Medical Physiology, 3rd Edition

Modulation of Ventilatory Control

The major parameters that feed back on the respiratory control system are the arterial blood-gas parameters—, , and pH. In addition, the respiratory system receives input from two other major sources: (1) a variety of stretch and chemical/irritant receptors that monitor the size of the airways and the presence of noxious agents, and (2) higher CNS centers that modulate respiration during nonrespiratory activities.

Stretch and chemical/irritant receptors in the airways and lung parenchyma provide feedback about lung volume and the presence of irritants

Sensors within the lungs and upper airways detect foreign bodies, chemical irritants, or immunological challenges and help protect the lungs—one of the few organs that have direct access to the outside world. Sensors also detect changes in lung volume as part of a feedback mechanism that helps control output to respiratory muscles. Respiratory afferent fibers from sensors in the thorax travel with CN X, and those from sensors in the upper airways travel with CN IX. Both synapse within the DRG in the medulla (see p. 705).

Slowly Adapting Pulmonary Stretch Receptors

Mechanoreceptors within the tracheobronchial tree detect changes in lung volume by sensing stretch of the airway walls. One type of pulmonary stretch receptor (PSR), the slowly adapting PSR, N32-23 responds to stretch with an increase in firing that then decays very slowly over time. One of the functions of these receptors may be to inform the brain about lung volume to optimize respiratory output.

Contributed by George Richerson, Emile Boulpaep, Walter Boron

Within the tracheobronchial tree are mechanoreceptors that detect changes in lung volume by sensing stretch of the airway walls. These are PSRs. One type of PSR responds to stretch with a sudden increase in firing that then decays (i.e., “adapts”) very slowly over time. These slowly adapting PSRs are located from the extrathoracic trachea down through the intrapulmonary bronchi; their afferent axons are myelinated. Except for hypocapnia, chemical stimuli do not selectively excite these receptors, whose function may be partly to inform the brain about lung volume to optimize respiratory output.

A reflex that involves slowly adapting PSRs is the Hering-Breuer reflex, one of the first examples in physiology of negative feedback. In 1868, Hering and Breuer found that lung inflation inhibits the output of phrenic motor neurons (Fig. 32-15), which protects the lungs from overinflation. Because the reflex also increases respiratory frequency, it maintains a constant alveolar ventilation. This reflex may be important in controlling tidal volume during eupnea in human infants. In adults, this reflex does not occur until lung volume is greater than during a normal inspiration. However, the sensor may provide feedback that the medulla uses to choose a combination of tidal volume and respiratory frequency that minimizes the work of breathing.

FIGURE 32-15 Hering-Breuer reflex. In a paralyzed and artificially ventilated animal, prevention of lung inflation during inspiratory activity (blue curves) leads to prolonged phrenic nerve output (i.e., if the animal were not paralyzed, then tidal volume would be large). Inflation of the lungs during inspiratory activity (red curves) produces feedback that shortens the duration of inspiratory activity (i.e., if the animal were not paralyzed, then the tidal volume would be smaller) and also causes the next breath to occur earlier (respiratory frequency would increase). (Data from von Euler C: Brainstem mechanisms for generation and control of breathing pattern. In Cherniack NS, Widdicombe J [eds]: Handbook of Physiology, Section 3: The Respiratory System, vol 2, part 1. Bethesda, MD, American Physiological Society, 1986, pp 1–67).

Rapidly Adapting Pulmonary Stretch (Irritant) Receptors

The rapidly adapting PSRs N32-24 respond to a sudden, maintained inflation with a rapid increase in firing rate, which then decreases by 80% or more within 1 second. Unlike slowly adapting PSRs, rapidly adapting PSRs are very sensitive to a variety of chemical stimuli, hence the term irritant receptors. These stimuli include serotonin, prostaglandins, bradykinin, ammonia, cigarette smoke, and ether. An important function of these receptors may be to detect pathophysiological processes in the airway, such as chemical irritation, congestion, and inflammation. These receptors also detect histamine (see p. 620 and Fig. 13-8B), which produces bronchoconstriction in asthma.

Contributed by George Richerson, Emile Boulpaep, Walter Boron

In addition to the slowly adapting PSRs discussed in N32-23, the lung has PSRs that respond to inflation at a higher volume. A sudden, maintained inflation causes their firing rate to increase suddenly and then to decrease (i.e., “adapt”) within 1 second to 20% or less of the initial rate. Rapid deflation also stimulates them. The distribution of these receptors is not as well characterized as that of the slowly adapting PSRs, but they seem to be located throughout the tracheobronchial tree. Their afferent axons are myelinated.

