Growth inhibition of fibroblasts from nasal polyps and normal skin by lysine acetylsalicylate

Some authors have shown that lysine acetylsalicylate (LAS) may help prevent nasal polyp relapses. As some anti-inflammatory drugs have been found to regulate cell growth, we investigated the antiproliferative effect of LAS on fibroblasts derived from nasal polyps. Moreover, we studied the effect of LAS on the growth of fibroblasts derived from normal skin to determine whether the response was similar to that obtained in the above-mentioned cells. Fibroblasts were obtaitied from tissue samples of nasal polyps from two aspirin-tolerant and two aspirin-intolerant patients, and from the normal skin of a healthy donor. The cells were treated with LAS (20–2000 μg/ml of culture medium). Cell growth and viability were evaluated after 3 and 6 days of culture. LAS had a growth-inhibitory effect on cells independently of their derivation. A reduction in cell growth was seen at the coticentrations of LAS tested, which correspond to those used in the local treatment of nasal polyposis.     

Inhaled verapamil in histamine-induced bronchoconstriction

Fifteen asthmatic subjects participated in a double-blind trial comparing the protective effects of inhaled verapamil, salbutamol, and saline against inhaled histamine. Inhaling verapamil between four repeated histamine inhalation tests produced no significant protection against histamine-induced bronchoconstriction, while there was significant protection with salbutamol (p < 0.001). Inhaling verapamil before a single inhalation test produced limited but significant protection (p < 0.05) compared with a saline control in eight asthmatic subjects. This small protective effect in the two-treatment study of eight asthmatics suggests that either the protective effect of verapamil is variable among subjects or a preceding histamine inhalation test blocks the verapamil effect.     

Protection against exercise-induced bronchoconstriction by montelukast in aspirin-sensitive and aspirin-tolerant patients with asthma

BACKGROUND: Montelukast, a cysteinyl-leukotriene receptor antagonist, was reported to have a protective effect against exercise-induced bronchoconstriction (EIB). Aspirin-induced asthma (AIA) is characterized by overproduction of cysteinyl-leukotrienes. OBJECTIVE: The aim of the study was to compare the response to exercise and the effect of montelukast on EIB in AIA as compared to aspirin-tolerant asthma (ATA). METHODS: A placebo-controlled, double blind, cross-over randomized study was performed in 19 AIA and 21 ATA patients with stable asthma. A single dose of montelukast (10 mg) or placebo (PL), was given orally one hour prior to exercise challenge. FEV1 was measured before and 5, 10, 15 min after exercise and then at 15-minute intervals for 4 h. Urinary LTE4 excretion and blood eosinophil count were measured at baseline, 2 h and 4 h following exercise challenge. RESULTS: Positive bronchial response to exercise was observed in 47.5% of all patients studied. Exercise led to almost identical maximal fall in FEV1 in AIA and ATA patients (23.5% +/- 6.8% vs. 21.8% +/- 12.0%, respectively; P = 0.7). Montelukast, as compared to PL, significantly attenuated EIB in 63.2% of 19 patients with positive exercise test preceded by PL. The mean of maximum fall in FEV1 from the pre-exercise value was 10.2% +/- 13.8 after montelukast as compared to 22.5% +/- 10.2 after placebo (P < 0.001). No significant differences between protective effect of montelukast was observed in AIA as compared to ATA patients (P = 0.63, anova). Urinary LTE4 excretion showed no change following exercise, irrespective of the result of the test in all subjects. CONCLUSION: Patients with AIA and ATA react similarly to exercise challenge and obtain similar protection against EIB by montelukast.     

