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Nasal receptors

Lung Mechanoreceptors

Myelinated pulmonary receptors

Slowly adapting stretch Rapidly adapting, or irritant

FIGURE 8 Mechanoreceptors and chemoreceptors in the upper airways and lungs that are important for respiratory reflexes. All of these sensory nerves travel in the vagus nerve, except the nasal receptors.

Vagal afferents

Pharyngeal receptors Laryngeal receptors

Myelinated pulmonary receptors

Slowly adapting stretch Rapidly adapting, or irritant

Non-myelinated pulmonary receptors

Bronchial C fiber Juxta-capillary (J) receptor

FIGURE 8 Mechanoreceptors and chemoreceptors in the upper airways and lungs that are important for respiratory reflexes. All of these sensory nerves travel in the vagus nerve, except the nasal receptors.

limb for most of these reflexes (Fig. 8). The following sections describe reflexes associated with different types of pulmonary receptors, where the term receptor refers to a specialized sensory nerve ending in the lungs—not a neurotransmitter or drug receptor. The efferent pathways for ventilation were described earlier, and auto-nomic efferent pathways in the lung are described at the end of this section.

Nose and Upper Airways

The nose has sensory nerves that transmit afferent information to the respiratory centers via the trigeminal (V) cranial nerve (Fig. 8). The ends of these sensory nerves respond to mechanical and chemical irritants in the nasal mucosa, so they are called mechanoreceptors and chemoreceptors, respectively. The sneeze reflex occurs when nasal mechanoreceptors are stimulated, for example, by inhaled dust, or nasal chemoreceptors are stimulated by noxious gases. Sneezing is a strong inspiration that is followed immediately by strong expiration, which directs air mainly through the nose to remove the offending stimuli. Stimulation of nasal chemoreceptors with water elicits the diving reflex. The diving reflex causes apnea (breath holding), laryngeal closure, and bronchoconstriction to protect the airways from water inhalation. A secondary cardiovascular reflex response to arterial chemoreceptor stimulation during apnea also slows the heart rate and diverts blood flow to vital organs such as the brain. This is considered an important part of the diving reflex because it conserves o2 supplies in the body until breathing can resume safely.

The pharynx and epipharynx (the nasal passages just above the pharynx) contain vagal mechanoreceptors (Fig. 8). Mechanical irritants in the epipharynx stimulate the aspiration, or sniff reflex, consisting of several short and strong nasal inspirations in rapid succession. This sniffs material down into the pharynx where it can be coughed out or swallowed. Mechanoreceptor stimulation in the pharynx causes the swallowing reflex. Swallowing inhibits inspiration and closes the larynx, which protects the lungs, while the tongue and other muscles move food or liquid into the esophagus.

The larynx contains mechanoreceptors and chemo-receptors from the recurrent laryngeal and superior laryngeal nerves, which are branches of the vagus (Fig. 8). The laryngeal chemoreceptors are sensitive to inhaled noxious gases (e.g., ammonia and sulfur dioxide) and smoke, which stimulate coughing and the expiratory reflex. The expiratory reflex is a short and strong expiratory effort, but coughing also involves inspiratory activity. Liquid can also stimulate laryngeal chemoreceptors to cause apnea, which protects the lungs from inhaling fluids.

Laryngeal mechanoreceptors respond to changes in airway pressure, upper airway muscle contraction, and temperature. Airway temperature can change with inspired gas temperature, ventilation rate and the velocity of air flow, and mouth versus nose breathing. Stimulation of laryngeal mechanoreceptors causes reflex changes in upper airway muscle tone, which decrease airway resistance and prevent upper airway collapse with negative pressures during inspiration. A short and strong inspiratory effort results in either a sigh or a hiccup, depending on whether or not the upper airway muscles are simultaneously activated. Changes in upper airway reflexes during sleep can cause snoring and sleep apnea (see Clinical Note).

Lungs and Lower Airways

Figure 8 show how the vagal sensory nerves from the lungs and lower airways fall into two functional groups: myelinated and nonmyelinated pulmonary receptors. Myelinated nerves conduct action potentials rapidly and are generally involved in fine motor control and rapid defense responses. Nonmyelinated nerves conduct action potentials more slowly and are involved in slower defense reflexes.

