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Biomedical subjects

D Proud

Publications and source records attributed to D Proud.

At least 55 records · Page 3Linked to original sources
PubMed1996

Effects of loratadine and terfenadine on the induced nasal allergic reaction.

OBJECTIVE: To evaluate the effect of terfenadine and loratadine on the early nasal allergic response to challenge and the subsequent cellular influx and hyperresponsiveness. DESIGN: Double-blind, placebo-controlled, triple-crossover study. SUBJECTS: Fourteen, asymptomatic, allergic volunteers. INTERVENTIONS: After an initial challenge with methacholine chloride, subjects received treatment with placebo, loratadine (10 mg by mouth daily), or terfenadine (60 mg by mouth twice daily) for 1 week, followed by a nasal allergen challenge with lavages; 24 hours later, while the subjects were still receiving medication, the quantity of cells in the nasal lavage was determined, and another challenge with methacholine was done. Mediator levels were quantified in the nasal lavages after the allergen c hallenge, and the weight of the methacholine-induced nasal secretions was measured. RESULTS: Both loratadine and terfenadine treatment resulted in significant reductions in allergen-induced sneezing and the levels of histamine, kinins, albumin, and N-alpha-tosyl-L-arginine methyl ester-esterase activity in recovered nasal lavages compared with the reductions that resulted from placebo treatment, with no significant difference among the treatments. Treatment had no effect on the levels of tryptase, prostaglandin D2 or leukotriene C4. A significant eosinophil influx into nasal secretions 24 hours after the allergen challenge in patients who were receiving placebo (P=.006) was not affected by loratidine or terfenadine treatment. Comparing methacholine-induced secretions between screening challenges and challenges with the patients who were being treated with either loratadine or terfenadine, there was a significant decrease in secretions after the use of these antihistamines (P<.05). CONCLUSION: Both loratadine and terfenadine partially inhibit the early nasal response to allergen challenge and the subsequent reactivity to a challenge with methacholine without affecting the influx of eosinophils into nasal secretions.

Adult↗
PubMed1996

Mechanisms of prostanoid synthesis in human synovial cells: cytokine-peptide synergism.

Bradykinin (BK)2 and interleukin-1 (IL-1) interact synergistically to stimulate prostaglandin synthesis in human synovial fibroblast-like cells. The effect of BK is rapid and correlates with its capacity to elevate cytosolic levels of calcium ([Ca2+]i), while IL-1's effect is slow and s dependent upon de novo protein synthesis. The mechanism of this synergistic interaction was investigated. In the basal state, high levels of arachidonic acid (AA) were spontaneously released from synovial cells but near absent levels of cyclooxygenase activity prevented metabolism of AA to prostanoid. BK was a potent stimulus for elevating AA, but not prostaglandins, above basal levels. IL-1, in contrast, increased prostaglandins but not AA, above basal levels. IL-1 treatment was not associated with a loss or redistribution of AA among phospholipid classes. These results are consistent with high basal phospholipase activity in synovial cells and demonstrate the ability of BK, presumably via its ability to raise [Ca2+]i, to further elevate this activity(ies). Metabolism of AA to prostanoid is minimal in resting and BK-stimulated synovial cells, however, without the concomitant induction of cyclooxygenase activity by IL-1. These studies clarify the different, but synergistic, mechanisms of action of a peptide and cytokine in stimulating prostanoid synthesis in synovial cells. In addition, these data extend the results of previous investigations in demonstrating that basal phospholipase activity provides sufficient AA substrate for IL-1 induced prostanoid synthesis without invoking the concomitant induction of phospholipase activity by IL-1.

Arachidonic Acid↗
PubMed1996

Evidence that enhanced nasal reactivity to bradykinin in patients with symptomatic allergy is mediated by neural reflexes.

