Activation of protease‐activated receptor‐2 reduces airways inflammation in experimental allergic asthma
Bruno D’AgostinoFiorentina RoviezzoRaffaele De PalmaStefania TerraccianoMarilisa De NardoLuca GallelliG. F. AbbateElena D’AiutoMaría Julieta RussoGiuseppe CirinoFrancesco Rossi
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Abstract:
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.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.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.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.In this experimental model, PAR-2 modulates bronchoconstriction interfering with antigen challenge-induced immune response in rabbits sensitized and challenged to Par j 1.Keywords:
Allergic Inflammation
Disodium cromoglycate
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We have examined the effect of azelastine, a new H1 histamine receptor antagonist, against bronchoconstriction induced by histamine and allergen. Twelve mild, atopic asthmatics each underwent two histamine and two allergen concentration-response inhalation challenges 4 hr after treatment with either 8.8 mg of azelastine or a matched placebo. Following azelastine the dose of histamine required to provoke a 20% fall in FEV1 (PD20 histamine) rose, from a geometric mean of 0.31 mg/ml to greater than 13.2 mg/ml. Azelastine also significantly inhibited allergen-induced bronchoconstriction, the PD20 allergen rising from 9.3 cumulative breath units (c.b.u.) to greater than 47.9 c.b.u., a greater than 5-fold increase. We conclude that azelastine effectively inhibits both histamine and allergen-induced bronchoconstriction, with considerably greater potency against histamine.
Azelastine
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Slow-reacting substance of anaphylaxis (SRS-A) is an important factor mediating bronchoconstriction in asthma. We developed a guinea pig model for SRS-A mediated bronchoconstriction induced by antigen inhalation. Using this model, we investigated the effect of inhaled WP871, a new anti-allergic drug, on bronchoconstriction. Aerosol WP871 (0.01 and 0.033%) to some extent inhibited the antigen-induced bronchoconstriction in a dose-dependent fashion, but high-dose WP871 (0.1%) inhalation itself produced a non-specific bronchoconstriction. However, aerosol WP871 (0.033%) showed no inhibitory effect on bronchoconstriction caused by direct inhalation of leukotriene C4, a component of SRS-A. These findings indicate that aerosol WP871 does not antagonize SRS-A, but inhibits synthesis and/or release of SRS-A and has some non-specific bronchoconstrictive effect in high concentration.
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Approximately 70-80% of all asthma sufferers develop acute airway obstruction with exercise, while at least 7% of children in the general population develop exercise-induced bronchoconstriction. The purpose of this study was: (i) to determine whether children in the Cape Peninsula who suffer from asthma and/or exercise-induced bronchoconstriction are as inactive and uninvolved in sport as asthmatic children in the USA; and (ii) whether this uninvolvement is a direct result of their susceptibility to exercise-induced bronchoconstriction. An in-depth study was done on the intensity, frequency and level of participation in sport by children with asthma and/or exercise-induced bronchoconstriction compared with a control group of healthy children without a history of asthma or exercise-induced bronchoconstriction. Children with asthma and/or exercise-induced bronchoconstriction generally maintained a similar level of sport participation as healthy children, and only children with serious asthma or exercise-induced bronchoconstriction experienced limitations with regard to physical activity. It was found that, in contrast to children in the USA, non-participation in sport could not be explained by asthma and/or exercise-induced bronchoconstriction.
Exercise-induced asthma
Physical exercise
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Cough variant asthma (CVA) is recognized as a precursor of bronchial asthma (BA). However, the cough response to bronchoconstriction differs between these similar diseases. Repeated bronchoconstriction and the resulting imbalance of endogenous lipid mediators may impact the cough response. We investigated the influence of repeated bronchoconstriction on the cough response to bronchoconstriction using naïve guinea pigs. Bronchoconstriction was induced for 3 consecutive days and changes in the cough response and lipid mediators, such as PGE2, PGI2, and cysteinyl-LTs (Cys-LTs), in BAL fluid (BALF) were assessed. We investigated the effect of endogenous PGI2 on the cough response by employing a PGI2 receptor antagonist. In order to investigate the cough response over a longer period, we re-evaluated the cough response 2 weeks after repeated bronchoconstriction. The number of coughs induced by bronchoconstriction were significantly decreased by repeated bronchoconstriction. The levels of PGE2, PGI2, and Cys-LTs, and the ratio of PGI2/PGE2 were significantly increased, following repeated bronchoconstriction. This decrease in the cough response was suppressed by pretreatment with a PGI2 receptor antagonist. Two weeks after repeated bronchoconstriction, the cough response returned to the same level as before repeated bronchoconstriction along with a concomitant return of lipid mediators, such as PGE2, PGI2, and Cys-LTs and the ratio of PGI2/PGE2. Our results suggest that repeated bronchoconstriction and the resulting imbalance of endogenous lipid mediators contribute to the difference in cough responses to bronchoconstriction in CVA and BA.
