vital capacity.

2. Chest movements are restricted by arthritic changes in the rib articulations and by decreased flexibility at the costal cartilages. Along with elastic tissue deterioration, the stiffening and reduction in chest movement effectively limit the respiratory minute volume. This restriction contributes to the reduction in exercise performance and capabilities with increasing age.

3. Some degree of emphysema is normal in individuals over age 50. However, the extent varies widely with the lifetime exposure to cigarette smoke and other respiratory irritants.

Patterns of Abnormalities in Pulmonary Function Test (see table).

Sickle cell disease: In an inherited homozygous condition known as sickle cell disease, individuals have an amino acid substitution (valine for glutamic acid) on the β chain of the Hgb molecule. This creates a sickle cell Hgb (HgbS), which when not bound to oxygen (deoxyhemoglobin or desaturated Hgb), can transform into a gelatinous material that distorts the normal biconcave shape of the red blood cell to a crescent or "sickle" form. This change in shape increases the tendency of the red blood cell to form thrombi or clots that obstruct small vessels and creates a clinical condition known as "acute sickle cell episode." The symptoms of such an episode vary depending on the site of the obstruction (i.e., stroke, pulmonary infarction) but are commonly associated with intense pain. The spleen is a common site of infarction, and the ensuing tissue damage compromises the immune capabilities of individuals and renders them susceptible to recurrent infections. In the homozygous form this is a life-shortening condition; however, in the heterozygous form, individuals are resistant to malaria. Thus, there is a survival advantage to a heterozygous individual in regions of the world where malaria is prevalent, which may explain why the sickle cell mutation has been preserved through evolution. The increased affinity of HgbF for O₂ renders advantages to individuals with sickle cell disease in that the cells do not desaturate as much when O₂ is released from Hgb to the tissue and thus are less likely to sickle. Sickle cell disease is most prevalent in individuals of African American descent but is also observed in Hispanic, Turkish, Asian, and other ethnic groups.