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PubMed1985

Pulmonary responsiveness to methacholine and disodium hexachloroplatinate (Na2PtCl6) aerosols in cynomolgus monkeys (Macaca fascicularis).

Hyperreactivity of the airways is a common finding in human asthma, and responsiveness to inhaled methacholine aerosols is routinely used for assessing airway irritability. Workers in precious metal refineries demonstrate pulmonary signs suggestive of asthma, presumably related to exposure to soluble platinum salts. In these workers, evidence of physiologic dysfunction precedes immunologic evidence (skin test) of disease, suggesting an initial pharmacologic mechanism. With a primate animal model for the screening of occupational asthmogens, 24 Cynomolgus monkeys were evaluated for their comparative pulmonary responsiveness to inhaled aerosols of methacholine and sodium hexachloroplatinate (Na2PtCl6). Average pulmonary flow resistance (RL), dynamic compliance (CLdyn), maximum expiratory flow volume (MEFV), and respiratory frequency changes were evaluated after bronchoprovocation challenge. Both agents produced dose-dependent increases in RL, dose-dependent decreases in CLdyn and MEFV, and no effect on respiratory rates. Analyses of the correlation between concentration effects of the two agents showed no association between cholinergic airway irritability status and Na2PtCl6-induced bronchoconstriction. Na2PtCl6 bronchoprovocation produced significantly greater flow impairment at lower lung volumes when compared to methacholine concentrations with equipotent effects on RL and CLdyn. These compounds have differential effects on peripheral airway function. The lack of respiratory rate change seen on bronchoprovocation with these compounds, in comparison to the rapid shallow breathing in anesthetized monkeys following irritant or histamine challenge, indicates that neither aerosol stimulated pulmonary irritant receptors.

Airway Resistance↗
PubMed1990

Beta-adrenergic responses and airway reactivity in healthy adults.

Healthy adults aged 18-90 years were tested for lymphocyte and granulocyte cyclic AMP responses to isoproterenol and prostaglandin E1 (PGE1), beta-adrenergic receptor density and antagonist binding properties, and for airway reactivity to methacholine. Our hypothesis was that reduced beta-adrenergic responses occur with aging and are associated with increased airway reactivity. This hypothesis was not supported by the data. Lymphocyte stimulation ratios (cyclic AMP level with stimulation/baseline cyclic AMP level) at higher concentrations of isoproterenol and PGE1 increased significantly with age. There were no significant age trends for any of the other variables. None of the beta-adrenergic responses or receptor properties correlated with airway reactivity to methacholine. beta-Adrenergic responses in lymphocytes and granulocytes from the same subject were weakly correlated at high concentrations. Prior studies which suggest that reduced beta-adrenergic responses and increased airway reactivity are concomitants of normal aging may differ from the present study in subject selection. In healthy older subjects, there appears to be no reduction in leukocyte beta-adrenergic responses or receptor properties and no change in airway reactivity.

Adolescent↗
PubMed1983

Effects of leukotrienes C4 and D4 on glycoprotein and lysozyme secretion by human bronchial mucosa.

The effects of leukotrienes C4 (LTC4) and D4 (LTD4) on the secretion by human bronchial mucosa of [14C]glucosamine-labeled, trichloro-acetic acid/phosphotungstic acid-precipitable glycoprotein and lysozyme were evaluated in vitro. LTC4 and LTD4, in the concentration range of 0.16 to 1600 nM, induced a dose-related increase in the release of radiolabeled glycoprotein, but not of lysozyme. This secretagogue effect was selective for high molecular weight glycoproteins of about 2-5 x 10(6) daltons, and the median effective concentrations (EC50) of LTC4 of 9.4 x 10(-9) M and of LTD4 of 2.44 x 10(-8) M, indicate that these leukotrienes are approximately 100-fold more potent than the cholinergic agonist methacholine. Incubation of [14C]glucosamine-labeled bronchial mucosal explants with LTC4 or LTD4 for six sequential 15-min periods revealed a rapid, progressive decrement in glycoprotein release, compatible with stimulatory action on secretion rather than augmentation of the rate of glycoprotein synthesis. This interpretation is also consistent with the finding that the specific activity (ratio of bound radiolabel: protein content) of the macromolecular glycoprotein secreted by the explants is not changed with stimulation of release by the leukotrienes. Based upon the activity of synthetic leukotriene analogs, the specific C-6 chirality of the sulfidopeptide of LTD4, the presence of a hydroxyl at C-5 and the presence of eicosanoid carbons 9-20 were of no importance for secretagogue activity. These findings contrast with the stereochemical requirements for the spasmogenic response to sulfidopeptide leukotrienes and suggest that leukotriene-induced secretion is not likely to be mediated via a specific receptor.

