Hypertonic Aerosols Research Articles

Mucus Transpiration as the Basis for Chronic Cough and Cough Hypersensitivity.

Chronic cough is characterized by a state of cough hypersensitivity. We analyze the process of transpiration, by which water appears to evaporate from laryngeal and tracheal mucus as from the surface of a leaf, as a potential cause of cough hypersensitivity. In this process, osmotic pressure differences form across mucus, pulling water toward the air, and preventing mucus dehydration. Recent research suggests that these osmotic differences grow on encounter with dry and dirty air, amplifying pressure on upper airway epithelia and initiating a cascade of biophysical events that potentially elevate levels of ATP, promote inflammation and acidity, threaten water condensation, and diminish mucus water permeability. Among consequences of this inflammatory cascade is tendency to cough. Studies of isotonic, hypotonic, and hypertonic aerosols targeted to the upper airways give insights to the nature of mucus transpiration and its relationship to a water layer that forms by condensation in the upper airways on exhalation. They also suggest that, while hypertonic NaCl and mannitol may provoke cough and bronchoconstriction, hypertonic salts with permeating anions and non-permeating cations may relieve these same upper respiratory dysfunctions. Understanding of mucus transpiration and its role in cough hypersensitivity can lead to new treatment modalities for chronic cough and other airway dysfunctions promoted by the breathing of dry and dirty air.

Cough-provocation tests with hypertonic aerosols.

Recent advances in cough research suggest a more widespread use of cough-provocation tests to demonstrate the hypersensitivity of the cough reflex arc. Cough-provocation tests with capsaicin or acidic aerosols have been used for decades in scientific studies. Several factors have hindered their use in everyday clinical work: i.e. lack of standardisation, the need for special equipment and the limited clinical importance of the response. Cough-provocation tests with hypertonic aerosols (CPTHAs) involve provocations with hypertonic saline, hypertonic histamine, mannitol and hyperpnoea. They probably act via different mechanisms than capsaicin and acidic aerosols. They are safe and well tolerated and the response is repeatable. CPTHAs can assess not only the sensitivity of the cough reflex arc but also the tendency of the airway smooth muscles to constrict (airway hyper-responsiveness). They can differentiate between subjects with asthma or chronic cough and healthy subjects. The responsiveness to CPTHAs correlates with the cough-related quality of life among asthmatic subjects. Furthermore, the responsiveness to them decreases during treatment of chronic cough. A severe response to CPTHAs may indicate poor long-term prognosis in chronic cough. The mannitol test has been stringently standardised, is easy to administer with simple equipment, and has regulatory approval for the assessment of airway hyper-responsiveness. Manual counting of coughs during a mannitol challenge would allow the measurement of the function of the cough reflex arc as a part of clinical routine.

The Cough Receptor TRPV1 Agonists 15(S)-HETE and LTB4 in the Cough Response to Hypertonicity

Asthmatic patients are hypersensitive to the cough-provoking effect of hypertonic aerosols. 15- hydroxyeicosatetraenoic acid (15(S)-HETE) and leukotriene (LT) B4 are asthma-related mediators which can be released upon hypertonic stimuli, and both are potent agonists of the transient receptor potential vanilloid subfamily member 1 (TRPV1), a major cough receptor. Therefore, they are potential mediators for hypertonicity-provoked cough. Twenty-six asthmatic and ten healthy subjects underwent a hypertonic saline cough provocation test. Exhaled breath condensate was collected before and after the test, and the concentrations of 15(S)-HETE and LTB4 were analysed. Neither the baseline concentrations of these mediators nor the saline test-induced changes in them were associated with cough responsiveness to hypertonicity. High baseline 15(S)-HETE was associated with aspirin hypersensitivity and high LTB4 with male sex and large variability in ambulatory peak flow measurements. The TRPV1 agonists 15(S)-HETE and LTB4 seem not to be involved in the cough response to hypertonicity in asthmatic patients.

