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Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness …
Science Magazine Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma. Polina L. Yarova,*,; Alecia L. Stewart,*,; Venkatachalem Sathish,*,; Rodney D. Britt Jr.,*,; Michael A. Thompson,; Alexander P. P. Lowe, … |
View full post on asthma – Google News
Conditions: Rhinitis; Asthma; Inflammation; Hypersensitivity
Intervention:
Sponsor: Guangzhou Institute of Respiratory Disease
Recruiting – verified February 2015
View full post on ClinicalTrials.gov: asthma | received in the last 14 days
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Mfge8 suppresses airway hyperresponsiveness in asthma by regulating smooth muscle contraction.
Proc Natl Acad Sci U S A. 2012 Dec 26;
Authors: Kudo M, Khalifeh Soltani SM, Sakuma SA, McKleroy W, Lee TH, Woodruff PG, Lee JW, Huang K, Chen C, Arjomandi M, Huang X, Atabai K
Abstract
Airway obstruction is a hallmark of allergic asthma and is caused primarily by airway smooth muscle (ASM) hypercontractility. Airway inflammation leads to the release of cytokines that enhance ASM contraction by increasing ras homolog gene family, member A (RhoA) activity. The protective mechanisms that prevent or attenuate the increase in RhoA activity have not been well studied. Here, we report that mice lacking the gene that encodes the protein Milk Fat Globule-EGF factor 8 (Mfge8(-/-)) develop exaggerated airway hyperresponsiveness in experimental models of asthma. Mfge8(-/-) ASM had enhanced contraction after treatment with IL-13, IL-17A, or TNF-?. Recombinant Mfge8 reduced contraction in murine and human ASM treated with IL-13. Mfge8 inhibited IL-13-induced NF-?B activation and induction of RhoA. Mfge8 also inhibited rapid activation of RhoA, an effect that was eliminated by an inactivating point mutation in the RGD integrin-binding site in recombinant Mfge8. Human subjects with asthma had decreased Mfge8 expression in airway biopsies compared with healthy controls. These data indicate that Mfge8 binding to integrin receptors on ASM opposes the effect of allergic inflammation on RhoA activity and identify a pathway for specific inhibition of ASM hypercontractility in asthma.
PMID: 23269839 [PubMed – as supplied by publisher]
View full post on pubmed: asthma
Airway hyperresponsiveness in asthma: mechanisms, clinical significance, and treatment.
Front Physiol. 2012;3:460
Authors: Brannan JD, Lougheed MD
Abstract
Airway hyperresponsiveness (AHR) and airway inflammation are key pathophysiological features of asthma. Bronchial provocation tests (BPTs) are objective tests for AHR that are clinically useful to aid in the diagnosis of asthma in both adults and children. BPTs can be either “direct” or “indirect,” referring to the mechanism by which a stimulus mediates bronchoconstriction. Direct BPTs refer to the administration of pharmacological agonist (e.g., methacholine or histamine) that act on specific receptors on the airway smooth muscle. Airway inflammation and/or airway remodeling may be key determinants of the response to direct stimuli. Indirect BPTs are those in which the stimulus causes the release of mediators of bronchoconstriction from inflammatory cells (e.g., exercise, allergen, mannitol). Airway sensitivity to indirect stimuli is dependent upon the presence of inflammation (e.g., mast cells, eosinophils), which responds to treatment with inhaled corticosteroids (ICS). Thus, there is a stronger relationship between indices of steroid-sensitive inflammation (e.g., sputum eosinophils, fraction of exhaled nitric oxide) and airway sensitivity to indirect compared to direct stimuli. Regular treatment with ICS does not result in the complete inhibition of responsiveness to direct stimuli. AHR to indirect stimuli identifies individuals that are highly likely to have a clinical improvement with ICS therapy in association with an inhibition of airway sensitivity following weeks to months of treatment with ICS. To comprehend the clinical utility of direct or indirect stimuli in either diagnosis of asthma or monitoring of therapeutic intervention requires an understanding of the underlying pathophysiology of AHR and mechanisms of action of both stimuli.
