Anti‐mitogenic effects of β‐agonists and PGE2on airway smooth muscle are PKA dependent
Huandong YanDeepak A. DeshpandeAnna M. MisiorMatthew MilesHimansh SaxenaEllen C. RiemerRodolfo M. PascualReynold A. PanettieriRaymond B. Penn
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Inhaled β-agonists are effective airway smooth muscle (ASM)-relaxing agents that help reverse bronchoconstriction in asthma, but their ability to affect the aberrant ASM growth that also occurs with asthma is poorly understood. β-Agonists exhibit PKA-dependent antimitogenic effects in several cell types. However, recent studies suggest that Epac, and not PKA, mediates the antimitogenic effect of cAMP in both ASM and fibroblasts. This study aims to clarify the roleof PKA in mediating the effect of GS-coupled receptors on human ASM growth. Pretreatmentof ASM cultures with β-agonists albuterol, isoproterenol, or salmeterol (100 nM to 10 µM) caused a significant (-25–30%) inhibition of EGF-stimulated ASM thymi-dine incorporation and cell proliferation, whereas a much greater inhibition was observed from pretreatment with PGE2 (75–80%). However, all agents were ineffective in cells expressing GFP chimeras of either PKI (a PKA inhibitor) or a mutant PKA regulatory subunit relative to the control cells expressing GFP. The antimitogenic efficacy of PGE2 in inhibiting control cultures was associated with greater ability to stimulate sustained PKA activation and greater inhibition of late-phase promitogenic p42/p44 and PI3K activities. These findings suggest that therapeutic approaches enabling superior PKA activation in ASM will be most efficacious in deterring ASM growth.—Yan, H., Deshpande, D. A., Misior, A. M., Miles, M. C., Saxena, H., Riemer, E. C., Pascual, R. M., Panettieri, R. A., Penn. R. B. Anti-mitogenic effects of β-agonists and PGE2 on airway smooth muscle are PKA dependent. FASEB J. 25, 389–397 (2011). www.fasebj.orgKeywords:
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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.
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Abstract The phosphodiesterase inhibitor 3‐isobutyl‐1‐methylxanthine (IBMX) showed inductive effect on larval settlement of the polychaete Hydroides elegans . It has been suggested that IBMX triggers larval settlement by elevating the cellular adenosine 3′,5′‐cyclic monophosphate (cAMP) level in this species. To test this hypothesis, we first examined cAMP‐level changes in both the competent (CL) and attached larvae (AL) and then characterized the cAMP‐dependent protein kinase in H. elegans , which is the major mediator of cAMP action. Tissue extracts of the larvae were assayed for cAMP by enzyme immunoassay; the results showed that IBMX increased cAMP production up to approximately two‐folds in the CL. However, there was no significant difference in the cAMP concentration between the CL and AL that were not treated with IBMX. The catalytic subunit of protein kinase A gene from H. elegans (designated HePKAc ) was cloned, and its expression in different developmental stages of H. elegans was examined using quantitative real‐time polymerase chain reaction. The gene expression level in the pre‐competent trochophore larvae was the lowest, increased in the CL, reached the highest in the larvae undergoing normal and IBMX‐induced metamorphosis, and then decreased in the adult stage. In situ hybridization results showed that HePKAc expressed mainly around eye regions and along body fragments of the CL and AL. Our results indicated that the IBMX‐induced cAMP changes and the cAMP‐dependent protein kinase gene may mediate larval development and settlement of H. elegans . J. Exp. Zool. (Mol. Dev. Evol.) 310B:417–427, 2008 . © 2008 Wiley‐Liss, Inc.
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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.
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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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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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