Pulmonary Stretch Receptors

The vagus contains myelinated afferents called slowly adapting pulmonary stretch receptors (sometimes abbreviated PSR or SAR), which are stimulated by changes in lung volume (see Fig. 8). These mechanoreceptors are located in the smooth muscle of the trachea and intrapulmonary airways. Stretch depolarizes these receptors, sending action potentials to respiratory centers in the brain via the vagus nerve. If volume is increased rapidly and maintained at a new level, the frequency of action potentials increases rapidly and then settles to a slightly lower frequency. However, the steady-state frequency is proportional to the steady-state volume, and the receptors are described as slowly adapting because frequency does not completely adapt back to the basal rate. Slowly adapting pulmonary stretch receptors are tonically active at functional residual capacity (FRC), so they can send afferent information about increases or decreases in lung volume to the CNS.

Slowly adapting pulmonary stretch receptors are involved in the control of tidal volume and respiratory frequency through the Hering-Breuer, or inflation inhibitory, reflex. Increasing lung volume causes increased action potential frequency from pulmonary stretch receptors. This afferent signal inhibits further inspira-tory nerve activity and terminates an inspiration through synaptic mechanisms in the pons and medulla. Hence, the inflation inhibitory reflex limits a breath from being larger or longer than necessary to achieve a given level of ventilation. This reflex is of historic interest because it was the first description of negative feedback in a physiologic control system in 1868. It is of physiologic interest because it explains the effect of the vagus on the pattern of breathing.

Cutting the vagus nerves in anesthetized animals results in slow, deep breathing, as predicted by the inflation inhibitory reflex. In contrast, removing all pulmonary afferent input in adult humans with a total lung transplant does not cause slow deep breathing. There is evidence that the inflation inhibitory reflex is not important in awake adults unless tidal volumes exceed FRC by more than 1 L. However, Fig. 9 shows that pulmonary stretch receptor activity can be important in adults during sleep. The inflation inhibitory reflex is greatly reduced in lung transplant patients during sleep, compared with normal individuals. This could reflect changes in central integration of respiratory reflexes during the sleep state or changes in chest wall mechanics. The inflation inhibitory reflex is more powerful in neonates and experimental animals, which have more compliant chest walls than adult humans.

Figure 9 also shows that the pattern of ventilation is more irregular in lung transplant patients. This also occurs in awake lung transplant patients and experimental animals with pulmonary denervation. Hence, pulmonary stretch receptors decrease breath-to-breath variations in tidal volume and frequency for a given level of ventilation. This fine-tuning of the ventilatory pattern is hypothesized to reduce the mechanical work of breathing.

Normal subject

Diaphragm

AA/VWWW1-

2 L passive inflation

VlM/lAiVWV

Diaphragm EMG

Lung transplant subject —»»w^ittimn'i» H»**» » up-m wwvwvww^—M/VWwwv i—i 2 L passive inflation

FIGURE 9 Ventilatory efforts (diaphragm EMG) and ventilation (tidal volume, Vt changes) in a normal subject (upper) and a bilateral lung transplant patient (lower panel) during sleep. Passive lung inflation inhibits ventilatory efforts for 40 sec (length of inflation bar) in normal patient by inflation inhibitory reflex; lung inflation is removed at the first sign of ventilatory effort on the EMG so breathing resumes. The vagus nerves are cut during lung transplantation so this reflex is virtually absent in the patient. Vagal denervation also increases variability in the breathing pattern of the lung transplant patient compared to the normal subject. (After Iber et al., Am J Respir Crit Care Med 1995;152:217.)

Pulmonary stretch receptors are also involved in the deflation reflex, which increases respiratory rate at low lung volumes. Recall that pulmonary stretch receptors are tonically active at FRC, so at low lung volumes the afferent input to respiratory centers is decreased.

Pulmonary Irritant Receptors

Pulmonary irritant receptors are the second type of myelinated vagal afferent in the lung (see Fig. 8). These sensory nerves are in the airway epithelium and respond to inhaled chemical irritants such as smoke, dust, and ammonia vapor. Irritant receptors also respond to endogenous chemical stimuli such as histamine, which is released from mast cells in the airways. It is hypothesized that irritant receptors may play a role in asthma because histamine is released during asthma. The reflex response to stimulating irritant receptors in the trachea and large bronchi includes (1) coughing, (2) mucous production, and (3) bronchoconstriction. This three-part response serves to remove noxious inhaled substances and protect the lungs from further exposure.

Irritant receptors also respond to mechanical stimuli, such as changes in lung volume. However, in contrast to slowly adapting pulmonary stretch receptors, irritant receptors are more sensitive to dynamic changes in volume than absolute volumes. As lung volume is increased, action potential frequency from irritant receptors initially increases but then rapidly adapts back toward the basal rate, despite the volume change being maintained. Hence, another name for irritant receptors is rapidly adapting pulmonary stretch receptors (sometimes abbreviated RAR). It is possible that the response of irritant receptors to some chemical stimuli results from mechanical changes in the receptor's microenvironment.

