L.-Y. Lee

Sensitivity of vagal afferent endings to chemical irritants in the rat lung

This study was carried out to investigate the relationship between the conduction velocity of the vagal afferents arising from the rat lungs and their sensitivities to capsaicin, other chemical irritants, and lung inflation. We recorded single-unit activities of vagal pulmonary afferents (n = 205) in anesthetized, open-chest rats, and distinguished C fibers (conduction velocity < 2 m/sec) from myelinated afferents; the latter group was further classified into rapidly adapting pulmonary receptors (RARs) and slowly adapting pulmonary stretch receptors (SARs) on the basis of their adaptation indexes to lung inflation. Right-atrial injection of capsaicin (1 microg/kg) evoked an abrupt and intense stimulatory effect in 88.9% (64/72) of the pulmonary C fibers tested, but only a mild stimulation in 6.3% (3/48) of the RARs and none of the SARs. Other inhaled and injected chemical stimulants (e.g., cigarette smoke, lactic acid) activated 68.9% (42/61) of the pulmonary C fibers. The same chemical irritants exerted a mild stimulatory effect in only 14.5% (8/55) of the RARs; this subgroup of RARs exhibited a low or no baseline activity, and half of them were located near the hilum. Chemical stimulants had little or no effect on SARs. The response of pulmonary C fibers to lung inflation (tracheal pressure = 30 cm H2O) was not only extremely weak, but also showed a longer onset latency and an irregular pattern. In a sharp contrast, lung inflation evoked rapid and vigorous discharges in both RARs and SARs. In conclusion, C fibers are the primary type of chemosensitive vagal pulmonary afferents in rat lungs.

Vagal bronchopulmonary C-fibers and acute ventilatory response to inhaled irritants

Experiments were carried out in anesthetized Sprague-Dawley rats to determine the role of vagal bronchopulmonary C-fiber afferents in regulating the respiratory responses to inhaled irritants. Spontaneous inhalation of 2 tidal breaths of a known airway irritant (sulfur dioxide, 0.5%; ammonia, 1%; cigarette smoke, 50%) into the lower airways invariably elicited an immediate and transient inhibitory effect on breathing, characterized by apnea or bradypnea and accompanied by bradycardia, which lasted for 3-8 breaths. A delayed hyperpnea was also induced by inhalation of cigarette smoke, but not by sulfur dioxide or ammonia. After perineural capsaicin treatment of both cervical vagi to selectively block the conduction of capsaicin-sensitive C-fibers, these inhaled irritants no longer evoked any inhibitory effect on breathing; conversely, an augmented inspiration was triggered within the first 3 breaths from the onset of cigarette smoke inhalation in > 85% of the rats studied, but after a delay of several breaths following inhalation of ammonia or sulfur dioxide in only 30% of the rats. The augmented breaths were completely abolished when both cervical vagi were cooled to 6-7 degrees C. Bilateral vagotomy eliminated all the immediate responses to these irritants. These results suggest that both vagal C-fiber endings and irritant receptors in the airways are activated by these inhaled irritants, but the more dominant and consistent inhibitory effect on breathing is elicited primarily by stimulation of C-fiber afferents.

The stimulatory effect of nicotine on vagal pulmonary C-fibers in dogs

Our recent studies suggested that a nicotine-induced stimulation of afferent vagal C-fibers in the lungs was involved in eliciting the immediate cardiorespiratory responses to inhaling cigarette smoke. To examine this possibility, afferent impulses were recorded from vagal pulmonary C-fibers in 16 anesthetized, open-chest and artificially ventilated dogs, before and after four separate doses of nicotine (2.5, 5, 10 and 20 micrograms/kg) were injected into the right atrium. The base-line activity did not change after injection of isotonic saline. In contrast, nicotine stimulated 24 of 29 C-fibers: a burst of discharge was evoked immediately (1-2 sec) after the injection and usually lasted 3-8 sec. The peak responses of these pulmonary C-fibers to nicotine injections showed a dose-dependent relationship. In 17 C-fibers tested, the responses evoked by right atrial injection of 10 micrograms/kg of nicotine were similar to those evoked by delivery into the lungs of a single breath of smoke generated from cigarette with a high-nicotine content. Based upon these results, we conclude that nicotine alone stimulates vagal pulmonary C-fibers in a dose-dependent manner and this stimulant action of nicotine may play a part in eliciting the immediate reflex cardiorespiratory responses to inhalation of cigarette smoke.