Cough response to isocapnic hyperpnoea of dry air and hypertonic saline are interrelated

BackgroundMechanisms behind asthmatic cough are largely unknown. It is known that hyperosmolar challenges provoke cough in asthmatic but not in the healthy subjects. It has been postulated that isocapnic hyperpnea of dry air (IHDA) and hypertonic aerosols act via similar mechanisms in asthma to cause bronchoconstriction. We investigated whether there is an association between cough response induced by IHDA and hypertonic saline (HS) challenges.MethodsThirty-six asthmatic and 14 healthy subjects inhaled HS solutions with increasing osmolalities administered via ultrasonic nebuliser until 15 cumulative coughs were recorded. The IHDA consisted of three three-minute ventilation steps: 30%, 60% and 100% of maximal voluntary ventilation with an end-point of 30 cumulative coughs. The challenges were performed on separate days at least 48 hours between them and within one week. Inhaled salbutamol (400 mcg) was administered before the challenges to prevent bronchoconstriction. The cough response was expressed as the cough-to-dose ratio (CDR) which is the total number of coughs divided by the maximal osmolality inhaled or the maximal ventilation achieved.ResultsCough response to IHDA correlated with the HS challenge (Rs = 0.59, p < 0.001). Cough response to IHDA was at its strongest during the first minute after the challenge. IHDA induced more cough among asthmatic than healthy subjects CDR being (mean ± SD) 0.464 ± 0.514 and 0.011 ± 0.024 coughs/MVV%, p < 0.001, respectively. Salbutamol effectively prevented bronchoconstriction to both challenges.ConclusionsAsthmatic patients are hypersensitive to the cough-provoking effect of hyperpnoea, as they are to hypertonicity. Cough response induced by IHDA and HS correlated well suggesting similar mechanisms behind the responses.

Hypertonic saline cough provocation test with salbutamol pre‐treatment: evidence for sensorineural dysfunction in asthma

Cough is one of the most common symptoms of asthma. However, studies using capsaicin, citric acid, or tartaric acid to document cough threshold have repeatedly failed to show statistically significant differences between asthmatic and healthy subjects. The studies using hypertonic aerosols as the cough stimulant have suggested an enhanced sensitivity in asthmatic subjects but the induced bronchoconstriction has made the interpretation of the results difficult. To determine the cough sensitivity to hypertonicity in healthy subjects, patients with chronic cough, and patients with asthma in a setting where the induction of bronchoconstriction is prevented. Nineteen healthy subjects, 21 non-asthmatic patients with chronic cough, and 26 asthmatic patients with chronic cough underwent an incremental hypertonic saline challenge including a pre-treatment with 0.4 mg of salbutamol. Spirometry was performed before the challenge, after salbutamol, and after the challenge. The patients with cough also underwent skin testing, histamine challenge, exhaled nitric oxide measurement, ambulatory peak flow monitoring, kept cough diary, and filled in the Leicester Cough Questionnaire. Eighteen patients repeated the saline challenge. The challenge did not induce bronchoconstriction in any group. The osmolality to provoke 15 cumulative coughs was significantly smaller in the asthmatic patients than in the healthy subjects (P<0.001) and in the cough patients without asthma (P=0.04). According to multivariate analysis among all the 47 patients with cough, female sex (P<0.001) and large spontaneous peak flow variation in the ambulatory recording (P=0.001) were associated with high sensitivity to saline. The saline challenge response was well repeatable (intraclass correlation coefficient 0.90). The findings of the present study are not affected by induced bronchoconstriction. Asthma or, more specifically, spontaneous, reversible airway obstruction is associated with an enhanced sensitivity to the cough-provoking effect of hypertonic saline. This suggests a pathological function of the sensorineural apparatus in this disorder.