OBJECTIVE: The aim of this study was to determine whether allergic inflammation induces nasal hyperreactivity to bradykinin by enhancing neuronal responsiveness. METHODS: We compared the response to localized, unilateral nasal challenge with bradykinin in patients with perennial allergic rhinitis and nonallergic subjects, and in patients with seasonal allergic rhinitis challenged in and out of season. Weights of secretions from each nostril were recorded, and levels of albumin and lactoferrin in secretions recovered from each nostril were assayed. Contralateral administration of atropine (0.32 mg) was used to evaluate the role of cholinergic reflexes in nasal hyperresponsiveness to bradykinin. RESULTS: In patients with symptomatic allergy, bradykinin induced greater symptom scores than in asymptomatic atopic or nonallergic control subjects. Moreover, bradykinin caused sneezing in a majority of patients with symptomatic allergy but in none of the asymptomatic atopic or nonallergic control subjects. Only patients with symptomatic allergy showed dose-dependent bilateral increases in secretion weights and levels of the serous glandular marker, lactoferrin. In contrast, bradykinin induced similar increases in ipsilateral, but not contralateral, levels of albumin in all patient populations. Atropine inhibited contralateral secretion and lactoferrin production (p < 0.05) in patients with symptomatic allergy. CONCLUSION: The induction of sneezing and of atropine-inhibitable contralateral glandular secretion demonstrates that allergic inflammation causes nasal hyperreactivity to bradykinin, at least in part, by enhancing neuronal responsiveness.

Adult↗
PubMed1996

Oral prednisone therapy in experimental rhinovirus infections.

This study was designed to test the effects of oral steroid therapy on the kinin levels and symptoms of experimental rhinoviral colds. Forty-seven men were randomized to receive prednisone (20 mg) or placebo. Therapy was administered three times a day for 5 days, after one dose was given 11 hours before inoculation with rhinovirus. Viral titers, symptom scores, and kinin and albumin concentrations in nasal washes were monitored. The mean kinin levels were lower in the steroid group (287 vs 449 pg/ml, p = 0.005) with significant differences in kinin levels on days 3 and 4 (p < 0.01). No significant difference in total symptom scores was seen between the two groups. Except for increased sneezing (p < 0.01) and mucus weights (p < 0.05) on day 1 in patients treated with prednisone, there were no significant differences in individual symptom scores. Headache tended to be less prominent in steroid recipients. Mean viral titers were higher in the steroid group (1.13 vs 0.79, p = 0.03) with significant differences in the daily viral titers on days 3 (p < 0.05) and 4 (p < 0.01). Steroids reduced kinin levels in rhinoviral infections, but that reduction was not associated with a significant reduction in symptoms. This study also provides evidence for the enhancement of viral growth in steroid recipients.

Administration, Intranasal↗
PubMed1996

Dissociation of bradykinin-induced plasma exudation and reactivity in the peripheral airways.

To determine if bradykinin, a potential mediator of asthma, acts, at least in part, at the level of the peripheral airways, we used a wedged bronchoscope technique to study asthmatic and normal subjects. Baseline peripheral airways resistance (Rp) was measured in the right upper lobe. Subjects then received saline, followed by increasing doses of bradykinin, aerosolized through the bronchoscope. Rp was measured after each challenge. At the end of the procedure, bronchoalveolar lavage was performed in both the challenged and a control segment. Fibrinogen content of recovered lavage fluids was measured as an index of plasma exudation. Bradykinin induced a dose-dependent increase in Rp in the asthmatics, but did not effect Rp in normal subjects. In asthmatics, there was no significant correlation between peripheral airways reactivity and whole lung reactivity to bradykinin. Fibronogen increased significantly in both groups after bradykinin challenge, and there was no significant difference between postchallenge levels for the two groups. Thus, hyperreactivity of the peripheral airways in asthmatics is not directly due to plasma exudation. The ability of bradykinin to increase peripheral airways resistance in asthmatic, but not in normal, subjects is consistent with a role of this peptide as a mediator of asthma.

Adult↗
PubMed1996

Lack of effect of hot, humid air on response to nasal challenge with histamine.

