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Biomedical subjects

J E Fish

Publications and source records attributed to J E Fish.

At least 73 records · Page 4Linked to original sources

Dose of cat (Felis domesticus) allergen 1 (Fel d 1) that induces asthma.

In 10 patients with cat asthma and hay fever, we quantified the doses of cat allergen (expressed as cat allergen 1 [Cat-1] in log Food and Drug Administration [FDA] units) inspired from the ambient air of a room containing living cats required to induce a 20% drop in FEV1. These doses were compared with the doses required to cause the same change in FEV1 when the patients were subjected to bronchial challenge with aerosols of cat hair and dander extract in the conventional manner. Patients highly sensitive to cat extract by skin, leukocyte histamine release, and bronchoprovocation tests and with measurable levels of anticat IgE by RAST were exposed for up to 2 hours in a room occupied full-time by two cats. At the same time, room air was sampled by a Durham gravity sampler, by an Andersen sampler, and by lapel fiberglass filters. When hair and dander particles trapped on greased slides by gravity and Andersen samplers were stained, sized, and counted, squamous cell fragments in the less than 10 mm range were abundant. Assays of extracts from the lapel filters for Cat-1 content by radioimmunoassay and for allergenic activity by leukocyte histamine release demonstrated a significant correlation (p less than 0.05) between the results of the two assays. All patients developed rhinitis and asthma during exposure. At the time of a 20% drop in FEV1, when air sampling was stopped, the lapel filters had trapped a total of -1.86 to less than -3.04 (median -2.74) log FDA units Cat-1. These measurements of Cat-1 exposure in the room correlated (p less than 0.01) with the doses of cat extract (-1.18 to -3.15 [median -2.26] log FDA units Cat-1 equivalents) required to induce a 20% fall in FEV1 in the conventional bronchoprovocation tests.

Administration, Intranasal↗

Effects of the calcium channel blocker, verapamil, on asthmatic airway responses to muscarinic, histaminergic, and allergenic stimuli.

The effect of calcium channel blocking agents on bronchomotor tone and airway responsiveness to inhaled provocative stimuli remains controversial. In this study we examined the effects of verapamil (a papaverine derivative) on baseline airway function as well as the response to methacholine, histamine, and ragweed allergen. Verapamil was chosen because of its aqueous solubility and hence suitability for aerosol administration in higher doses than previously given. The effects of 5 mg and 12.5 mg aerosolized verapamil doses were compared with placebo as separate parts of the same study in subjects with ragweed-allergic asthma. Neither dose of verapamil was found to produce bronchodilatation within 30 min after aerosol administration. At the 12.5 mg dose, however, we observed mild to moderate bronchospasm occurring within 5 min of administration, with a return toward baseline within 30 to 40 min. This bronchoconstrictor effect was unrelated to the low osmolarity of the drug solution (33 mosmol/L). Responses to methacholine, histamine, and ragweed allergen were unaltered by drug pretreatment at the 5-mg dose. At the 12.5-mg dose, however, we found significant inhibition of methacholine responsiveness but no effect on histamine or allergen responses. From these studies we conclude that verapamil can influence airway function by modulating agonist-induced bronchoconstriction. The selectivity of this inhibitory effect on muscarinic responses alone, however, leaves questionable the importance of this activity with regard to its clinical implications.

Adult↗

Nasal challenge with cold, dry air results in release of inflammatory mediators. Possible mast cell involvement.