Unlike the slowly adapting PSRs, the rapidly adapting PSRs are also very sensitive to a variety of chemical stimuli, hence the term irritant receptors. These stimuli include histamine, serotonin, prostaglandins, bradykinin, ammonia, cigarette smoke, and ether. In some cases, the chemical directly stimulates the receptor. In others, the chemical first triggers a bronchoconstriction, and this volume change then activates the stretch receptor. An important function of these receptors may be to detect pathophysiological processes in the airway, such as chemical irritation, congestion, and inflammation. The response to histamine produces bronchoconstriction in asthma.

C-Fiber Receptors

A rich network of small, unmyelinated axons (C fibers; see p. 302) have nerve endings—juxtacapillary or J receptors—in alveoli and conducting airways. Like slowly adapting PSRs, which are extensions of myelinated axons, these C-fiber receptors respond to both chemical and mechanical stimuli. Stimulation of C-fiber receptors elicits a triad of rapid and shallow breathing, bronchoconstriction, and increased secretion of mucus into airways—all of which may be defense mechanisms. Bronchoconstriction and rapid, shallow breathing enhance turbulence (see p. 617), which favors the deposition of foreign substances in mucus higher up in the bronchial tree, where mucus-secreting cells are located (Box 32-4).

The respiratory apparatus engages in a variety of motor behaviors that help maintain normal lung function and gas exchange by protecting the alveoli from collapse or preventing obstruction of the upper airways.

Sigh or “Augmented Breath”

A sigh is a slow and deep inspiration, held for just a moment, followed by a longer-than-normal expiratory period (see Fig. 32-3). A normal person sighs ~6 times per hour. Local collapse of alveoli (atelectasis) may initiate a sigh, which is an important mechanism for stimulating release of surfactant (see pp. 613–614) and thus reopening these alveoli. Hypoxia and respiratory acidosis increase sigh frequency, consistent with the idea that sighs counteract decreased alveolar ventilation.

Yawn

An exaggerated sigh, a yawn takes lung volume to total lung capacity for several seconds. The mouth is fully open. In the extreme case, the arms are stretched upward, the neck is extended to elevate the pectoral girdle, and the back is extended—maneuvers that maximize lung volume (see p. 602). Yawning is even more effective than sighing in opening up the most resistant atelectatic alveoli. Everyone “knows” that yawns are contagious, and some evidence suggests that this is actually true. Yawns may (1) minimize atelectasis as one prepares for sleep (as during a boring lecture), and (2) reverse—on arousal—the atelectasis that has accumulated during sleep. Interestingly, many trained athletes yawn just before a big event, presumably preparing the lungs for enhanced gas exchange.

Cough Reflex

Coughing is important for ridding the tracheobronchial tree of inhaled foreign substances. There is probably no single class of “cough receptors.” N32-25 The tickling sensation that is relieved by a cough is analogous to the cutaneous itch and is probably mediated by C-fiber receptors. Thus, a cough is a respiratory scratch.

When lower airway receptors trigger a cough, it begins with a small inspiration that increases the coughing force. Mechanosensitive and irritant receptors in the larynx can trigger either coughing or apnea. When they trigger a cough, the inspiration is absent, which minimizes the chances that the offending foreign body will be pulled deeper into the lungs. In either case, a forced expiratory effort against a closed glottis raises intrathoracic and intra-abdominal pressures to very high levels. The glottis then opens suddenly, and the pressure inside the larynx falls almost instantaneously to near-atmospheric levels. This sudden drop in luminal pressure produces dramatic increases in the axial (alveolus to trachea) pressure gradient that drives air low (see pp. 616–617). In the trachea, this pressure drop also decreases the radial transmural pressure difference across the tracheal wall, thereby collapsing the trachea (see p. 626), especially the membranous (i.e., noncartilaginous) part of the trachea. As a result, tracheal cross-sectional area may fall to as little as one sixth of its original value. The net effect is a brief but violent rush of air out of the trachea at velocities near 800 km/hr (~65% of the speed of sound) that loosens mucus or foreign bodies and moves them upward. Protracted bouts of severe coughing can lead to lightheadedness or even syncope because the high intrathoracic pressure decreases venous return and reduces cardiac output (see pp. 548–551). N32-26

Sneeze

Sensors in the nose detect irritants and can evoke a sneeze. Curiously, these same receptors are probably also responsible for apnea in response to water applied to the face or nose, which is part of the diving reflex that evolved in diving mammals such as the seal to prevent aspiration during submersion. A sneeze differs from a cough in that a sneeze is almost always preceded by a deep inspiration. Like a cough, a sneeze involves an initial buildup of intrathoracic pressure behind a closed glottis. Unlike a cough, a sneeze involves pharyngeal constriction during the buildup phase and an explosive forced expiration through the nose as well as the mouth. This expiration is accompanied by contraction of facial and nasal muscles, so that the effect is to dislodge foreign bodies from the nasal mucosa.