Simultaneous versus video counting of coughs in hypertonic cough challenges

BackgroundThe coughs occurring during cough provocation tests are usually counted at the same time when the test is being conducted, i.e., simultaneously. It is unknown whether cough counting from video recording might increase the accuracy of the cough counting. During recent years, cough challenges with hypertonic aerosols have been introduced. They often provoke very frequent coughing which may complicate the simultaneous cough counting.ObjectiveTo assess whether cough counting from video recording is superior to simultaneous cough counting in two different hypertonic cough challenges.MethodsThe analysis includes 82 hypertonic saline challenges performed on 66 subjects, providing 1984 observation minutes with both simultaneous and video cough counting. The cough sensitivity was expressed as the osmolality to provoke 15 cumulative coughs (CUM15). The analysis also includes 136 hypertonic histamine challenges performed on 114 subjects providing 5373 observation minutes with both simultaneous and video counting. The cough sensitivity was expressed as the cumulative number of coughs divided by the final histamine concentration administered (CCR). This challenge involved several additional measurements to cough counting.ResultsFor the saline challenge, the mean difference between the counting types was 0.0 coughs per minute with 95% limits of agreement of -1.2 to 1.2 coughs per minute. For the hypertonic histamine challenge the respective figures were 0.3 (-1.9 to 2.5) coughs per minute. At high coughing frequency the video counts tended to outnumber the simultaneous counts. The counting type had no effect on the hypertonic saline CUM15 and only a marginal effect on its repeatability. On the contrary, video counting resulted to significantly higher hypertonic histamine CCR values than simultaneous counting (p < 0.001).ConclusionThe agreement between simultaneous and video counting of coughs is generally good. However, as the coughing frequency increases, simultaneous counting may miss coughs, especially if the nurse has to share his/her attention to several activities simultaneously. Video recording is advisable for the hypertonic histamine challenge but unnecessary for the hypertonic saline challenge. To ensure reliable simultaneous cough counting, cough provocation tests should be performed in a quiet environment, applying as little unnecessary equipment and measurements as possible.

Hypertonicity of the challenge solution may increase the diagnostic accuracy of histamine challenge

There is significant overlap in the responsiveness to direct airway challenges, such as the histamine challenge, between asthmatic and non-asthmatic subjects, which decreases their accuracy in the diagnosis of asthma. To minimise this overlap, a new test, hypertonic histamine challenge, was developed. Fifteen healthy subjects, 16 subjects with steroid-naive asthma, and 16 asthmatic subjects undergoing inhaled corticosteroid treatment underwent inhalation challenges with hypertonic saline, isotonic histamine, and hypertonic histamine, using an ultrasonic nebuliser and 2-min tidal breathing method. The increase in histamine solution tonicity decreased the histamine PC20 values only in the steroid-naive asthmatic subjects (1.1 (0.5-2.7) vs. 0.5 (0.2-1.2) mg/ml, P = 0.047). Using 1mg/ml as the cut-off value, the sensitivity, specificity, and accuracy of the hypertonic histamine challenge to detect steroid-naive asthma was 81%, 100%, and 90%. The respective values for the isotonic histamine challenge were 56%, 100%, and 77%. Furthermore, there was a statistically significant difference in the hypertonic histamine PC20 between steroid-naive and steroid-treated asthmatic subjects, which could not be detected in the isotonic histamine PC20. The hypertonic histamine PC20 was highly repeatable, with a single determination 95% range of +/-1.35 doubling concentrations. The hypertonic histamine challenge was safe but provoked more cough and throat irritation than the other two challenges. In conclusion, compared with a conventional, isotonic histamine challenge, hypertonic histamine challenge may be more accurate in the diagnosis of asthma and also, more capable to detect the effects of inhaled corticosteroid treatment.

Methods for "indirect" challenge tests including exercise, eucapnic voluntary hyperpnea, and hypertonic aerosols.

Bronchial provocation tests that use stimuli that act indirectly to cause airway narrowing have a high specificity for identifying people with active asthma who have the potential to respond to treatment with antiinflammatory drugs. The first test to be developed was exercise and it was used to assess the efficacy of drugs such as sodium cromoglycate. Eucapnic voluntary hyperpnea was developed later, as a surrogate test for exercise. Hypertonic aerosols were introduced to mimic the dehydrating effects of evaporative water loss that occurs during hyperpnea. A wet aerosol of 4.5% saline or a dry powder formulation of mannitol is used. At present the indirect challenge tests are becoming increasingly recognised as appropriate for monitoring treatment with inhaled steroids. Indirect tests identify those with potential for exercise-induced bronchoconstriction, an important problem for some occupations, such as the defence forces, fire fighters and the police force and for some athletic activities. The advantage in using an indirect challenges, over a direct challenge with a single pharmacological agonist, is that a positive response indicates that inflammatory cells and their mediators (prostaglandins, leukotrienes and histamine) are present in the airways in sufficient numbers and concentration to indicate that asthma is active at the time of testing. The corollary to this is that a negative test in a known asthmatic indicates good control or mild disease. Another advantage is that healthy subjects do not have significant airway narrowing to indirect challenge tests. The protocols used for challenge with indirectly acting stimuli are presented in detail.