Potentiation of the antireactive, antiasthmatic effect of inhaled furosemide by inhaled lysine acetylsalicylate

Nonsteroid antiinflammatory drugs interfere with the diuretic activity of furosemide, implying that this effect is at least partially dependent on renal prostaglandin synthesis. To investigate whether prostaglandin production could also modulate the bronchial antireactive activity of this diuretic drug, we investigated the effect of inhaled Iysine acetylsalicylate (162 mg) and of furosemide (18 mg), alone and in combination, on the bronchial obstructive response to ultrasonically nebulized water in asthmatic patients. The study was also prompted by the conflicting results obtained in previous studies of oral nonsteroid antiinflammatory drugs. Fifteen asthmatic patients underwent bronchial challenge with a mist of ultrasonically nebulized distilled water at the same time of day on four occasions, 2–4 days apart, 15 min after premedication according to a double-blind, randomized protocol. After placebo, mean PD₁₅ to water mist did not differ from a preliminary test (2.1 ± 0.2 and 2.5 ± 0.4 ml, M ± SE, respectively). After lysine acetylsalicylate, mean PD., rose to 5.0 ± 0.7 ml (2.8 ± 0.6 times higher than placebo); after furosemide, to 9.0± 1.5 ml (4.4 ± 0.9 times over placebo); and after the two drugs in combination, to 32.2 ± 5.6 ml (16.3 ± 3.0 times higher than placebo). Similar results were obtained with inhaled indomethacin, whereas sodium salicylate had no effect. These data indicate that the bronchial antireactive activity of inhaled furosemide is greatly enhanced by inhaled lysine acetylsalicylate through a mechanism which probably involves inhibition of the local synthesis of prostaglandins, and could have therapeutic implications.     

The effect of lysine acetylsalicylate on joint capsule mechanoreceptors in rats with polyarthritis

Summary Joint capsule mechanoreceptors in arthritic rats are more sensitive to pressure than similar receptors in normal animals. This greater sensitivity was reversed by the intravenous or topical administration of lysine acetylsalicylate in anaesthetised rats in doses of 15 to 50 mgm ASA-equivalent/kg. The reduction in sensitivity began within 5–10 min and reached a minimum mean value of 35% of the control after 35 to 40 min. During this period there was a negative linear or exponential relation between the amplitude of response to a controlled mechanical stimulus and time after administration of lysine acetylsalicylate. Control values of sensitivity were reached about 65–70 min following treatment with lysine acetylsalicylate. The results are interpreted as indicating that the high sensitivity of the arthritic joint capsule receptors is due to locally produced prostaglandins, such as prostacyclin.     

Exercise-induced bronchoconstriction in children with asthma: An observational cohort study

Background/purposeThe diagnosis of exercise-induced bronchoconstriction (EIB) was established by changes in lung function after exercise challenge. The prevalence of EIB and factors related to EIB were not fully described in children with asthma. The aim of this study was to investigate the prevalence and predictors of EIB in children with asthma.MethodsA total of 149 children with physician-diagnosed asthma above 5 years of age underwent standardized treadmill exercise challenge for EIB and methacholine challenge for airway hyper-responsiveness from October 2015 to December 2016.ResultsEIB presented in 52.5% of children with asthma. Compared with children without EIB, there were more patients with atopic dermatitis in children with EIB (p = 0.038). Allergic to Dermatohagoides pteronyssinus and Dermatophagoides farinae were also found more in children with EIB (p = 0.045 and 0.048 respectively). Maximal decrease in forced expiratory volume in 1 s (FEV₁) were highest in patients who were most sensitive to methacholine provocation (provocation concentration causing 20% fall in FEV1 [PC₂₀] ≤ 1 mg/mL). Patients, who were more sensitive to methacholine challenge (with lower PC₂₀ levels), develop EIB with more decline in FEV₁ after exercise challenge (p = 0.038). Among patients with EIB, airflow limitation development in patient with methacholine-induced airway hyper-responsiveness was more abrupt and severe compared with patients without airway hyper-responsiveness (p = 0.045 and 0.033 respectively).ConclusionEIB presented in 52.5% of children with asthma. The more severe methacholine-induced hyper-responsiveness, the higher prevalence of EIB as well as the severity.     