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To examine the role of substance P (SP) in cough during bronchoconstriction, we studied the effects of an aerosolized beta-adrenoceptor agonist, procaterol, and a specific inhibitor of SP (NK1) receptor, FK 888, on bronchoconstriction and cough induced by aerosols of histamine and acetylcholine (ACh) in unsensitized guinea pigs and by those of ovalbumin (OA) antigen in guinea pigs sensitized to OA. Intensity of bronchoconstriction was evaluated by the time to onset of bronchoconstriction after the inhalation of bronchoconstrictors. Both procaterol (10(-6) to 10(-4) M, 2 min) and FK 888 (10(-7) to 10(-5) M, 2 min) dose dependently decreased the number of coughs and increased the time to onset of bronchoconstriction induced by histamine (10(-2) M, 15 s). Procaterol attenuated histamine-induced cough only at the concentrations effective to inhibit bronchoconstriction. However, FK 888 at concentrations of 10(-7) and 10(-6) M decreased the number of coughs without effect on bronchoconstriction. Likewise, the inhibitory effects of procaterol (10(-5) M, 2 min) on the number of coughs were parallel to those on bronchoconstriction induced by ACh (10(-1) M, 15 s) and OA antigen (0.1% concentration, 30 s), but FK 888 (10(-6) M, 2 min) decreased the number of coughs without effect on bronchoconstriction induced by them. The number of coughs induced by histamine (10(-2) M, 15 s) was inhibited by systemic capsaicin treatment and enhanced by phosphoramidon (10(-5) M, 5 min) without effect on bronchoconstriction. (ABSTRACT TRUNCATED AT 250 WORDS)
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Because asthmatics who exhibit exercise-induced bronchonconstriction are also known to be sensitive to the cholinergic drug methacholine, an attempt was made in this study to block exercise-induced bronchoconstriction in nine asthmatics with a known history of exercise-induced bronchoconstriction by pretreatment with atropine. Inhalation of atropine before exercise produced milder exercise-induced bronchoconstriction in three of the nine asthmatics and a total inhibition of exercise-induced bronchoconstriction in two patients. The remaining four asthmatics still exhibited bronchoconstriction during exercise, despite pretreatment with atropine. There was no correlation between a past history of reagenic bronchial allergy or aspirin hypersensitivity and the extent of atropine inhibition of exercise-induced bronchoconstriction. This varied effect of atropine was considered to be due in part to varying amounts of the drug reaching those parts of the bronchial tres most involved in triggering exercise-induced bronchoconstriction.
Methacholine
Exercise-induced asthma
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Abstract Purpose: Exercise-Induced Bronchoconstriction describes the narrowing of the airway that occurs during or immediately after exercise. People with Exercise-Induced Bronchoconstriction are very sensitive to both low temperatures and dry air, the physiological mechanism of Exercise-Induced Bronchoconstriction is not very clear. This study aims to investigate the physiological mechanisms of Exercise-Induced Bronchoconstriction in view of the body self-protection response. Methods: The values of the extracellular volume of 23 Exercise-Induced Bronchoconstriction alone compared with the values of 23 healthy adults by comparing the values of their 24-hour urinary sodium excretion, since it is a non-invasive examination. Result: The values of the extracellular volume of the patients were lower than that of healthy adults. Conclusion: We propose that the exercise-induced bronchoconstriction is a kind of an unconditional response that protects the body from water loss, more specifically, the decrease of extracellular volume triggers Exercise-induced bronchoconstriction to protect the body from water loss.
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Deep inspirations (DIs) have a dilatory effect on airway smooth muscle (ASM) that helps to prevent or reduce more severe bronchoconstriction in healthy individuals. However, this bronchodilation appears to fail in some asthmatic patients or under certain conditions, and the reason is unclear. Additionally, quantitative effects of the frequency and magnitude of DIs on bronchodilation are not well understood. In the present study, we used a computational model of bronchoconstriction to study the effects of DI volumes, time intervals between intermittent DIs, relative speed of ASM constriction, and ASM activation on bronchoconstriction and the emergence of ventilation defects (VDefs). Our results showed a synergistic effect between the volume of DIs and the time intervals between them on bronchoconstriction and VDefs. There was a domain of conditions with sufficiently large volumes of DIs and short time intervals between them to prevent VDefs. Among conditions without VDefs, larger volumes of DIs resulted in greater airway dilation. Similarly, the time interval between DIs, during which the activated ASM re-constricts, affected the amplitude of periodic changes in airway radii. Both the relative speed of ASM constriction and ASM activation affected what volume of DIs and what time interval between them could prevent the emergence of VDefs. In conclusion, quantitative characteristics of DIs, such as their volume and time interval between them, affect bronchoconstriction and may contribute to difficulties in asthma. Better understanding of the quantitative aspects of DIs may result in novel or improved therapeutic approaches.
Bronchodilation
Constriction
Nitrogen washout
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To examine the role of substance P (SP) in cough during bronchoconstriction, we studied the effects of an aerosolized χ-adrenoceptor agonist, procaterol, and a specific inhibitor of SP (NK1) receptor, FK 888, on bronchoconstriction and cough induced by aerosols of histamine and acetylcholine (ACh) in unsensitized guinea pigs and by those of ovalbumin (OA) antigen in guinea pigs sensitized to OA. Intensity of bronchoconstriction was evaluated by the time to onset of bronchoconstriction after the inhalation of bronchoconstrictors. Both procaterol (10−6 to 10−4 M, 2 min) and FK 888 (10−7 to 10−5 M, 2 min) dose dependently decreased the number of coughs and increased the time to onset of bronchoconstriction induced by histamine (10−2 M, 15 s). Procaterol attenuated histamine-induced cough only at the concentrations effective to inhibit bronchoconstriction. However, FK 888 at concentrations of 10−7 and 10−6 M decreased the number of coughs without effect on bronchoconstriction. Likewise, the inhibitory effects of procaterol (10−5 M, 2 min) on the number of coughs were parallel to those on bronchoconstriction induced by ACh (10−1 M, 15 s) and OA antigen (0.1% concentration, 30 s), but FK 888 (10−6 M, 2 min) decreased the number of coughs without effect on bronchoconstriction induced by them. The number of coughs induced by histamine (10−2 M, 15 s) was inhibited by systemic capsaicin treatment and enhanced by phosphoramidon (10−5 M, 5 min) without effect on bronchoconstriction. These results suggest that a β-adrenoceptor agonist inhibits cough predominantly via a bronchodilating action, and SP released from sensory nerves may mediate cough during bronchoconstriction.
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