Furosemide Protective Effect Against Airway Obstruction

Furosemide (frusemide) is mainly employed as a powerful diuretic that inhibits Na and K reabsorption in renal tubules. However other valuable pharmacological effects have been discovered that include a protective action from bronchospasm. The effects of furosemide on airways have been recognized to be more and more complex as far as an increasing amount of studies have been produced on this subject. The drug shows no acute bronchodilator effect, but prevents or attenuates bronchospasm caused by many factors, such as hyperpnea, drugs (metabisulphite, bradykinin, AMP), physical agents (hypo- and hypertonic aerosols), and allergen challenge in asthmatic patients. Furosemide is also active on upper airway mucosa, on which the drug decreases nasal resistance in patients affected by non-allergic rhinitis and exhibits a protective effect on nasal mucosa reactivity to the specific allergen in atopic subjects. The mechanism of action of furosemide on airways has not yet been fully cleared and interference with electrolyte epithelial transport, prostaglandins, inflammatory cell activity, vascular and neural regulation has been hypothesized. The interest for clinical application of inhaled furosemide has grown in last years. Some Authors have investigated whether the drug is effective in acute asthma attacks or not. Furosemide is one of the drugs currently used to prevent exercise-induced asthma. More recently, inhaled furosemide has been observed to decrease the sensation of experimentally-induced dyspnea. Apart from possible therapeutic application, studies about furosemide effects on respiratory mucosa can contribute to better understand the physiology of upper and lower airways.

Aerosol deposition and clearance measurement: a novel technique using dynamic SPET.

Planar gamma camera scintigraphy is a well-established technique for characterising the deposition and clearance of radiolabelled aerosols. While single-photon emission tomography (SPET) can offer superior assessment of radioaerosol deposition and better differentiation between peripheral and central deposition, the long acquisition times of single-headed SPET have largely prevented its use for measuring clearance or deposition of fast-clearing radioaerosols. This study investigated the feasibility of fast dynamic SPET imaging (1 min/frame) using a three-headed gamma camera to assess the regional and total deposition and clearance of different radioaerosols over a period of 26 min. Six subjects inhaled nebulised technetium-99m diethylene triamine penta-acetic acid radiolabelled aerosols with small and large droplet sizes [mass median aerodynamic diameter (MMAD) 3.2 +/- 0.2 and 6.5 +/- 0.2 microm, span 1.8 and 1.7, respectively] and in normal (0.9%) or hypertonic (7%) saline with controlled breathing on four separate occasions. The penetration indices (PIs) calculated from the SPET data for normal saline were 0.50 +/- 0.04 and 0.36 +/- 0.02 for the small and large droplet sizes, respectively. Consistent with the hygroscopic growth of the hypertonic aerosols, the PIs for hypertonic saline were lower, at 0.43 +/- 0.02 and 0.34 +/- 0.02 for the small and large droplet sizes, respectively. PIs calculated from the planar data showed similar trends, but failed to detect the significant difference seen with SPET between small normal and small hypertonic saline radioaerosols. In conclusion, the feasibility of using fast dynamic SPET for imaging radioaerosol deposition and associated radiolabel clearance in the lung has been successfully demonstrated. The fast SPET was able to reveal important differences in aerosol deposition that were not detected by planar imaging.

Hypertonic saline alters ion transport across the human airway epithelium.

Aerosolized hypertonic saline is currently being investigated as a new agent for the treatment of impaired mucociliary clearance which occurs in many respiratory diseases. Mannitol aerosols, in particular dry powder inhalers, have been proposed as an alternative treatment to saline, offering the same osmotic load with other benefits. However, the effects of these hypertonic aerosols on airway epithelial ion transport processes have not been tested in human subjects in vivo. This report examines the effect of these solutions on airway ion transport using the nasal potential difference (PD) technique. Seven healthy nonsmoking adult volunteers were studied. On different days, a dose-response curve was constructed for the saline added to Krebs N-[2-hydroxyethyl] piperazine-N'-[2-ethanesulphonic acid] (HEPES) diluent. The reversibility of this saline effect was measured, and the response to additional saline (500 mM) and mannitol (1 M) compared. Hypertonic saline decreased nasal PD in a dose-related manner, with mean (SEM) decreases in PD (less negative) of 6.6 (1.5), 7.6 (1.6), 10.0 (2.0), 13.1 (2.9) and 14.8 (3.2) mV (n =4) for addition of 150 mM, 250 mM, 500 mM, 1,200 mM and 2,000 mM NaCl to the Krebs HEPES diluent, respectively. The effect of hypertonic saline was fully reversible with washout for 3 min (presaline 15.9 (0.5) mV, postwashout 15.8 (1.1) mV, (n=4)). The hypertonic saline response was rapid in onset, sustained for at least 4 min, and decreased PD from 13.7 (1.7) mV to 5.1 (1.3) mV (n = 7, p < 0.001). In contrast, addition of mannitol to the perfusate did not significantly alter nasal PD, with a nonsignificant trend towards an increase (more negative) in the PD, (premannitol 13.9 (1.6) mV, postmannitol 15.3 (2.0) mV, n=7). As the osmotic stimulus of the 1 M mannitol is similar to that of the 500 mM sodium chloride, the divergent nasal potential difference responses suggest that the response to the saline was specific to the sodium chloride itself and not the simultaneous change in osmolarity. This demonstrates that the human airway epithelium in vivo can respond to topical hypertonic saline independent of the altered osmolarity.