Bronchi↗
PubMed1983

The effect of synthetic leukotrienes on tracheal microvascular permeability.

The effect of synthetic leukotrienes (LT) C4, D4 and E4 on the permeability of the airway microvasculature to plasma albumin was quantitatively evaluated using an in situ guinea pig tracheal model. Vascular permeability was measured as extravascular albumin content by employing 125I-bovine serum albumin and, in order to correct for blood volume, 51Cr-erythrocytes were used. Intratracheal injection of synthetic LTC4, LTD4 and LTE4 (0.1-1000 ng) produced dose-dependent increases in tracheal extravascular albumin content. The leukotrienes were approximately 100-1000 fold more potent than histamine, although histamine did produce a greater maximal increase in extravascular albumin than the leukotrienes. Methacholine did not increase extravascular albumin content. The microvascular permeability effect of LTD4 was antagonized by FPL 55712 but not by mepyramine; conversely, the effect of histamine was antagonized by mepyramine and not by FPL 55712. Additionally, indomethacin did not alter the LTD4-induced increases in tracheal vascular permeability. These results suggest that the effect of LTD4 on tracheal microvascular permeability is directly mediated and is not the indirect result of cholinergic stimulation, histamine release or de novo synthesis of cyclooxygenase products.

Animals↗
PubMed1986

Ascorbic acid promotes prostanoid release in human lung parenchyma.

Ascorbic acid reduces airway reactivity to inhaled bronchoconstrictor agents in man and guinea pigs. The precise mechanism(s) responsible for this effect are unknown, but in both species an acute indomethacin treatment reverses the action of the ascorbic acid. To determine if ascorbic acid promotes prostanoid synthesis and/or inhibits degradation, human lung parenchymal slices (100-200 mg) were incubated for 60 minutes in oxygenated Tyrode's solution alone or with sodium ascorbate (0.001 M-1 M) and/or methacholine (1 microM-100 microM) and/or indomethacin (0.17 microM-17 microM). Aliquots of the incubation medium were assayed by radioimmunoassay for PGE2, PGF2 alpha, thromboxane B2 and 6-keto-PGF1 alpha. Ascorbic acid increased the accumulation of all four prostanoids in the incubation medium, especially thromboxane B2 and 6-keto-PGF1 alpha. This stimulatory effect of ascorbic acid was concentration-dependent and was inhibited by indomethacin. We conclude that ascorbic acid can alter prostanoid generation by human lung tissue and this effect may, in part, explain its antibronchoconstrictor activity in man.

Ascorbic Acid↗
PubMed1988

Is the epithelium-derived inhibitory factor in guinea-pig trachea a prostanoid?

To examine further the possible prostanoid involvement in the influence of the epithelium on guinea-pig tracheal smooth muscle responsiveness, we have analyzed the effects of LTD4, methacholine and histamine on the level of airway smooth muscle tone and on the amounts of PGE2, PGF2 alpha and PGI2 (determined by radioimmunoassay) in the presence and absence of the epithelium. Removal of the epithelium increased the sensitivity of guinea-pig trachea to the contractile effects of LTD4, methacholine and histamine. LTD4 (3-100 nM), methacholine (0.1-10 microM) or histamine (0.3-30 microM) did not increase prostanoid release above control values in either the presence or absence of the epithelium. The unstimulated release of PGE2 and PGF2 alpha, but not PGI2, was decreased in tissues lacking epithelium. Indomethacin (1 microM) reduced the baseline tone to a smaller extent in the absence of epithelium. In the presence but not the absence of the epithelium, indomethacin increased the sensitivity of preparations to the contractile effect of methacholine. The results support the postulate of an epithelium-derived inhibitory factor modulating guinea-pig tracheal smooth muscle responsiveness. The identity of this factor is not known but is not PGI2 and is unlikely to be PGF2 alpha or PGE2. However, the possibility remains that the basal release of PGE2 and/or PGF2 alpha derived from the epithelium may markedly affect the responsiveness of guinea-pig tracheal smooth muscle. Furthermore, the epithelium is a significant source of PGE2 and PGF2 alpha which may be involved in the maintenance of baseline tone.