Mechanical stimulation of irritant receptors includes decreased lung compliance and deflation of the lung. Hence, irritant receptors may be involved in the deflation reflex described earlier. Stimulating irritant receptors in small bronchi can elicit the gasp reflex. This is an unusual case of positive feedback, in which irritant receptor stimulation by large rapid increases in lung volume causes a further increase in tidal volume, or a gasp. The physiologic significance of this reflex is not clear.

Bronchial C-Fibers

Cfiber is another term for a nonmyelinated fiber, where the C designates conduction velocity in an alphabetical system (C < 2.5 m/sec). Pulmonary C-fibers can be defined further by their blood supply. Bronchial C-fibers are supplied by the systemic circulation, in contrast to juxtacapillary C-fibers, which are supplied by the pulmonary capillaries (see Fig. 8).

Bronchial C-fibers can be stimulated by chemicals injected in the bronchial circulation, such as capsaicin (the hot ingredient in red chilies) and phenyldiguanide (a serotonin receptor agonist). Physiologically, bronchial C-fibers are probably stimulated by local release of cytokines, such as histamine, prostaglandin, and brady-kinin in the airways.

The reflex response to bronchial C-fiber stimulation is an airway defense reflex, including rapid shallow breathing, bronchoconstriction, and mucous secretion. Bronchial C-fibers may contribute to the cough reflex also. Finally, bronchial C-fibers are involved in broncho-constriction and changes in vascular permeability in the airways with airway inflammation. Bronchoconstriction involves both autonomic effectors (see section titled Autonomic Nervous System in the Lungs) and a local axon reflex. The axon reflex is a local response to a neuropeptide (substance P) released from a sensory nerve ending.

Juxtacapillary Receptors

Pulmonary vagal C-fibers that can be stimulated by chemicals in the pulmonary circulation are called juxtacapillary receptors, or J-receptors, because of their presumed location next to the pulmonary capillaries. J-receptors can be stimulated by capsaicin injected in the pulmonary artery, and the reflex response is tachypnea, or rapid shallow breathing. Apnea (no breathing) may precede tachypnea depending on the dose and timing of chemical stimulation. The cardiovascular system also responds with bradycardia (a decrease in heart rate) and hypotension.

Physiologically, J-receptor stimulation occurs with pulmonary embolism, congestion, and edema, and causes the rapid shallow breathing observed in these conditions. J-receptor stimulation probably explains the tachypnea and sensation of breathlessness (dyspnea) with interstitial lung disease also. Nonmyelinated vagal afferents are responsible for all sensation, including pain, from the lower airways.

Autonomic Nervous System in the Lungs

The airways in the lungs receive both parasympathetic and sympathetic innervation, which controls bronchial smooth muscle constriction, mucous secretion, vascular smooth muscle, fluid transport across the airway epithelium, and vascular permeability in the pulmonary and bronchial circulations. In normal conditions, para-sympathetic control of bronchial smooth muscle tone is the most important of these functions. Acetylcholine released from the vagus nerve causes bronchoconstric-tion, and tonic vagal activity determines bronchial smooth muscle tone. Sympathetic innervation of the lung is less important. Circulating epinephrine from the adrenal medulla causes bronchodilation through fi-adrenergic receptors on airway smooth muscle. Nore-pinephrine released from sympathetic nerves in the airways can cause bronchodilation indirectly via a-adrenergic receptors on parasympathetic ganglia in the lung. Activating these a-adrenergic receptors inhibits parasympathetic activity and cholinergic broncho-constriction.

These different autonomic mechanisms provide a physiologic basis for treating bronchoconstriction in lung disease. Chronic bronchoconstriction from chronic obstructive pulmonary disease is treated with acetylcho-line receptor antagonists to reduce the effects of vagal tone. Acute and severe bronchoconstriction during an asthma attack is treated with fi2-adrenergic agonists. fi2-Adrenergic agonists are selective for bronchial smooth muscle and have fewer cardiac effects.

Neuropeptides are also important in controlling airway function. The bronchoconstriction from substance P released directly from sensory nerves by the axon reflex was described earlier. This is also called the excitatory nonadrenergic, noncholinergic system (e-NANC) to distinguish it from autonomic control. In contrast, the neuropeptide VIP (vasoactive intestinal peptide) causes bronchodilation. VIP is released from nerves arising from parasympathetic ganglia, which are called the inhibitory nonadrenergic, noncholinergic system (i-NANC). Nitric oxide (NO) may be involved in i-NANC bronchodilation also.

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