We have previously shown that whole body exposure of human subjects to environmental conditions of 37 degrees C and 90% relative humidity (RH) prior to and during nasal challenge with antigen decreases the early response. In this study, we evaluated 1) whether the decreased responses observed resulted from decreased end organ sensitivity to histamine and 2) whether the effect of hot, humid air persisted after the subject exited the hot, humid environment. Ten asymptomatic seasonal allergic subjects and 11 nonallergic subjects were randomized to environmental chamber conditions of either 20 degrees C, 30% RH or 37 degrees C, 90% RH for 1 hour prior to and during performance of a nasal challenge with histamine. Twenty-two hours after exiting the environmental chamber, the allergic subjects were challenged with antigen. During both chamber conditions, histamine challenge was associated with a significant increase in all measured parameters compared to sham challenge, except for the sensations of pruritus and congestion. The response to histamine challenge was not different under the two experimental conditions or between allergic and nonallergic subjects. Following both exposure conditions, allergen challenge was associated with an increase in all measured parameters compared to sham challenge, with no significant difference between the two conditions. Exposure to 37 degrees C, 90% RH minimally affects the response to nasal challenge with histamine, and thus, the previously reported decreases in the early nasal response to antigen may primarily result from reduction in mast cell activation. The effect on antigen does not persist 22 hours after exposure.

Adult↗
PubMed1995

Expression of the chemokine RANTES by a human bronchial epithelial cell line. Modulation by cytokines and glucocorticoids.

The chemokine RANTES is a potent chemoattractant for eosinophils, lymphocytes, and monocytes, and has been detected recently in the epithelium of human airways mucosa. We have studied, therefore, the expression of RANTES mRNA and protein in the human bronchial epithelial cell line BEAS-2B. Using Northern blot analysis, RANTES mRNA was not detectable in unstimulated BEAS-2B cells. Incubation of cells with TNF-alpha or IFN-gamma induced the expression of RANTES mRNA and protein within 16 h. The combination of TNF-alpha and IFN-gamma displayed a marked synergism in inducing RANTES expression. Pretreatment of cells with the glucocorticoid budesonide (10(-10)-10(-7) M) for 24 h inhibited expression of RANTES mRNA and protein stimulated by either TNF-alpha or TNF-alpha plus IFN-gamma in a concentration- and time-dependent manner. Nonglucocorticoid steroids did not inhibit RANTES mRNA expression. Production of RANTES by epithelium could contribute to the mechanism of selective cellular recruitment occurring in the airways during inflammation, thus playing a relevant role in the pathogenesis of diseases such as asthma, rhinitis, and polyposis. The down-regulation of RANTES production by glucocorticoids in epithelial cells may contribute to the efficacy of these compounds in reducing cellular infiltration and, ultimately, to their anti-inflammatory properties.

Blotting, Northern↗
PubMed1995

Inhibition of the response to nasal provocation with bradykinin by HOE-140: efficacy and duration of action.

The present studies were undertaken as a first step to evaluate the potential usefulness of the bradykinin antagonist HOE-140 in delineating the role of kinins in the pathogenesis of chronic rhinitis. Intranasal single-dose administration of HOE-140, at doses up to 500 micrograms, was safe and well tolerated. Bradykinin-induced symptoms and increased vascular permeability could be inhibited, in a dose-dependent manner, by preadministration of HOE-140 5 min prior to kinin challenge. The results of dose-ranging experiments suggested that bradykinin and HOE-140 were approximately equipotent at bradykinin receptors. Preadministration of HOE-140 2 h before kinin challenge caused a significant but much weaker level of inhibition than that seen with 5-min preadministration. Comparison of data with those obtained during dose-ranging studies suggested that more than 90% of the administered HOE-140 was lost during this 2-h period. We conclude that topical HOE-140 is an effective inhibitor of the effects of bradykinin on the nasal mucosa but that the short duration of action of this drug may severely limit the utility of HOE-140 in delineating the role of kinins in the pathogenesis of chronic rhinitis.

Adolescent↗
PubMed1995

Allergen-induced hyperresponsiveness to bradykinin is more pronounced than that to methacholine.