The purpose of our study was to assess the effect of cold, dry air (CDA) on the nasal mucosa of selected individuals in relation to the release of inflammatory mediators associated with mast cells. 12 subjects with a history of nasal symptoms of rhinorrhea and congestion upon cold or dry environmental exposure were challenged by nasal breathing of CDA and warm, moist air (WMA). Each subject was tested on two occasions with the order of the challenges reversed. Symptom scores were recorded, and the levels of histamine, prostaglandin (PG) D2, kinins, and [3H]-N-alpha-tosyl-L-arginine methyl ester (TAME)-esterase activity in nasal lavage fluids were measured. CDA caused a significant increase in mediator levels and in symptom scores as compared to baseline or to WMA. No significant increase in symptom scores or mediators was noted after WMA challenge, with the exception of a marginal increase in kinins. The response to CDA was similar, regardless of challenge order. Changes in mediators correlated with one another, and symptom scores correlated significantly with the levels of histamine, kinins, and PGD2. Five subjects without a history of nasal symptoms on cold air exposure had no change in mediators or symptom scores after CDA or WMA challenge. We conclude that CDA causes the release of inflammatory mediators possibly associated with mast cells and speculate that such a mechanism may be involved in the bronchospasm induced by CDA in asthmatics.

Adolescent↗

Modulation of the bronchomotor effects of chemical mediators by prostaglandin F2 alpha in asthmatic subjects.

Prostaglandin F2 alpha (PGF2 alpha) is generated by human lung tissue in response to a number of stimuli and is widely viewed as a bronchoconstrictor mediator. We have shown that aerosolized PGF2 alpha in concentrations between 1 and 100 micrograms/ml caused dose-related bronchoconstriction, but that continued stimulation at higher concentrations resulted in a partial return of pulmonary function toward control, suggesting that airways were refractory to further stimulation. To explore the mechanism and specificity of airway refractoriness induced by PGF2 alpha, we examined bronchomotor responses evoked by repeated PGF2 alpha stimulation, repeated histamine stimulation, and PGF2 alpha stimulation followed by histamine. Studies were carried out on 3 separate days in 7 subjects with allergic asthma. For each subject the aerosol concentration of each agonist remained constant throughout the study. Responses were measured as the percent change in FEV1 versus time, and comparisons were made between the first and second agonist challenge of each study day. We found that prior stimulation with PGF2 alpha resulted in diminished airway responsiveness, not only to PGF2 alpha but to histamine as well. In contrast, similar refractoriness could not be induced by repeated histamine stimulation, indicating that the PGF2 alpha-induced decrease in responsiveness was not a nonspecific effect of bronchoconstriction per se. Further, the finding that PGF2 alpha caused a decrease in the response to histamine suggests that diminished airway responsiveness was not due to down-regulation of specific PGF2 alpha receptors. Our findings suggest that in addition to its bronchoconstrictor properties, PGF2 alpha may play a role in the modulation of acute airway responses.

Adolescent↗

Calcium channel antagonists in the treatment of asthma.

The pathophysiologic processes that contribute to airway obstruction in asthma involve Ca2+-dependent excitation-contraction and stimulus-secretion coupling mechanisms. The emergence of new compounds that specifically inhibit Ca2+ flux across membrane ionic channels has stimulated widespread interest in the therapeutic potential of these agents in asthma. Studies with these agents in relevant in vitro test systems and animal models, however, have yielded conflicting results and have thus far failed to furnish strong support for a therapeutic role. In human studies, these agents have been found to inhibit exercise-induced bronchospasm, but their ability to inhibit the effects of other stimuli and to dilate airways is equivocal. In general, clinical trials with currently approved drugs--diltiazem, nifedipine, and verapamil--are limited by potency, formulation, and side effects of these agents. What future role, if any, Ca2+ channel antagonists will have in the treatment of asthma is likely to depend on the development of newer agents with greater tissue selectivity at the level of airway smooth muscle and mast cells.

Airway Resistance↗

Upper airway disease and bronchial hyperreactivity.

Bronchial irritability is seen in illnesses involving the upper respiratory tract. In allergic rhinitis, it appears to coexist, and constitutes a risk factor for the development of asthma. In acute respiratory infections, asthmatic attacks may occur coincidentally with viral infections, and infection with some viruses may cause normal persons to develop bronchial irritability. There is suggestive evidence that the associated bronchial irritability may take months to clear and may predispose subjects to permanent hyperreactivity.

Asthma↗

Novel effects of PGF2 alpha on airway function in asthmatic subjects.