Contributed by George Richerson, Emile Boulpaep, Walter Boron

A rich network of extremely thin, unmyelinated axons—C fibers—innervates receptors in the alveoli and conducting airways. Like the slowly adapting PSRs, N32-23 which are innervated by myelinated nerve fibers, C-fiber receptors respond to both chemical and mechanical stimuli. Alveolar C-fiber receptors become active very soon (i.e., 1 to 2 seconds) after the injection of certain chemicals into the blood of the right atrium of the heart,* which suggests that the receptors may be very near pulmonary capillaries. Hence the name juxtacapillary or J receptors. The J receptors respond “chemically” to inflammatory agents released in the airway wall: histamine, serotonin, bradykinin, and prostaglandins. They also respond to mechanical stimuli, including lung or vascular congestion.

The C-fiber receptors in conducting airways are less sensitive to lung inflation than their alveolar counterparts, but are more sensitive to chemical mediators of inflammation. Stimulating C-fiber receptors elicits a triad of rapid and shallow breathing, bronchoconstriction, and increased secretion of mucus into airways—all of which may be defense mechanisms. Bronchoconstriction and rapid, shallow breathing would enhance turbulence (see Fig. 27-12C), favoring the deposition of foreign substances in mucus higher up in the bronchial tree, where mucus-secreting cells are located.

The afferent nerve fibers for all sensors located in the tracheobronchial tree and lung parenchyma travel to the medulla in the vagus nerve (CN X) via either myelinated or unmyelinated fibers. The myelinated fibers rapidly transmit impulses from PSRs and are readily blocked by cooling (~8°C to 10°C). Unmyelinated nerve fibers—the C fibers discussed above—slowly transmit impulses from J receptors near alveoli, as well as other receptors in conducting airways, and conduct impulses even at 4°C. This differential temperature sensitivity is a useful tool for studying respiratory reflexes. For a discussion of the effects of myelination and axon diameter on axon conduction velocity, see the passage in the text that begins on page 302.

^*After entering the ventricle and being injected into the pulmonary veins, this blood rapidly reaches the alveolar capillaries, very near where the alveolar C-fiber receptors are thought to be.

Contributed by George Richerson, Emile Boulpaep, Walter Boron

The example of severe coughing leading to syncope is a special case in which the external compression of the vessels in the thorax causes an increase in their resistance and thus a decrease in venous return. Keep in mind that not only does the inferior vena cava have a rather low pressure, but all pulmonary vessels (i.e., arteries, capillaries, and veins) also have a low pressure. Thus, all of these vessels are particularly susceptible to collapse by an increase in the surrounding pressure.

Higher brain centers coordinate ventilation with other behaviors and can override the brainstem's control of breathing

The role of the CNS in controlling ventilation is far more complex than generating a regular pattern of inspirations and expirations, and then modifying this pattern in response to input from mechanical and chemical sensors. The CNS also must balance the need to control , , and pH with the need to control ventilation for nonrespiratory purposes, such as speaking, sniffing, and regulating temperature (e.g., panting in dogs). In addition, the CNS must coordinate breathing with behaviors that require the absence of airflow, such as chewing, swallowing, and vomiting.

Many nonrespiratory regions of the CNS tonically stimulate or inhibit respiration. For example, the reticular activating system (see p. 270) in the brainstem is one of the sources of tonic drive to the respiratory CPG. An increase in this drive occurs during arousal from sleep, when a general alerting reaction increases ventilation and heart rate and activates the brain as evidenced on an electroencephalogram.

Coordination with Voluntary Behaviors That Use Respiratory Muscles

Numerous voluntary actions initiated in the cerebral cortex involve a change in airflow—voluntarily hyperventilating, breath holding, speaking, singing, whistling, and playing musical wind instruments. Although voluntary control over muscles of respiration can be exquisitely precise, this control is not absolute. For example, voluntary breath holding can last only so long before being overwhelmed by ventilatory drive from chemoreceptors. The cerebral cortex controls the respiratory system by at least two major mechanisms. First, some cortical neurons send axons to respiratory centers in the medulla. Second, some cortical premotor neurons send axons to motor neurons that control muscles of respiration. One consequence of this dual control mechanism is that lesions in specific areas of the cerebral cortex can abolish voluntary breath holding, a condition known as respiratory apraxia. Another consequence is that small CNS lesions may specifically knock out one set of connections. For example, patients with intractable pain are sometimes treated with partial transection of the upper cervical ventrolateral spinal cord to cut axons carrying pain sensation to the thalamus (spinothalamic tract). When this procedure inadvertently damages respiratory projections within the reticulospinal tract, patients breathe properly while awake but experience respiratory failure while asleep—Ondine's curse (Box 32-5). The lesion may cut automatic premotor neurons descending to the spinal cord from respiratory centers in the medulla, but not voluntary ones from the cortex.