6-Ketoprostaglandin F1 alpha↗
PubMed1988

The modulatory effects of leukotrienes C4 and D4 on methacholine- and substance P-induced salivary secretion in rats.

Although certain prostaglandins have been found to be inhibitory to nerve-evoked salivary flow, little is known of the effects the leukotrienes on salivary secretion. It was the purpose of this investigation to examine the effects of leukotrienes C4 (LTC4) and D4 (LTD4) on salivary secretion in the rat, using methacholine or substance P to induce basal secretion, and to test whether or not the observed effects of these eicosanoids were receptor-mediated by using the leukotriene receptor blocker FPL-55712. Methacholine (3 x 10(-4) M), or substance P (1 x 10(-6) M) was infused intra-arterially to stimulate secretion and saliva was collected separately from the parotid gland and the submandibular gland of anesthetized rats. LTC4 and LTD4 (each at 1 x 10(-9) to 1 x 10(-6) M) were found to reduce methacholine- and substance P-induced salivary flow in a dose-related manner. Salivary protein concentration and amylase activity were not significantly altered by the leukotrienes; however, arginine-esterase activity, stimulated by substance P, was increased by both leukotrienes. FPL-55712 (1 x 10(-8) M) was shown to reduce the inhibitory effects of LTC4 and LTD4, suggesting the involvement of leukotriene receptors for these agents in their action.

Amylases↗
PubMed1988

Inhibition of the 5-lipoxygenase pathway with piriprost (U-60,257) protects normal primates from ozone-induced methacholine hyperresponsive small airways.

Weekly exposure to ozone in seven normal Rhesus monkeys led to induction of methacholine hypersensitive airways (RL increases 242 +/- 60% and Cdyn decreases 68 +/- 13% of baseline methacholine responses). It took 19 weeks to establish this hyperresponse that persisted for greater than 15 weeks once ozone was stopped. A second exposure led to similar response peaks in 6 weeks. At the peak of the second response, weekly 1% piriprost exposure before ozone led to a return to baseline that was not different between placebo and piriprost treated animals (9.4 +/- 1.0 and 4.3 +/- 2.9 weeks, placebo and treated, respectively P = 0.09 NS). A statistical difference in the mecholyl response in placebo and piriprost treated groups while on ozone was shown only in the Cdyn measurement (Cdyn% change 68 +/- 13 vs 24 +/- 14, placebo and piriprost, respectively P = 0.03). Off ozone (or return to baseline), a statistical difference could be detected both in RL and Cdyn (RL% changed 151 +/- 41 vs 31.1 +/- 49, P = 0.03, and for Cdyn 62.7 +/- 8 vs 9 +/- 10, P = 0.0006, placebo and piriprost, respectively). We conclude tha the primate provides a chronic model of airways reactivity in which the role of lipoxygenase is implicated because of the beneficial role of piriprost, and further that the ozone lesion is primarily in the smaller airways (possibly and alveolitis).

Airway Resistance↗
PubMed1981

Exercise-induced anaphylaxis as a manifestation of cholinergic urticaria.

Two patients presented with a history of exercise-induced hypotension associated with severe pruritus and either generalized urticaria or facial angioedema. Each patient was exercised under controlled conditions with use of bicycle ergometer exerciser (900 KPM/min) for 20 to 30 min at 23 degrees C. Each patients complained of generalized pruritus and then erupted in lesions typical of cholinergic urticaria. In one patient the lesions became confluent about the face and were followed by eyelid edema, lip swelling, and transient hypotension. Plasma histamine levels were elevated in each patient and reached a maximal level between 20 and 25 min. Neither patient had a change in forced expiratory volume in one second during the episode and detailed pulmonary function testing in one patient revealed no change in airway resistance, specific conductance, forced expiratory vital capacity, or forced expiratory flow rates. One patient had a positive methacholine chloride (Mecholyl) skin test with satellite lesions, and the second patient was skin-test negative. The skin test-positive patient, who was not hypotensive when initially challenged, was strenuously exercised for 15 min/day. Progressively less severe reactions were seen associated with diminished histamine release, and the patient is now on a daily exercise program; symptoms in the second patient are controlled with hydroxazine. Our results indicate that some patients with the exercise-induced anaphylactic syndrome are unusual examples of severe cholinergic urticaria. Furthermore, the utility of a regular exercise program as part of the management of some patients with cholinergic urticaria requires further investigation.

