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Molecule That Decreases Airway Inflammation Could Lead To New Asthma …
RedOrbit Researchers at the Brigham and Women's Hospital (BWH) in Boston have discovered a molecule that controls cells responsible for decreasing airway inflammation in asthma patients, and their discovery could lead to new treatments for the millions of … |
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Inflammation signals airway smooth muscle cell proliferation in asthma …
7thSpace Interactive (press release) It is now well recognized that chronic inflammation, as well as airway hyper-responsiveness and remodeling of airway during inflammation, are crucial to asthma. ASM is caused by increased cell proliferation or by hypertrophy of ASM cells depending on … |
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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]
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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]
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Programmed cell death ligand 2 regulates T(H)9 differentiation and induction of chronic airway hyperreactivity.
J Allergy Clin Immunol. 2012 Nov 19;
Authors: Kerzerho J, Maazi H, Speak AO, Szely N, Lombardi V, Khoo B, Geryak S, Lam J, Soroosh P, Van Snick J, Akbari O
Abstract
BACKGROUND: Asthma is defined as a chronic inflammatory disease of the airways; however, the underlying physiologic and immunologic processes are not fully understood. OBJECTIVE: The aim of this study was to determine whether T(H)9 cells develop in vivo in a model of chronic airway hyperreactivity (AHR) and what factors control this development. METHOD: We have developed a novel chronic allergen exposure model using the clinically relevant antigen Aspergillus fumigatus to determine the time kinetics of T(H)9 development in vivo. RESULTS: T(H)9 cells were detectable in the lungs after chronic allergen exposure. The number of T(H)9 cells directly correlated with the severity of AHR, and anti-IL-9 treatment decreased airway inflammation. Moreover, we have identified programmed cell death ligand (PD-L) 2 as a negative regulator of T(H)9 cell differentiation. Lack of PD-L2 was associated with significantly increased TGF-? and IL-1? levels in the lungs, enhanced pulmonary T(H)9 differentiation, and higher morbidity in the sensitized mice. CONCLUSION: Our findings suggest that PD-L2 plays a pivotal role in the regulation of T(H)9 cell development in chronic AHR, providing novel strategies for modulating adaptive immunity during chronic allergic responses.
PMID: 23174661 [PubMed – as supplied by publisher]
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Increasing Evidence for Small Airway Role in Asthma Intensity
Monthly Prescribing Reference Increasing Evidence for Small Airway Role in Asthma Intensity. (HealthDay News) – There is increasing evidence that the small airways contribute significantly to the clinical expression and severity of asthma, according to research published online Nov. |
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Increasing evidence for small airway role in asthma intensity
Medical Xpress Maarten van den Berge, M.D., Ph.D., from the University of Groningen in the Netherlands, and colleagues reviewed the clinical relevance of small airway disease and its implications for the treatment of asthma. The researchers found that, based on … |
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Increasing Evidence for Small Airway Role in Asthma Intensity
Doctors Lounge TUESDAY, Nov. 20 (HealthDay News) — There is increasing evidence that the small airways contribute significantly to the clinical expression and severity of asthma, according to research published online Nov. 9 in Allergy. Maarten van den Berge, M.D … |
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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