Asthma in medium altitude--exercise-induced bronchoconstriction in hypobaric environment in subjects with asthma

BACKGROUND: Hypoxic gas inhalation has been reported to enhance airway responsiveness and results in bronchoconstriction in animal models and in humans with asthma. However, the data have so far been conflicting. The aim of the present study was to examine the effect of reduced barometric pressure on exercise-induced bronchoconstriction (EIB) in subjects with asthma. METHODS: Twenty subjects (10-45 years old, male symbol/female symbol = 13/7) with asthma (at least 10% reduction in forced expiratory volume in 1-second postexercise) participated in exercise testing in barometric pressure corresponding to altitudes of 200 (normobaric) and 2500 (hypobaric) m above sea level in random order on separate days. Lung function was measured before and after exercise, as well as after inhalation of salbutamol. Heart rate, oxygen uptake (), arterial oxygen saturation (S(p)O(2)), respiratory gas exchange ratio (RER) and minute ventilation () were measured during exercise. RESULTS: There was no difference in lung function after exercise. The and HR(peak) during exercise did not differ. The RER(peak) was higher (P = 0.04) in hypobaric environment. The decreased 10.1% (7.2-13.0) [mean (95% confidence intervals)] (P < 0.001) from normobaric to hypobaric environment. At the same time, S(p)O(2) at decreased from 94.4 (92.2-96.6) to 85.6% (82.8-88.4) (P < 0.001). CONCLUSIONS: A barometric pressure corresponding to altitude of 2500 m did not increase EIB in subjects with asthma. The reduction in is most probably due to the lower S(p)O(2) in hypobaric environment.     

Contribution of histamine and prostanoids to bronchoconstriction provoked by inhaled bradykinin in atopic asthma

Bradykinin, a nonapeptide cleavage product of high molecular weight kininogen, is a potent bronchoconstrictor agonist in asthma; however, its mechanism of action is not known. Since bradykinin has been shown to stimulate mediator release from mast cells and augment the release of prostanoids, we have examined the effect of a selective histamine H1 receptor antagonist, terfenadine and a potent cyclooxygenase inhibitor, flurbiprofen on bronchoconstriction provoked by inhaled bradykinin in asthma. As a bronchial provocation procedure bradykinin challenge was repeatable to within 1 doubling dilution. In nine atopic asthmatic subjects, terfenadine 180 mg, when compared to placebo, increased the geometric mean provocation concentration of inhaled agonist required to reduce FEV1 by 20% of baseline (PC20) from 0.7 to greater than 22.9 mg/ml for histamine (P less than 0.01) and 0.3 to 0.5 mg/ml for bradykinin (P less than 0.01). In a further nine atopic asthmatics, flurbiprofen 150 mg when compared to placebo produced a small but significant protection of the airways against bradykinin, geometric mean PC20 increasing from 0.40 to 0.79 mg/ml (P less than 0.05). We conclude that bradykinin is a potent bronchoconstrictor agonist in asthma, being approximately 9.5 times more potent than histamine in molar terms. Pharmacological intervention with terfenadine and flurbiprofen led to a significant protection of the airways against the constrictor effect of bradykinin but the effect in each case was small. Thus, while histamine and prostanoids may contribute as mediators of bradykinin-induced bronchoconstriction, they are unlikely to account for the majority of the response.     

Exercise and other indirect challenges to demonstrate asthma or exercise-induced bronchoconstriction in athletes

The prevalence of exercise-induced bronchoconstriction is reported to be high among recreational and elite athletes, yet diagnosis is often symptom-based. Indirect challenges such as the laboratory exercise challenge provide objective criteria for proper diagnosis and treatment. However, a standardized protocol using appropriate exercise intensity, duration, and dry air inhalation is often not implemented, and thus a false-negative test may result. This article reviews and describes the symptom-based diagnosis, the exercise challenge, and other indirect challenges such as eucapnic voluntary hyperpnea, hypertonic saline inhalation, and inhaled powdered mannitol as methods to diagnose and evaluate exercise-induced bronchoconstriction. Advantages and disadvantages of each diagnostic procedure are presented.     