Ondine's Curse

Ondine, a water nymph in a German legend, was immortalized in the 1811 fairy tale by Friedrich Heinrich Karl, Baron de la Motte-Fouqué. In the play Ondine by Jean Giraudoux in 1939, Ondine married a mortal man, Hans, with the understanding that Hans would never marry a mortal woman. However, when Ondine later returned to the sea, her husband did remarry. Ondine's father punished Hans by requiring him to make a continuous conscious effort to maintain lung ventilation (and all other automatic body functions). If he fell asleep, he would stop breathing and die. Hans explained to Ondine how hard it is to live with his curse: “One moment of inattention and I shall forget to hear, to breathe. They will say he died because breathing bored him.” Some patients have the same disorder—minus the relationship with a water nymph. The majority of these patients have congenital central hypoventilation syndrome (CCHS) due to mutations in PHOX2B (see p. 340), which encodes a transcription factor required for development of the autonomic nervous system and a limited number of other neurons, including a subset in the RTN (see p. 714). These patients can be treated by providing mechanical ventilation when they sleep; they can maintain normal ventilation on their own while awake.

Sleep

Sleep, or even closing one's eyes, has powerful effects on the breathing pattern and CO₂ responsiveness. During non–rapid eye movement (NREM) sleep, the regularity of eupneic breathing increases; also, the sensitivity of the respiratory system to CO₂ decreases compared with wakefulness, and the outflow to the muscles of the pharynx decreases. During rapid eye movement (REM) sleep, the pattern of breathing becomes markedly irregular, sometimes with no discernible rhythm, and the sensitivity of the respiratory system to CO₂ decreases further. Thus,  often increases during NREM sleep, and usually even more so during REM sleep. Barbiturates at low doses depress drive to the respiratory system and, if superimposed on normal sleep, can halt ventilation altogether.

Sleep Apnea

The collection of disorders in which ventilation ceases during deeper stages of sleep, particularly during REM sleep, is known as sleep apnea. Some cases of sleep apnea are related to Ondine's curse and are due to a lack of central drive—central sleep apnea. However, most cases are due to collapse of the airway with sleep—obstructive sleep apnea—usually in obese people. The airway collapse is due to an exaggeration of the normal decrease in airway tone during sleep, superimposed on the structural problem of reduced airway diameter due to obesity. This is a common disorder associated with severe and excessive snoring, poor and interrupted sleep, daytime somnolence, and behavioral changes, possibly leading ultimately to hypertension and cardiac arrhythmias.

Coordination with Complex Nonventilatory Behaviors

One of the jobs of the brain is to coordinate complex behaviors such as yawning, chewing, swallowing, sucking, defecating, grunting, and vomiting. During yawning and vomiting, for example, groups of neurons orchestrate an array of simultaneous actions, only some involving the respiratory system. The premotor neurons that project from medullary respiratory centers to respiratory motor neurons are probably distinct from descending pathways involved in these complex nonventilatory behaviors.

Modification by Affective States

Fear, horror, rage, and passion can be associated with major and highly characteristic changes in the respiratory pattern. For example, if a child runs in front of the car you are driving, the sudden application of the brakes is almost always accompanied by an equally sudden and rapid inspiration, with mouth open widely, increasing lung volume to nearly total lung capacity. The tendency of prevarications to be associated with changes in the breathing pattern is the basis for one part of the polygraph test used as a lie detector. Descending pathways from the limbic system (see p. 349) of the forebrain may mediate these emotional effects on breathing.

Balancing Conflicting Demands of Gas Exchange and Other Behaviors

Ventilation, or lack thereof, is involved in a wide variety of behaviors, many of which have nothing to do with alveolar gas exchange per se. How is it that the brain is able to weigh the need for alveolar gas exchange against these competing demands on the respiratory system? Playing a musical wind instrument is an example of a situation in which respiratory and nonrespiratory needs are reconciled. Musicians must make rapid and deep inspirations, followed by slow and prolonged expirations that can lead to considerable breath-to-breath variations in alveolar . Nevertheless, these variations balance out, so that professionals can follow a musical score for prolonged periods without significant changes in average alveolar ventilation.

In other cases, conflicting demands are not so easily resolved. In infants, suckling relegates alveolar ventilation to a lower priority, and  rises. Subjects reading aloud tend to increase their alveolar ventilation by ~25%, and  falls. Thus, during speech, chemical drive is overwhelmed by voluntary behavior. On the other hand, when strenuous exercise increases the need for alveolar ventilation, the CNS permits only brief gasps for speech—the ability of voluntary behavior to subvert body homeostasis can go only so far.