Mechanisms of cigarette smoke-induced stimulation of rapidly adapting receptors in canine lungs

The stimulation of rapidly adapting receptors (RARs) in the lungs evoked by cigarette smoke consists of an initial and either a type I or a type II delayed response (Kou and Lee, J. Appl. Physiol. 68: 1203, 1990). In the type I response, receptor activity increased during expirations and exhibited a prominent cardiac modulation, whereas in the type II response, receptor discharge reached its peak during inspiration at peak transpulmonary pressure. To investigate the mechanisms of this stimulation, we recorded the vagal afferent activity arising from 39 RARs and delivered a single breath (120 ml) of cigarette smoke in 15 anesthetized, open-chest and artificially ventilated dogs. Studies were repeated after a pretreatment with aerosolized hexamethonium (3-8 breaths, 10%), aerosolized isoproterenol (12-15 breaths, 2%), or after the cardiac impact on the lung had been minimized by elevating the apex of the heart. The initial response of RARs was totally abolished by hexamethonium but was not affected by isoproterenol. The increase of total lung resistance induced by cigarette smoke and the concomitant type II delayed response of RARs were both abolished by isoproterenol. The type I delayed response of RARs was eliminated or largely attenuated after the apex of the heart had been elevated. Based upon these results, we conclude that a direct effect of nicotine on these receptors may be responsible for the immediate stimulation while the systemic effects of absorbed nicotine may play a part in evoking the delayed stimulation.

Involvement of tachykinins in endotoxin-induced airway hyperresponsiveness.

Abstract. Inhaled endotoxin, lipopolysaccharide (LPS), has been shown to result in bronchial hyperresponsiveness (BHR) to endogenous bronchoconstrictive mediators such as histamine. To determine the role of sensory neuropeptides released from bronchopulmonary C-fibers in LPS-induced BHR, 24 guinea pigs were allocated randomly to the following four groups. Animals in Groups I and IV were challenged with intratracheal instillation of 100 μl of saline vehicle, and those in Groups II and III with 1 mg of LPS (Escherichia coli, 0111:B4) in 100 μl of saline. Groups III and IV also received a high dose capsaicin (HDC) treatment to deplete tachykinins from C-fibers 1–2 weeks prior to the experiment. Animals were anesthetized and paralyzed, and total lung resistance (RL) and compliance (Cdyn) were measured continuously during the experiment. Dose responses of RL and Cdyn to histamine (0–8 μg/kg, intravenously) and capsaicin (0–1.6 μg/kg, intravenously), a specific C-fiber stimulant, were obtained prior to and at 1, 2, and 3 h following LPS/saline vehicle challenge. At 2 h after LPS, ΔRL caused by histamine (8 μg/kg) was significantly higher in Group II (1.145%) than that in Group I (280%; p < 0.05); similarly, ΔRL caused by capsaicin (1.6 μg/kg) was also increased after LPS (Group I, 107%; Group II, 267%; p < 0.05). Although HDC treatment completely abolished the bronchomotor response to capsaicin in both Groups III and IV, it enhanced the LPS-induced BHR to histamine (8 μg/kg; Group III, 1.834%; p < 0.05). In conclusion, these results suggest that the role of tachykinins in LPS-induced BHR may be dependent upon the type and the route of administration of the bronchoactive substance studied.n

Effect of a single breath of cigarette smoke on slowly adapting receptors in canine lungs