Reduction of histamine-induced bronchoconstriction by magnesium in asthmatic subjects

The effects of inhaled MgSO4 on histamine bronchoprovocation test (BPT) were studied in nine asthmatics in clinical remission (FEV1 greater than 80% of predicted). Patients performed histamine BPT on 2 separate days, one day after saline and the other after MgSO4 inhalation, in a randomized double-blind design. Spirometry and flow/volume curve were recorded on each test day before and 5 min after NaCl or MgSO4. No significant difference was observed in lung function measurements 2 days before and after either NaCl or MgSO4. The dose of histamine which produced a 20% decrease in control FEV1 (PD20FEV1) was significantly increased by aerosolized MgSO4 (from 0.177 +/- 0.036 mg after NaCl to 0.350 +/- 0.085 after MgSO4, P less than 0.05. After MgSO4 the dose-steps of histamine concentration increased two-fold in two subjects and one-fold in five.     

Interleukin‐8 inhalation directly provokes bronchoconstriction in guinea pigs

BACKGROUND: Although it has been reported that the concentration of interleukin (IL)-8 in nasal lavage fluid and sputum and its production in bronchial epithelium were increased in asthmatic subjects, the direct effects of IL-8 on the airways in vivo is unclear. METHODS: We examined bronchoconstriction in response to IL-8 inhalation through an endotracheal cannula in anesthetized, artificially ventilated guinea pigs. RESULTS: Inhalation of IL-8 at concentrations of 1 and 10 microg/ml caused significant bronchoconstriction, as revealed by the elevation of pressure at the airway opening. Moreover, the bronchoconstriction induced by IL-8 was significantly inhibited by the antihistamines diphenhydramine and terfenadine, suggesting the involvement of histamine release in the IL-8-induced bronchoconstriction. No significant leukocyte infiltration was observed in the bronchoalveolar lavage fluid or histologic findings 25 min after the first IL-8 inhalation. CONCLUSIONS: IL-8 provokes bronchoconstriction without leukocyte accumulation in the airways, mediated in part by histamine release, in guinea pigs.     

Effect of Oral and Inhaled Sodium Cromoglycate in Exercise–Induced Asthma

Ten patients with bronchial asthma reacting with bronchoconstriction after exercise were studied to compare the effect of oral sodium cromoglycate against sodium cromoglycate inhalation and placebo. Only sodium cromoglycate inhalations protected against exercise-induced asthma. The effect of sodium cromoglycate seems to be a local action of mucosal surfaces.     

Mechanisms of asthma in Olympic athletes--practical implications

Athletes' symptoms may only occur in extreme conditions, which are far from normal. Exercise may increase ventilation up to 200 l/min for short periods in speed and power athletes, and for longer periods in endurance athletes such as swimmers and cross-country skiers. Increasing proportions of young athletes are atopic, i.e. they show signs of IgE-mediated allergy which is, along with the sport event (endurance sport), a major risk factor for asthma and respiratory symptoms. Mechanisms in the etiology and clinical phenotypes vary between disciplines and individuals, and it may be an oversimplification to discuss athlete's asthma as a distinct and unambiguous disease. Nevertheless, the experience on Finnish Olympic athletes suggests at least two different clinical phenotypes, which may reflect different underlying mechanisms. The pattern of 'classical asthma' is characterized by early onset childhood asthma, methacholine responsiveness, atopy and signs of eosinophilic airway inflammation, reflected by increased exhaled nitric oxide levels. Another distinct phenotype includes late onset symptoms (during sports career), bronchial responsiveness to eucapnic hyperventilation test, but not necessarily to inhaled methacholine, and a variable association with atopic markers and nitric oxide. A mixed type of eosinophilic and neutrophilic airway inflammation seems to affect especially swimmers, ice-hockey players, and cross-country skiers. The inflammation may represent a multifactorial trauma, in which both allergic and irritant mechanisms play a role. There is a significant problem of both under- and overdiagnosing asthma in athletes and the need for objective testing is emphasized. Follow-up studies are needed to assess the temporal relationship between asthma and competitive sporting, taking better into account individual disposition, environmental factors (exposure), intensity of training and potential confounders.     