Adult↗
PubMed1983

Relationship between types of asthmatic reaction, nonspecific bronchial reactivity, and specific IgE antibodies in patients with red cedar asthma.

We studied the relationship between specific IgE antibodies, nonspecific bronchial reactivity to methacholine, and the type of asthmatic reaction in patients with red cedar asthma. The level of circulating specific IgE antibodies (expressed as RAST ratios) was not related to the type of asthmatic reaction, the degree of nonspecific bronchial hyperreactivity [expressed by the provocative concentration of methacholine producing a 20% decrease in the forced expiratory volume in 1 sec (PC20)] or the index of reactivity to plicatic acid. On the other hand, methacholine PC20 was found to correlate with the index of reactivity to plicatic acid in the late asthmatic reaction (LAR) and both the immediate and late components of the dual asthmatic reaction (DAR). Development of the LAR is associated with increase in nonspecific bronchial hyperreactivity. Repeated inhalation challenge with plicatic acid in eight patients with LAR resulted in DAR in all. The results suggest that the mechanism responsible for the LAR is associated with an increase in nonspecific bronchial reactivity; furthermore, the immediate component of DAR could also be related to heightened bronchial hyperreactivity.

Adult↗
PubMed1983

Relationship between bronchial responsiveness to hyperventilation with cold and methacholine in asthma.

Twenty-seven subjects with asthma and normal baseline lung function were challenged with aerosols of methacholine (M) and by isocapnic hyperventilation with cold air (HV). Stimulus-effect relationships were determined for each provocational technique on separate days and were expressed as the dose required to produce a 20% fall in forced expired volume in 1 sec (FEV1) obtained by linear interpolation from log stimulus vs. response curves (PD20). Each stimulus was applied with a sufficient intensity to produce a 20% or greater fall in FEV1 in each subject. The PD20 for M correlated significantly with the PD20 for HV (p less than 0.001) when the latter was expressed in liters per minute. The correlation between cumulative M PD20 and HV PD20 expressed as a percent of maximal voluntary ventilation was significant but less strong. We conclude that the airway response to HV reflects nonspecific bronchial hyperresponsiveness and that the dose of HV is best determined as the absolute level of ventilation.

Adolescent↗
PubMed1983

Effects of aspirin on nasal responses in atopic subjects.

Preliminary experiments indicated that solutions of aspirin (ASA) in buffered saline, pH 7.35, did not significantly change nasal airways resistance (NAR) when 0.1 ml of solution containing 22.5 mg (or less) per deciliter was sprayed into each nostril. Subsequently it was shown that this quantity of ASA administered intranasally did not significantly change NAR responses 15 min later to intranasal administration of increasing concentrations of histamine, methacholine, or an irritant (NH3 gas). However, the same atopic subjects demonstrated significantly decreased responses to intranasal challenge with short ragweed extract (SRW) after intranasal ASA. In addition, prior oral administration of ASA, Na salicylate, and indomethacin significantly inhibited nasal challenge responses to SRW in sensitive subjects under controlled conditions.

Administration, Intranasal↗
PubMed1984

A comparison of late reactions to antigen and exercise.

Immediate and late asthmatic reactions may occur after inhalation of specific antigens such as house dust mites or pollens. Recently, similar dual reactions have been found to occur after asthma induced by exercise. The immediate reaction to an antigen is believed to be due to the release of preformed and newly formed mediators derived primarily from mast cells via IgE antibodies. The late reaction also appears to be the result of an IgE reaction but involves inflammation in which cells play a role. The late reaction to antigen is often more severe than the immediate reaction and may be followed by a prolonged period of "nonspecific" bronchial hyperreactivity. By contrast, the late reaction to exercise is usually less severe than the immediate reaction. Both immediate and late exercise reactions are also associated with peaks of neutrophil chemotactic factor activity. Cromolyn sodium administered before challenge modifies both the immediate and the late response to antigen and exercise. Glucocorticoids block the late but not the early reaction to antigens. Their effect on the late exercise reaction is not yet known. Albuterol prevents the initial reaction to both exercise and antigen and may modify the late reaction to exercise as well.