Bradykinin reduces airflow in asthmatic patients via indirect mechanism(s), possibly involving sensory nerve stimulation and increased vascular permeability. We hypothesized that allergen inhalation, which affects reactivity of nerves and vessels, would differentially alter reactivity to bradykinin and the smooth muscle spasmogen methacholine. We compared reactivity to methacholine and bradykinin 1, 2, 4, 7, 11, and 14 days after allergen provocation in 12 atopic asthmatic patients with stable baseline reactivity to bradykinin. Maximal allergen-induced shifts from baseline in reactivity were 0.73 +/- 0.12 log unit for bradykinin compared with 0.27 +/- 0.13 log units for methacholine (P = 0.0005). Nine subjects showed significant increases in bradykinin reactivity, with four subjects increasing reactivity by > 1 log unit. Moreover, the maximal mean change in bradykinin reactivity occurred 2 days postallergen. Thus, allergen-induced changes in reactivity to bradykinin and methacholine differ in magnitude and time course. Bradykinin inhalational challenge provides a sensitive index of the airway's response to allergen.

Adult↗
PubMed1995

Cold dry air-induced rhinitis: effect of inhalation and exhalation through the nose.

Ten subjects with a history of cold air-induced nasal symptoms participated in a randomized two-period crossover study to evaluate the occurrence and magnitude of the reaction induced by inhalation and exhalation of cold dry air through the nose. The protocol involved breathing of either warm moist or cold dry air for 45 min at resting breathing rates. The nasal response was quantified by determining the amount of produced secretions as well as by measuring histamine and N-alpha-p-tosyl-L-arginine methyl (TAME) esterase activities in recovered nasal lavage fluids. Symptom scores were obtained. Warm moist air did not increase symptoms nor did it result in any significant changes in secretions or mediator levels. Compared with baseline, cold dry air induced significant rhinorrhea and increased both secretion weights (9.6 +/- 1.3 vs. 28.1 +/- 6.5 mg; P = 0.01) and the levels of histamine (3.9 +/- 1.2 vs. 10.6 +/- 2.7 ng/ml; P = 0.02) and TAME esterase activity (3.1 +/- 0.8 vs. 7.0 +/- 2.0 counts.min-1.10(-3); P = 0.01). We conclude that bidirectional nasal breathing of cold dry air results in a reaction that is qualitatively similar to that induced when air is only inhaled through the nose and exhaled through the mouth.

Adult↗
PubMed1995

Ozone exposure in humans: inflammatory, small and peripheral airway responses.

We exposed eight normal adults to filtered air (FA) and 0.35 ppm ozone (O3) and compared responses in spirometry, including isovolume (isoV) flows at intermediate-to-low lung volumes, against levels of inflammatory markers in bronchoalveolar lavage fluid (BALF) and peripheral lung resistance (Rp) measured through a wedged bronchoscope. Spirometry was performed at the end, 25 min and 24 h after exposure, bronchoscopy at 24 h after exposure. The percentages of neutrophils, fibrinogen, albumin, PGE2, PGF2 alpha, and kinins were elevated in BALF after O3 compared with FA. The percentage reduction in (isoV) FEF25-75 at 25 min and 24 h after administration of O3 correlated closely with the rise in fibrinogen concentrations in BALF, a marker of altered vascular permeability. Rp, a measurement dominated by very small or peripheral airways, was unaffected in 7 of 8 subjects. The absence of change in Rp might have reflected insufficient penetration of O3 into these airways to produce or sustain an effect for 24 h; alternatively, the bronchoscopic procedure which included atropine and lidocaine pretreatment may have reversed an O3 effect. An unexpected finding was the significant association between baseline Rp (after FA) and the magnitude of the spirometric response to O3. Our results suggest that small airway dysfunction in the immediate post-O3 period is a marker of lung inflammation.

Adult↗
PubMed1995

Effects of intranasal administration of endothelin-1 to allergic and nonallergic individuals.