Inhaled cornstarch glove powder increases latex-induced airway hyper-sensitivity in guinea-pigs

BACKGROUND: Breathing is one of the most important modes of sensitization to natural rubber latex (NRL) for health-care workers, a group most at risk. Cornstarch powder (CSp) from medical powdered NRL gloves is known to be an allergen carrier, and sensitization to NRL can occur by inhaling airborne particles from such gloves. OBJECTIVE: The aim of this study was to demonstrate, using an experimental model, which CSp may act as an adjuvant in NRL-induced airway hyper-responsiveness. METHODS: Guinea-pigs were exposed to aerosolized NRL-contaminated CSp or to NRL in saline solution for 1 h every day for 2 weeks. The control groups were exposed either to CSp or to saline alone. An additional group of guinea-pigs was exposed to aerosolized ovalbumin (OVA) in saline. Three weeks after the last exposure, specific bronchial challenges were performed. In addition, Specific IgG and IgG1 in sera and thromboxane (Tx) B(2) levels in bronchoalveolar lavage fluid (BALF) were measured. RESULTS: The NRL challenge caused significant bronchospasm in the animals that had been exposed to NRL compared with those in the control groups (P<0.02). Guinea-pigs exposed to OVA also demonstrated a significant bronchospasm after OVA challenge (P<0.001). The guinea-pigs that had inhaled NRL-contaminated CSp had a significantly higher bronchoconstriction level than those that had inhaled NRL alone (P<0.02). Specific IgG and IgG1 were undetectable in sera from all groups, whereas significant amounts of TxB(2) (P<0.001) were found in the lungs of the guinea-pigs exposed to NRL or OVA. CONCLUSION: Inhaling CSp increases the airway response to NRL. The fact that specific IgG and IgG1 were not detected might be the result of an immune response limited to the airways. This finding is supported by a significant increase of TxB(2) level in the BALF of sensitized guinea-pigs.     

Role of leukotrienes in post-allergic propranolol-induced bronchoconstriction in guinea-pigs

Background Administration of propranolol can provoke bronchoconstriction only in asthmatic patients. Recently we developed an animal model for propranolol-induced bronchoconstriction (PIB). Our working hypothesis is that such bronchoconstriction may result from the inflammatory mediators released by an allergic reaction. Objectives Our goal in this study was to determine which products of arachidonate 5-lipoxygenase pathway are involved in the PIB. Methods Propranolol at a concentration of 10mg/mL was inhaled 20min after antigen challenge in passively sensitized, anaesthetized and artificially ventilated guinea-pigs. Two different sulfidopeptide leukotriene (s-LT) antagonists, ICI198 615 in the doses of 0.03 and 0.3 mg/kg and vehicle and KCA757 in the doses of 1 and 5 mg/kg and vehicle, and a LTB4 antagonist ONO4057 in the doses of 1 and 10 mg/kg and vehicle were injected intravenously 15min after antigen challenge. Effects of an anticholinergic agent atropine sulphate (5 mg/kg) and an α-adrenergic biocker pbentolamine (0.3 and 3 mg/kg) were exatnined in the same way. Results Bronchoconstriction occurred when 10 mg/mL of propranolol was inhaled 20 min after antigen challenge. Both ICI198 615 and KCA757 administered intravenously 15 min after antigen challenge reduced the PIB in a dose-dependent manner while ONO4057 did not alter the PIB . Atropine or phentolamine did not change the PIB . Conclusions These results suggest that mediator mechanism, but not cholinergic or α-adrenergic nerve, is important in the PIB which developed after the allergic bronchoconstriction in our guinea-pig model and that s-LTs but not LTB4 have an important role in the pathophysiology of the PIB.     