Albuterol↗
PubMed1984

Methacholine challenge--relevance for the allergic athlete.

Methacholine challenge for diagnosing hyperreactive airways has been valuable in both research and clinical care settings. There are two methods of challenge that are commonly used. With the dosimeter method, five breaths of sequential concentrations of methacholine are inhaled with use of a solenoid valve timing device to standardize the quantity of inhaled methacholine solution. Pulmonary function is assessed after each concentration is inhaled. With the continuous breathing method, each concentration of methacholine is inhaled by tidal volume breathing for 2 min. Pulmonary function is assessed after each concentration. With both methods, a fall in FEV1 of 20% after inhalation of methacholine is diagnostic of hyperreactive airways. Several evaluations demonstrate that pharmacologic bronchial provocation with methacholine is more sensitive than exercise challenge for making the diagnosis of hyperreactive airways. If the allergic athlete complains of exercise-related symptoms, such as cough, dyspnea, or chest pain, and an exercise tolerance test fails to reproduce these symptoms, a methacholine challenge should be performed before the possibility of exercise-induced asthma is dismissed. If the allergic athlete has symptoms of cough or dyspnea that are unrelated to exercise, methacholine challenge is the most sensitive method to evaluate airways hyperreactivity indicative of asthma.

Bronchial Provocation Tests↗
PubMed1984

Simplified eucapnic voluntary hyperventilation challenge.

A simplified scheme for eucapnic voluntary hyperventilation ( EVH ) is described that requires only that a source of dry gas containing 5% CO2, 21% O2, and 74% N2 be hyperventilated at 40 L/min or greater. Refrigeration or measurement of end tidal CO2 is not required. When the ventilation pattern of a standardized treadmill exercise challenge in a group of exercise-sensitive asthmatics breathing dry air was matched according to this EVH procedure, the magnitude of the resultant bronchospasm and the exclusive nature of the postchallenge refractory period were similar, since patients in both cases were still fully responsive to methacholine. It is concluded that such an EVH challenge may be used to reproduce the bronchial heat and water fluxes that occur with exercise challenge as well as the consequential challenge-specific refractoriness that follows.

Air↗
PubMed1984

Rhinitis in the athlete.

Trauma is the most common problem involving the nose in sports and athletic events. Injury may lead to "vasomotor syndrome" and chronic rhinitis. Nasal and sinus obstruction may cause additional discomfort. Exposure to irritants, particularly solvents, cleaning solutions, paints, and varnishes as well as air pollutants exacerbates vasomotor rhinitis. Allergic rhinitis is another major problem of atopic athletes. It may be caused by exposure to pollens, molds, dust, or animal danders. Treatment is aimed at reducing the exposure to etiologic factors as well as pharmacologic management. Antihistamines, topical cromolyn, and topical steroids may be used to control rhinitis without violating " antidoping " regulations.

Allergens↗
PubMed1985

Mediators, airway responsiveness, and asthma.

There appears to be a close interrelationship among airway responsiveness to mediators and to natural stimuli, the presence and severity of asthma, and endogenous mediator release in the airways. Histamine and methacholine have been most commonly used to measure airway responsiveness. Airway responsiveness to the two drugs is increased in patients with current symptoms of asthma, and the degree of increase relates closely to the degree of variable airflow obstruction and the therapy to control symptoms. The degree of airway responsiveness to histamine also correlates closely with the degree of responsiveness to methacholine and less closely with responsiveness to PGF2 alpha and to natural stimuli such as exercise and allergens. The less close correlations with responsiveness to exercise and allergens is probably because of variations in the ease and type of endogenous mediator release in the airways by these stimuli. Endogenous mediator release from a number of stimuli including allergens and ozone causes inflammation in the airways, asthma, and airway hyperresponsiveness. These various interrelationships indicate that the treatment of asthma should be directed to reduce airway responsiveness, prevent mediator release, and prevent or reverse inflammation.

Airway Resistance↗