Inhalation of cigarette smoke has been shown to induce bronchoconstriction which should stimulate slowly adapting pulmonary stretch receptors (PSRs). To test this possibility, the activity of PSRs was recorded from fine afferent filaments of the vagus nerve before and after 120 ml of smoke generated from high-nicotine cigarettes was delivered into the lungs in a single breath in anesthetized, open-chest and artificially ventilated dogs. The base-line activity of PSRs did not change during the first two breaths following smoke delivery. However, PSR activity started to increase by the third breath (post-smoke), concomitant with an increase in tracheal (transpulmonary) pressure. Both the smoke-induced increase in tracheal pressure and the delayed effect on PSRs were prevented by a pretreatment with aerosolized isoproterenol, a bronchodilator, suggesting that the delayed response of PSRs to smoke was elicited by the change in bronchomotor tone. Although smoke evoked a delayed stimulation in the majority (61%) of the PSRs studied, it caused a mild delayed inhibition (24%) or had no effect (15%) in some of the receptors. The variable responses to smoke among PSRs are probably related to the smoke-induced heterogeneous changes of mechanical properties in the lungs and their different anatomic locations.

Are there CO2 sensors in the Lung

Previous investigators have suggested the existence of CO2 sensors in the lung and an important role of these receptors in detecting the increase in venous CO2 flux and in regulating ventilatory response to meet the metabolic demand during exercise (38). However, no direct and definitive evidence has been established in identifying the CO2 receptor in the lung. When the conduction of myelinated fibers in both vagus nerves was selectively blocked by differential cooling (29) or by anodal hyperpolarization (32), the increase in respiratory rate during the hypercapnic challenge persisted, suggesting the involvement of bronchopulmonary C-fibers in the hyperpneic response to CO2 (29, 32). Recent studies have shown that pulmonary C-fibers are consistently activated when pH in the arterial blood (pulmonary venous blood) is lowered to ~7.1 by a bolus intravenous injection of acid solution (e.g., lactic acid, formic acid) (19, 24). Thus, an increase in alveolar CO2 during hypercapnia challenge may lead to a decrease in the pulmonary interstitial pH, which can then activate the pulmonary C-fibers. This study was, therefore, carried out to determine whether pulmonary C-fibers are activated by an increase in the CO2 concentration of alveolar gas. Recent studies have clearly demonstrated that airway mucosal inflammation induces a pronounced increase in the sensitivity of pulmonary C-fiber afferents to various stimuli including hydrogen ion (25, 26). Since both airway inflammation and hypercapnia are common symptoms encountered in patients who suffer from either acute or chronic obstructive pulmonary diseases, the second aim of this study was to determine if the CO2 sensitivity of these afferents is altered during airway inflammation and, if so, whether the action is mediated through the production of hydrogen ions.

Bronchoconstriction and apnea induced by cigarette smoke: Nicotine dose dependence

Recently, evidence was presented to suggest that nicotine absorbed from cigarette smoke was the main cause of smoke-induced bronchoconstriction (Hartiala et al., J Appl Physiol (1985) 59(1): 64–71). However, due to the qualitative nature of the data, it remains unclear whether cigarette-smoke-induced bronchoconstriction is related to the nicotine content of the smoke in a dose-dependent manner. Experiments were performed on intact anesthetized dogs (n = 6). Each animal spontaneously inhaled 300 cc smoke containing low (0.37 mg), medium (1.46 mg), or high (1.80 mg) levels of nicotine. Isometric tension was measured in an isolated tracheal segment not exposed to the smoke as an index of bronchoconstriction. In all dogs there was a nicotine dose-dependent increase in tracheal tension. The time in expiration (Te) in the breath following smoke inhalation was prolonged, the magnitude of prolongation being dependent upon the nicotine content of the smoke. These results suggest that bronchoconstriction and changes in Te induced by cigarette smoke are nicotine-dependent.

A comparison of breathing pattern between transient and steady state hypoxia in awake Dogs

AbstractTo quantitatively examine and compare the breathing patterns during transient and steady state hypoxia, studies were performed repeatedly in five awake, chronic dogs. Transient hypoxia of 30 s was induced with 5–7 consecutive breaths of nitrogen; steady state isocapnic hypoxia with step changes in end-tidal O2 concentration (range 5–8.5%) and maintained for 6–9 min at each level. Linear relationships were found between minute ventilation (n