The effects of inhaled prostaglandin F2 alpha (PGF2 alpha) have been examined in eight subjects with asthma. Incremental PGF2 alpha aerosol concentrations, ranging from 1 to 5,000 micrograms/ml, were administered at 15-min intervals. Plethysmographic specific airway conductance (sGaw), forced expiratory volume at 1 s (FEV1), and maximum expiratory flow at 50% vital capacity breathing air (Vmax50% air) and 80% He-20% O2 (Vmax50% He-O2) were measured after each dose and compared with saline control values. We observed unexpected triphasic dose-response characteristics, i.e., an initial decline in physiological variables at low concentrations (1-100 micrograms/ml), followed by improvement at intermediate concentrations (100-1,000 micrograms/ml) and a subsequent steep decline at high concentrations (1,000-5,000 micrograms/ml). Improvement in FEV1 and Vmax50% air between 100 and 1,000 micrograms/ml was associated with sGaw increases above control levels in six subjects and a significant fall in density-dependent index (Vmax50% He-O2/Vmax50% air) when compared with values before challenge and at low concentrations. Inhaled atropine (5 mg) improved prechallenge lung function but had no effect on PGF2 alpha dose-response characteristics. Intermediate PGF2 alpha concentrations given as a single dose consistently induced greater FEV1 reductions than the same concentration during graded dose challenges. Our findings are consistent with the demonstration of in vivo airway tachyphylaxis and indicate that airway effects of PGF2 alpha are far more complex than previously reported. Moreover, these novel effects suggest that, in addition to its well-known bronchoconstrictor effects, PGF2 alpha directly or indirectly causes airway relaxation, predominantly in large airways.

Adolescent↗

Occupational asthma: a spectrum of acute respiratory disorders.

Occupational asthma is a general term applied to a variety of clinical disorders, each characterized by acute, reversible respiratory symptoms caused by exposure to environmental or work-related stimuli. The diverse pathologic basis for this group of disorders includes bronchoconstriction, airway inflammation and edema, toxic or inflammatory alveolitis/bronchiolitis, or noncardiogenic pulmonary edema. On the basis of the abnormalities and the mechanisms responsible for lung injury, occupational asthma may be classified as (1) toxic or inflammatory reactions: (2) immediate "allergic" hypersensitivity reactions; (3) hypersensitivity reactions of unknown origin; (4) irritant reactions; and (5) delayed hypersensitivity reactions. Physical and chemical properties of the causative agent, host factors, and intensity of exposure largely determine the type of reaction produced. At the practical level, different reactions may be distinguished on the basis of characteristic clinical features and laboratory findings. Therefore, an understanding of the different reaction categories is useful in the identification of specific causative agents, in successful patient management, and in the development of environmental safeguards.

Air Pollutants, Occupational↗

Regulation of bronchomotor tone by lung inflation in asthmatic and nonasthmatic subjects.

We examined the effects of lung inflation on induced airway obstruction in 14 atopic asthmatic and 14 atopic nonasthmatic subjects. Subjects were challenged with aerosols of methacholine (MCh) and pollen antigen (Ag), and the effects of inflation were assessed with partial ad full flow-volume curves and by comparing airway conductance measurements before and after deep inspiration to total lung capacity (TLC). Whereas bronchoconstriction was transiently abolished or reduced with inspiration in nonasthmatics, these effects were absent or diminished in asthmatic subjects. Dissimilarities could not be explained by differences in base-line lung function or degree of obstruction produced. Deep inspiration had a greater effect in reducing airway obstruction produced with MCh than with Ag in nonasthmatics. In addition, atropine pretreatment had no effect on inspiration responses in asthmatics given Ag, suggesting that vagal reflexes were not the cause of an impaired ability to reduce bronchomotor tone by lung inflation. Our findings reveal the existence of an intrinsic means of regulating bronchomotor toe by active changes in lung volume and that such a mechanism is impaired in asthma. We suggest that airway hyperactivity in asthma is perhaps less a reflection of enhanced end-organ responsiveness than a reflection of this impaired capacity.

Adult↗

Indomethacin modification of immediate-type immunologic airway responses in allergic asthmatic and non-asthmatic subjects: evidence for altered arachidonic acid metabolism in asthma.