Endothelin-1 (ET-1), a 21 amino acid peptide, and its receptors are distributed in the mammalian respiratory tract. To examine the responses of human upper airways to ET-1, we investigated the effects of intranasal administration of ET-1 to nine symptomatic allergic and nine nonallergic volunteers. Paper discs were used to administer ET-1 or diluent to one side of the nasal mucosa, and to collect secretions from the ipsilateral (challenged) and contralateral (opposite) nostrils. ET-1 (0.3-10 micrograms), but not diluent, induced dose-dependent bilateral increases in secretion weights, lysozyme secretion, symptoms of rhinorrhea and itch, and sneezing in both populations. ET-1 did not induce albumin secretion, histamine release, or symptoms of nasal congestion. Compared with the nonallergic subjects, allergic individuals sneezed more and had significantly higher bilateral secretion weights, contralateral lysozyme secretion, and symptoms of rhinorrhea following ET-1 provocation. In summary, ET-1 induced symptoms relevant to inflammatory upper airway diseases in allergic and nonallergic subjects. However, responses of allergic subjects were more pronounced, particularly with respect to symptoms associated with neural reflex responses, such as sneezing and contralateral secretion. Therefore, allergic inflammation enhances responsiveness of the nasal mucosa to ET-1.

Administration, Intranasal↗
PubMed1995

Human eosinophil-granule major basic protein and synthetic polycations induce airway hyperresponsiveness in vivo dependent on bradykinin generation.

In the current series of experiments we investigated the role of bradykinin in airway hyperresponsiveness induced by human eosinophil-granule major basic protein (MBP). Bronchoalveolar lavage was performed after intratracheal instillation of MBP or poly-L-lysine in anesthetized, intubated rats, and levels of immunoreactive kinins and kallikrein-like activity were determined. Both MBP and poly-L-lysine induced a three- and eightfold increase in levels of kallikrein-like activity and i-kinins, respectively. To determine whether kinin production is required for the development of airway hyperresponsiveness induced by cationic proteins, dose-response curves to methacholine were constructed before and 1 h after intratracheal instillation of either MBP or poly-L-lysine (100 micrograms). MBP and poly-L-lysine induced an increase in airway responsiveness, which was inhibited by pretreatment with a selective BK-2 receptor antagonist, NPC 17713 (250 micrograms/ml). Our results demonstrate that MBP and poly-L-lysine activate kallikrein and stimulate the generation of i-kinins in vivo, an effect that may be related to the cationic charge of these proteins. Furthermore, the ability of these proteins to increase airway responsiveness appears to be dependent on the generation of i-kinins.

Amino Acid Sequence↗
PubMed1995

Infection of a human respiratory epithelial cell line with rhinovirus. Induction of cytokine release and modulation of susceptibility to infection by cytokine exposure.

Rhinovirus infections cause over one third of all colds and are a contributing factor to exacerbations of asthma. To gain insights into the early biochemical events that occur in infected epithelial cells, we develop, for the first time, a model in which a pure respiratory epithelial cell population can be routinely infected by rhinovirus. Viral infection was confirmed by demonstrating that viral titers of supernatants and lysates from infected cell increased with time and by PCR. Infection by rhinovirus 14 was inhibited by homotypic antiserum and by antibodies to intercellular adhesion molecule-1 (ICAM-1), the receptor for this virus. Susceptibility of epithelial cells to infection by rhinovirus 14 (but not rhinovirus 2, an ICAM-1 independent strain) can be increased by preexposure of cells to TNF alpha, whereas IFN gamma reduces susceptibility to infection by both rhinovirus strains. Rhinovirus infection per se does not markedly alter ICAM-1 expression on epithelial cells. Finally, we demonstrate that rhinovirus infection induced increased production of IL-8, IL-6, and GM-CSF from epithelial cells. Production of IL-8 correlated with viral replication during the first 24 h after infection. This model should provide useful insights into the pathogenesis of rhinovirus infections.

Base Sequence↗
PubMed1994

Bradykinin is a potent and relatively selective stimulus for cytosolic calcium elevation in human synovial cells.