Leukotriene bronchoconstriction induced by allergen and exercise.

Airway hyperresponsiveness to a wide variety of bronchoconstrictor agonists is a characteristic finding in patients with current, symptomatic asthma. The agonists include inhaled pharmacological agonists, such as histamine (1) acting on airway H 1 receptors, the cholinergic agonist methacholine (2) acting on airway M 3 receptors, the cysteinyl-leukotrienes (3) acting on airway Cys-LT 1 receptors, and the stimulatory prostaglandins (PG)D 2 (4) and PGF 2a (5) likely acting on airway TP receptors. These agonists are considered to be direct stimuli causing bronchoconstriction in individuals with asthma, because their action is directly on specific airway receptors. Airway hyperresponsiveness is also present to a number of physical stimuli such as exercise (6), isocapnic hyperventilation of cold, dry air (7), and hypo- and hypertonic aerosols (8). The bronchoconstriction that develops after exposure to the physical stimuli is indirect, because it occurs through the release of constrictor mediators from cells within the airways, which subsequently act on their specific receptors to mediate bronchoconstriction. Another important indirect stimulus for bronchoconstriction in many individuals with asthma is environmental allergens. The responses after inhaled allergens are often quite different from those after the other indirect stimuli, in that the acute bronchoconstrictor responses are often followed by the development of late-phase bronchoconstrictor responses (9), airway inflammation (10), and an increase in airway hyperresponsiveness (11). The focus of this article is to evaluate the evidence that the cysteinyl-leukotrienes (LT) C 4 , D 4 , and E 4 are released in asthmatic airways and are the main cause of bronchoconstriction after exposure to exercise and environmental allergens, and of the changes in airway hyperresponsiveness after the inhalation of allergen.

Regional deposition of nebulized hypodense nonisotonic solutions in the human respiratory tract.

Deposition of nonisotonic therapeutic and diagnosis aerosols can cause changes in airway fluid composition and bronchoconstriction in sensitive subjects. "Hypodense" aerosols containing a relatively low concentration of droplets in the carrier air were used in the studies of regional deposition of radiolabelled nebulized solutions of hypo- and hypertonic saline, in order to investigate whether the number of droplets per volume of carrier can affect deposition. Solutions with and without 0.5% nedocromil sodium were nebulized in order to examine the effects of a potential modifier of the rates of heat and mass transfer. The deposition was quantified using penetration index (PI) calculated from images obtained by single photon emission computerized tomography (SPECT) in 11 healthy volunteers per study. There was an increase in the penetration index (10.9%, for the saline only; 15.5%, for the nedocromil study) of the hypotonic compared to the hypertonic aerosol, although the initial size distribution of both types of aerosols was very similar (mass median aerodynamic diameter (MMAD) 3.7 and 3.8 microns; geometric standard deviation (GSD) 1.8 and 1.5 for the hypo- and hypertonic aerosols, respectively). The present results confirm the effects of tonicity on deposition of aerosols found in a parallel study reported in this issue of the Journal. They also give support to the theory that, in addition to the concentration of the nebulized solutions, the number of droplets per volume of the carrier air is a factor affecting deposition of aqueous aerosols. The presence of 0.5% nedocromil sodium in the solutions did not appear to interfere with the processes of heat and water transfer in the airways.