Activation of protease-activated receptor-2 reduces airways inflammation in experimental allergic asthma

BACKGROUND: Proteinase-activated receptors (PAR)-2 are members of the family of G-protein-coupled receptors activated by proteases. These receptors are widely expressed in several tissues and in virtually all cells involved in rhinitis and asthma. In particular, proteinases activating PAR-2 may affect airway functions and play a role in human diseases. OBJECTIVE: Assessment of the role of PAR-2 in bronchoconstriction, airway responsiveness and immune response after allergic challenge, in rabbits sensitized to Par j 1, the major allergen of Parietaria judaica pollen. METHODS: Evaluation of antigen challenge in rabbits treated with PAR-2-activating peptide (PAR-2AP) (SLIGRL) or the scrambled peptide LSIGRL or vehicle immediately before allergen exposure measuring airway responsiveness. Characterization of bronchoalveolar lavage (BAL) following histamine challenge and phenotype analysis of cells by flow cytometry and analysis of cytokine production by quantitative PCR. RESULTS: PAR-2AP pre-treatment, but not the scrambled peptide, was able to significantly inhibit bronchoconstriction, airway hyper-responsiveness and to modulate the immune response induced by allergic challenge in sensitized rabbits. The phenotype analysis of the cells recovered from BAL showed an increase in RLA-DR-positive cells while RTLA-positive cells were unchanged. IFN-gamma and IL-2 production were inhibited, with a concomitant increase in IL-10 of about 10-fold over the control values. CONCLUSIONS: In this experimental model, PAR-2 modulates bronchoconstriction interfering with antigen challenge-induced immune response in rabbits sensitized and challenged to Par j 1.     

Decrease of T-lymphocyte proliferation in exercise-induced asthma

The present study was designed to examine the effect of physical exercise on T-lymphocyte proliferation in patients with exercise-induced asthma (EIA). Indeed, a decrease in different immune functions is described in normal man after exercise. Thirty subjects (10 normal and 20 asthmatic subjects with or without EIA) underwent a submaximal exercise test on an electrically driven treadmill. Before and after this test, ventilatory variables were measured, and venous blood was taken to study plasma histamine (RIA) and spontaneous and phytohemagglutinin (PHA)-pulsed T-lymphocyte proliferation (mononuclear cells isolated on Ficoll-Hypaque; tritiated thymidine incorporation). Ten minutes after the end of the exercise, there was a significant FEV₁ decrease only in asthmatic subjects with EIA (mean: 24 ± 5%). In the same group, the mean plasma histamine level was 0.31 ng/ml 1 (± 0.06) before the challenge. It rose to 0.62ng/ml^-1 (± 0.14) 10 min after the end of the exercise ( P < 0.05), and returned to normal limits 20 min after the test. In this group, there was also a significant decrease (by about 35%) of spontaneous and PHA-pulsed T-lymphocyte proliferation 2 and 4 h after the exercise. By contrast, exercise challenge had no effect on either plasma histamine level or T-lymphocyte proliferation in the normal group. Our results show a rapid and transient increase in plasma histamine in EIA. This was followed 2 and 4 h later by a significant decrease of T-lymphocyte proliferation. A possible relationship between these two phenomena is discussed.     

Voice reactions to histamine inhalation in asthma

Susceptibility to voice reactions during a histamine provocation test was studied in 21 asthmatics and 21 healthy subjects. Speech samples were recorded before, and 5 and 15 min after histamine inhalation, and the samples were rated by six speech pathologists. Deterioration of voice quality occurred in 2/12 asthmatic men and in 3/9 asthmatic women within 5 min after histamine inhalation; no change was observed between 5 and 15 min. Voice reactions were not related to the degree of bronchial obstruction: the subjects with the most pronounced decrease in peak expiratory flow (PEF) (60–61% in three subjects) did not develop voice reactions, and PEF did not decrease in one subject with voice reactions. No voice reactions were observed in the healthy subjects.