PMID: 23233839 [PubMed – in process]
View full post on pubmed: asthma
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Bronchial Hyperresponsiveness to Methacholine and AMP in Children With Atopic Asthma.
Allergy Asthma Immunol Res. 2012 Nov;4(6):341-5
Authors: Kang SH, Kim HY, Seo JH, Kwon JW, Jung YH, Song YH, Hong SJ
Abstract
PURPOSE: Bronchial hyperresponsiveness (BHR) is typically measured by bronchial challenge tests that employ direct stimulation by methacholine or indirect stimulation by adenosine 5′-monophosphate (AMP). Some studies have shown that the AMP challenge test provides a better reflection of airway inflammation, but few studies have examined the relationship between the AMP and methacholine challenge tests in children with asthma. We investigated the relationship between AMP and methacholine testing in children and adolescents with atopic asthma.
METHODS: The medical records of 130 children with atopic asthma (mean age, 10.63 years) were reviewed retrospectively. Methacholine and AMP test results, spirometry, skin prick test results, and blood tests for inflammatory markers (total IgE, eosinophils [total count, percent of white blood cells]) were analyzed.
RESULTS: The concentration of AMP that induces a 20% decline in forced expiratory volume in 1 second [FEV1] (PC20) of methacholine correlated with the PC20 of AMP (r(2)=0.189, P<0.001). No significant differences were observed in the levels of inflammatory markers (total eosinophil count, eosinophil percentage, and total IgE) between groups that were positive and negative for BHR to methacholine. However, significant differences in inflammatory markers were observed in groups that were positive and negative for BHR to AMP (log total eosinophil count, P=0.023; log total IgE, P=0.020, eosinophil percentage, P<0.001). In contrast, body mass index (BMI) was significantly different in the methacholine positive and negative groups (P=0.027), but not in the AMP positive and negative groups (P=0.62). The PC20 of methacholine correlated with FEV1, FEV1/forced vital capacity (FVC), and maximum mid-expiratory flow (MMEF) (P=0.001, 0.011, 0.001, respectively), and the PC20 of AMP correlated with FEV1, FEV1/FVC, and MMEF (P=0.008, 0.046, 0.001, respectively).
CONCLUSIONS: Our results suggest that the AMP and methacholine challenge test results correlated well with respect to determining BHR. The BHR to AMP more likely implicated airway inflammation in children with atopic asthma. In contrast, the BHR to methacholine was related to BMI.
PMID: 23115730 [PubMed – in process]
View full post on pubmed: asthma
Hesperidin-3′-o-methylether is more potent than hesperidin in phosphodiesterase inhibition and suppression of ovalbumin-induced airway hyperresponsiveness.
Evid Based Complement Alternat Med. 2012;2012:908562
Authors: Yang YL, Hsu HT, Wang KH, Wang CS, Chen CM, Ko WC
Abstract
Hesperidin is present in the traditional Chinese medicine, “Chen Pi,” and recently was reported to have anti-inflammatory effects. Therefore, we were interested in comparing the effects of hesperidin and hesperidin-3′-O-methylether on phosphodiesterase inhibition and airway hyperresponsiveness (AHR) in a murine model of asthma. In the present results, hesperidin-3′-O-methylether, but not hesperidin, at 30??mol/kg (p.o.) significantly attenuated the enhanced pause (P(enh)) value, suppressed the increases in numbers of total inflammatory cells, macrophages, lymphocytes, neutrophils, and eosinophils, suppressed total and OVA-specific immunoglobulin (Ig)E levels in the serum and BALF, and enhanced the level of total IgG(2a) in the serum of sensitized and challenged mice, suggesting that hesperidin-3′-O-methylether is more potent than hesperidin in suppression of AHR and immunoregulation. The different potency between them may be due to their aglycons, because these two flavanone glycosides should be hydrolyzed by ?-glucosidase after oral administration. Neither influenced xylazine/ketamine-induced anesthesia, suggesting that they may have few or no adverse effects, such as nausea, vomiting, and gastric hypersecretion. In conclusion, hesperidin-3′-O-methylether is more potent in phosphodiesterase inhibition and suppression of AHR and has higher therapeutic (PDE4(H)/PDE4(L)) ratio than hesperidin. Thus, hesperidin-3′-O-methylether may have more potential for use in treating allergic asthma and chronic obstructive pulmonary disease.