Regional deposition of saline aerosols of different tonicities in normal and asthmatic subjects

Nonisotonic aerosols are frequently used in the diagnosis and therapy of lung disease. The purpose of this work was to study the difference in the pattern of deposition of aerosols containing aqueous solutions of different tonicities. 99mTechnetium-diethyltriaminepentaacetic acid (99mTc-DTPA)-labelled saline aerosols, with mass median aerodynamic diameter 3.7-3.8 microns and geometric standard deviation 1.4, were inhaled under reproducible breathing conditions on two occasions. Hypotonic and hypertonic solutions were used in 11 normals subjects, isotonic and hypertonic solutions in 9 asthmatics. The regional deposition was quantified by a penetration index measured with the help of a tomographic technique. There was a small but significant increase (6.7%) in the penetration index of the hypotonic as compared to the hypertonic aerosols in the normal subjects. The region that was markedly affected was the trachea. The differences in the penetration of the isotonic and hypertonic aerosols in the asthmatics appeared to be strongly dependent on the state of the airways at the time of the study. These findings can be interpreted in terms of effects of growth or shrinkage of nonisotonic aerosols, as well as of airway narrowing, on regional deposition of aerosols. Tonicity of aerosols appears to affect their deposition both through physical and physiological mechanisms. This should be taken into account when interpreting the effects of inhaled aqueous solutions of various tonicities in patients in vivo.

Dry air- and hypertonic aerosol-induced bronchoconstriction and cellular responses in the canine lung periphery.

Dry air and hypertonic saline both create an osmotic stress to the airways, whilst dry air alone induces transient cooling of the airway mucosa. It is unclear whether these two stimuli lead to bronchoconstriction via the same mechanisms. We compared airflow- and hypertonic aerosol-induced bronchoconstriction (AIB and HIB, respectively) in the canine lung periphery, using a wedged bronchoscope to measure collateral system resistance (Rcs). Bronchoalveolar lavage (BAL) was used to examine changes in cells and mediators during AIB and HIB. We found that: 1) peripheral airways are not refractory to either dry air or hypertonic aerosols, and do not exhibit cross-refractoriness to these stimuli; 2) differences in strength of stimulus can alter the magnitude but not the time course of HIB; 3) within an individual, AIB and HIB are significantly correlated; 4) epithelial cells recovered in BAL fluid (BALF) are significantly elevated after AIB, and are similarly increased after HIB; 5) when compared to control, mediators recovered in BALF are significantly elevated after AIB but not HIB; 6) HIB is not altered by cyclo-oxygenase inhibition; and 7) lavage with hypertonic fluid does not affect the number of epithelial cells recovered, although the concentrations of some mediators are increased. We speculate that differences in cell and mediator profiles reflect differences in the time course of AIB and HIB that result from the modulation of temperature sensitive pathways that occurs during dry air, but not during hypertonic aerosol challenge.

Hyperosmotic-induced bronchoconstriction in the canine lung periphery.

Hypertonic aerosol- and dry airflow-induced bronchoconstriction were examined in the canine lung periphery by the use of a wedged bronchoscope technique. Collateral resistance was measured in anesthetized dogs before and after exposure to isotonic and hypertonic aerosols and dry airflow. Hypertonic aerosols produced significantly greater responses than isotonic aerosols, and resistance increased in an exposure-dependent manner. Atropine attenuated responses to these challenges, indicating that aerosol-induced peripheral lung constriction was, in part, muscarinic in origin. Paired hypertonic- and dry airflow-induced constriction exhibited marked differences in magnitude and time course: responses to hypertonic aerosol peaked immediately; dry air-induced responses rose slowly to a maximum 5-min postchallenge. These differences may reflect differences in stimulus strength or differences in the regulatory pathways activated by each challenge. Despite this, a significant correlation exists between aerosol- and dry air-induced responses in the canine lung periphery and suggests that changes in airway fluid osmolality have an important role in the initiation of airflow-induced bronchoconstriction.