To examine the role of arachidonic acid metabolism in the modulation of immediate-type immunologic airway responses, we compared the effects of indomethacin (50 mg every 6 h for 96 h) and placebo on responses to antigen inhalation challenge in allergic asthmatic subjects and a group of nonasthmatic subjects with allergic rhinitis. Sensitivity to antigen was determined for changes in one-second forced expiratory volume, specific airway conductance, and expiratory flow at 25% of the forced vital capacity measured from partial flow-volume curves. The groups differed in terms of prechallenge pulmonary function and non-immunologic airway reactivity as determined by methacholine challenge, but were comparable with respect to intradermal sensitivity to ragweed antigen. After placebo, asthmatic subjects demonstrated approximately 3.5-fold greater sensitivity to antigen than that of nonasthmatic subjects. Indomethacin had no effect on prechallenge pulmonary function in either group. However, after indomethacin, non-asthmatic subjects had a significant increase in antigen sensitivity. Indomethacin had no effect on antigen sensitivity in asthmatic subjects as measured by one-second forced expiratory volume or expiratory flow at 25% of the forced vital capacity, and produced a slight but significant decrease as measured by specific airway conductance. Indomethacin failed to alter methacholine sensitivity in atopic, non-asthmatic subjects. These findings indicate that products of arachidonic acid metabolism participate in vivo in the modulation of airway responses to immediate-type immunologic stimuli, and that this participation differs in asthmatic and non-asthmatic subjects.

Adult↗

Experimental squamous cell lung tumors in Sprague-Dawley and murine pneumonitis-free rats.

Squamous cell bronchogenic carcinoma was produced in 34% of a group of specific pathogen-free rats in a mean time of 139 days by the use of point-source irradiation. In a group of Sprague-Dawley rats, identical tumors developed in 54% of animals after an average exposure time of 147 days. This study was undertaken to clarify whether the bronchogenic squamous cell carcinomas produced by this method are due to the effects of the point source of irradiation alone or to the additive effects of irradiation and chronic murine pneumonitis. The results of this study in specific pathogen-free rats indicate that murine pneumonitis is not a prerequisite for the development of neoplasia by this method. The electron microscopic findings presented support the histologic diagnosis of a well-differentiated squamous cell bronchogenic carcinoma, similar in appearance to the tumor found in humans.

Animals↗

Measurements of responsiveness in bronchoprovocation testing.

The relative sensitivity and usefulness of FEV1 and SGaw measurements in determining airway responsiveness to stimuli causing changes in bronchomotor tone depend to a great extent on the population studied. Though neither test provides a great deal of information regarding the site of airway obstruction, when used together they provide a reliable and sensitive indicator of airway responsiveness.

Airway Resistance↗

Effects of inhaled lidocaine on airway function in asthmatic subjects.

We measured the effect of inhaled lidocaine on pulmonary function in 8 asthmatic subjects. Plethysmographic specific airways conductance (SGaw) and the 1-sec forced expired volume (FEV1) were measured before and after the inhalation of 2cm3 of lidocaine (4%). Responses were also measured after patients were pretreated with either aerosolized isoproterenol, aerosolized atropine, or intramuscular atropine. In response to lidocaine alone, we observed a 23.4 +/- (SE) 4.8% fall in FEV1 and a 64.1 +/-(SE)3.8% fall in SGaw (p is less than 0.001). These effects were reversed with aerosolized atropine or isoproterenol. After pretreatment with aerosolized atropine or isoproterenol, the bronchoconstrictor effect of lidocaine were either prevented or markedly reduced. The protective effects of intramuscular atropine varied in different subjects, but in general, aerosolized bronchodilators afforded better protection against the bronchoconstrictor effect of lidocaine. Although lidocaine is theoretically capable of blocking neurogenic reflexes in the lung, our studies indicate that this topical anesthetic agent produces untoward reflex-mediated bronchoconstriction in patients with asthma and hyperirritable airways.

Adult↗