PMID: 23082087 [PubMed – in process]
View full post on pubmed: asthma
Are mouse models of asthma appropriate for investigating the pathogenesis of airway hyper-responsiveness?
Front Physiol. 2012;3:312
Authors: Kumar RK, Foster PS
Abstract
Whether mouse models of chronic asthma can be used to investigate the relationship between airway inflammation/remodeling and airway hyper-responsiveness (AHR) is a vexed question. It raises issues about the extent to which such models replicate key features of the human disease. Here, we review some of the characteristic pathological features of human asthma and their relationship to AHR and examine some limitations of mouse models that are commonly used to investigate these relationships. We compare these conventional models with our mouse model of chronic asthma involving long-term low-level inhalational challenge and review studies of the relationship between inflammation/remodeling and AHR in this model and its derivatives, including models of an acute exacerbation of chronic asthma and of the induction phase of childhood asthma. We conclude that while extrapolating from studies in mouse models to AHR in humans requires cautious interpretation, such experimental work can provide significant insights into the pathogenesis of airway responsiveness and its molecular and cellular regulation.
PMID: 23060800 [PubMed – in process]
View full post on pubmed: asthma
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Study identifies Olympic athletes with asthma and airway hyper-responsiveness
News-Medical.net Based on data from the last five Olympic games, a study by the University of Western Australia has identified those athletes with asthma and airway hyper-responsiveness. With a prevalence of around 8% they are the most common chronic conditions among … |
View full post on asthma – Google News
Grape Seed Proanthocyanidin Extract Attenuates Airway Inflammation and Hyperresponsiveness in a Murine Model of Asthma by Downregulating Inducible Nitric Oxide Synthase.
Planta Med. 2011 Mar 30;
Authors: Zhou DY, Du Q, Li RR, Huang M, Zhang Q, Wei GZ
Allergic asthma is characterized by hyperresponsiveness and inflammation of the airway with increased expression of inducible nitric oxide synthase (iNOS) and overproduction of nitric oxide (NO). Grape seed proanthocyanidin extract (GSPE) has been proved to have antioxidant, antitumor, anti-inflammatory, and other pharmacological effects. The purpose of this study was to examine the role of GSPE on airway inflammation and hyperresponsiveness in a mouse model of allergic asthma. BALB/c mice, sensitized and challenged with ovalbumin (OVA), were intraperitoneally injected with GSPE. Administration of GSPE remarkably suppressed airway resistance and reduced the total inflammatory cell and eosinophil counts in BALF. Treatment with GSPE significantly enhanced the interferon (IFN)- ? level and decreased interleukin (IL)-4 and IL-13 levels in BALF and total IgE levels in serum. GSPE also attenuated allergen-induced lung eosinophilic inflammation and mucus-producing goblet cells in the airway. The elevated iNOS expression observed in the OVA mice was significantly inhibited by GSPE. In conclusion, GSPE decreases the progression of airway inflammation and hyperresponsiveness by downregulating the iNOS expression, promising to have a potential in the treatment of allergic asthma.
PMID: 21452107 [PubMed – as supplied by publisher]
View full post on pubmed: asthma
Conditions: Intrinsic Asthma; Allergic Asthma; Allergy; Bronchial Hyperresponsiveness
Interventions: Other: methacholine bronchial challenge; Other: methacholine bronchial challenge
Sponsor: Johann Wolfgang Goethe University Hospitals
Not yet recruiting – verified September 2010
View full post on ClinicalTrials.gov: “Asthma” | updated in the last 30 days