Airway Hyperresponsiveness: Mechanisms in Experimental Models

Airway hyperresponsiveness can be defined as exaggerated airway narrowing in response to a wide variety of stimuli. 1 Boushey HA Holtzman M Sheller JR Nadel JA Bronchial hyperractivity: state of the art.. Am Rev Respir Dis. 1980; 121: 389-413 PubMed Google Scholar Some of these stimuli are listed in Table 1. These include endogenous mediators such as acetylcholine, histamine, leukotrienes, prostaglandins and bradykinin, and also exogenous stimuli, many of which are involved in producing clinical exacerbations in patients with asthma. Physicians are interested in airway hyperresponsiveness because this phenomenon helps to explain many of the clinical manifestations of asthma. Figure 1 shows a wiring diagram of airway smooth muscle. This diagram points out that stimuli deposited in the airway lumen can cause contraction of this muscle by a number of different pathways, probably the least important of which is direct effects on the muscle. The muscle sits at some distance from the airway lumen, and before contacting the muscle, any stimulus put into the lumen comes in contact with several other cells. These include mast cells and eosinophils that are present in the lumen, in the airway epithelium and in the vicinity of nerves and muscle. They also include macrophages, the most populous free cell in the airway lumen. By far the largest number of cells in the airway lumen are airway epithelial cells which themselves have the potential for releasing mediators, when stimulated, that can effect the behavior of airway smooth muscle. There also is the potential for recruitment of new cells and mediators from the blood vessels. For a long time it was thought that the only significant neural pathway for contraction of airway smooth muscle was the reflex that had its efferent limb in the parasympathetic fibers of the vagus nerve. It is clear that another important pathway involves release of mediators from afferent nerves themselves. Finally, airway smooth muscle cells can be contracted by direct stimulation of receptors present on their surface. Table 1Stimuli that Cause Exaggerated Airway Narrowing in Patients with Airway Hyperresponsiveness Endogenous Mediators Exogenous Stimuli Acetylcholine Dry Air (Exercise) Histamine Sulfur Dioxide Leukotrienes (C4, D4, E4) Acid Aerosols Prostaglandins (D2, F2) Hypotonic and Hypertonic Aerosols Bradykinin Open table in a new tab

Exercise-induced asthma and late phase reactions

The hypothesis that respiratory heat loss was an initiating event in EIA was first proposed by CHEN and HoRTON [1) and later supported by McFADDEN et al. [2], who suggested that the severity of EIA is dependent upon the rapidity and magnitude of airway rewarming after exercise. It has been suggested that the airway cooling which results from hyperpnoea during exercise is followed by a rapid re-supply of heat to the airway mucosa when exercise ceases. This may cause an exaggerated rebound hyperaemia and airway oedema, thereby causing asthma. However, HAHN et al. [3] exercised asthmatic subjects under varying conditions of temperature and humidity and demonstrated that the severity of EIA did not differ even when the inspired air temperature varied by 26·c as long as the humidity was kept constant. This suggests that the response to exercise depends on the degree of respiratory water loss rather than on cooling of the airways. ANDERSON [4] has suggested that the rate of respiratory water loss caused by the hyperpnoea of exertion induces a transient hyperosmolarity of the airway epithelium and that this is the stimulus for EIA. This hypothesis is supported by several lines of evidence. Inhalation of hypertonic aerosols will induce bronchoconstriction in asthmatic subjects which is attenuated by the prior administration of sodium cromoglycate [5] and specific histamine H 1 antagonists [6] in a similar manner to that seen for inhibition of EIA [7, 8]. In the previous issue of this Journal, BELCHER and eo-workers [9] have demonstrated a correlation between airways responsiveness to inhaled hypertonic saline aerosol and to exercise in a group of ten asthmatic subjects. Asthmatic subjects demonstrate cross-refractoriness between hypertonic saline-induced bronchoconstriction and EIA [10], sug-

Use of Superheated Saline Aerosols as a Diagnostic Measure in Pulmonary Tuberculosis: A Preliminary Report

SUMMARY A study of the value of inhaling heated hypertonic aerosols in the diagnosis of pulmonary tuberculosis was carried out in 62 patients. Comparative observations were made on 24-hour spontaneous sputum. A total of 163 paired sputum specimens were tested. The heated aerosol technique resulted in cultures positive for tubercule bacilli in 15 instances in which spontaneous sputum, collected during the same 36-hour period was negative, or in which no sputum was expectorated. An analysis of the experimental data indicates that positive sputum would have been missed in only one of 163 (0.6 per cent) instances in which the heated aerosol technique was employed. With the use of the 24-hour sputum for culture, positive sputum would have been missed in 15 instances (9.2 per cent).