Previously, we have shown that bradykinin elicits the production of prostaglandin E2 (PGE2) in human synovial cells only after pre-exposure of the cells to IL-1. The observation that calcium ionophores, but not a variety of physiologic receptor-mediated agonists, can mimic bradykinin in its synergy with IL-1 led us to hypothesize that the ability of bradykinin to induce prostanoid synthesis was a result of its selective ability (among physiologic agonists) to raise the cytosolic free ionized calcium concentration ([Ca2+]i) levels of synovial cells. Extending this hypothesis, it follows that the relative potency of an agonist in inducing PGE2 production from IL-1-treated cells should be dependent on its ability to raise [Ca2+]i. In these studies, we have confirmed the potent ability of bradykinin to elevate [Ca2+]i in resting human synovial cells. That the effect of bradykinin on [Ca2+]i was mediated through the previously described synovial cell kinin receptor was confirmed by a pharmacologic profile consistent with a high affinity B2 kinin receptor. Furthermore, the relative specificity and potency of the PGE2 response of bradykinin in IL-1-treated cells was paralleled, in resting cells, by a similar pattern in the [Ca2+]i response. Finally, IL-1 had no direct effect on [Ca2+]i levels, nor did it alter agonist-induced elevations in [Ca2+]i. We conclude that the potency of a receptor-mediated agonist in inducing prostanoid synthesis in synovial cells is dependent on its ability to raise [Ca2+]i. However, this effect is not enough, in and of itself, to induce prostanoid synthesis; the concomitant induction by IL-1 of a PG-generating enzyme is also required.

Bradykinin↗
PubMed1994

The human nasal response to capsaicin.

Airway sensory nerves play a role in reactions to inhaled allergens, irritants, and physical stimuli. Capsaicin, the pungent principle of hot peppers, stimulates a subcategory of sensory nerves. To study the consequences of selective activation of airway sensory nerves in the human nose, we administered capsaicin nasal challenges to eight volunteers (four normal subjects and four subjects with perennial allergic rhinitis). Capsaicin (20 mumol/L), when sprayed into the nose, induced burning, rhinorrhea, and lacrimation. Capsaicin also induced a significant increase in total protein content of nasal lavage fluid after challenge compared with vehicle (increase from before challenge to 1 minute after challenge, 172 +/- 55 vs 46 +/- 29 micrograms/ml, p < 0.001). In contrast to many animal studies, capsaicin did not increase vascular permeability in the airway, because albumin content of nasal lavage fluid was not increased (p = 0.86). On the other hand, lactoferrin, a marker of glandular secretion, was increased (p < 0.005). Repetitive capsaicin challenge every 10 minutes led to tachyphylaxis of symptoms, total protein secretion, and lactoferrin secretion. Compared with vehicle, unilateral capsaicin (6 mmol/L) disk challenge induced significant secretion both ipsilateral (21.3 +/- 4.2 vs 4.9 +/- 2.1 mg, p < 0.01) and contralateral (18.2 +/- 4.4 vs 7.4 +/- 1.9 mg, p < 0.04) to challenge. Thus we have shown that capsaicin challenge to the human nose leads to airway sensory nerve activation. Further, we have demonstrated that capsaicin stimulates a predominantly central neuronal response and that the induced secretory response is of glandular rather than vascular origin.

Adult↗
PubMed1994

Increased levels of interleukin-1 are detected in nasal secretions of volunteers during experimental rhinovirus colds.

The potential involvement of interleukin-1 (IL-1) in the pathogenesis of experimental rhinovirus colds was examined. Nasal lavages were recovered before and for 5 days after rhinovirus infection from 44 subjects, 22 of whom were randomized to receive prophylaxis with glucocorticoids, while the rest received placebo. Immunoreactive IL-1 beta was significantly increased in subjects who were infected and symptomatic compared with noninfected volunteers or subjects who were infected but asymptomatic. Concentrations of immunoreactive IL-1 beta correlated with levels of kinins and albumin in lavage fluids. Studies of IL-1 bioactivity established that most activity in lavages from infected subjects was IL-1 beta. Glucocorticoid prophylaxis did not inhibit IL-1 production, nor did it significantly affect the symptomatic response to infection or, in a subset of patients, neutrophil infiltration. These data are consistent with the hypothesis that IL-1 could contribute to the pathogenesis of rhinovirus infections.

Adolescent↗