Tag: Inhibition

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Concomitant inhibition of primary equine bronchial fibroblast proliferation and differentiation by selective ?2-adrenoceptor agonists and dexamethasone.

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Concomitant inhibition of primary equine bronchial fibroblast proliferation and differentiation by selective ?2-adrenoceptor agonists and dexamethasone.

Eur J Pharmacol. 2014 Aug 13;

Authors: Franke J, Abraham G

Abstract
Altered airway cell proliferation plays an important role in the pathogenesis of human bronchial asthma and chronic obstructive pulmonary disease (COPD) as well as the equine recurrent airway obstruction (RAO) with consistent changes, i.e. narrowing the airway wall, explained by proliferation and differentiation of fibroblasts. In permanent cell lines, it has been suggested that ?2-adrenoceptor agonists and glucocorticoids regulate cell proliferation via the ?2-adrenoceptor pathway; indeed, no study was carried out in fresh isolated primary equine bronchial fibroblasts (EBF). We characterized the ?-adrenoceptors in EBF, and compared effects of long-acting (clenbuterol) and short-acting (salbutamol, isoproterenol) ?2-agonists and dexamethasone on proliferation, differentiation and collagen synthesis. High density (Bmax; 5037±494 sites/cell) of ?2-adrenoceptor subtype was expressed in EBF. ?2-agonists inhibited concentration-dependently EBF proliferation with potency of clenbuterol>salbutamol l» isoproterenol which was inhibited by ICI 118.551 and propranolol but not by CGP 20712A. In contrast, dexamethasone alone inhibited less EBF proliferation, but the effect was high when dexamethasone was combined with ?2-agonists. Transforming growth factor-?1 (TGF-?1) increased transformation of fibroblasts into myofibroblasts, and which was inhibited by clenbuterol and dexamethasone alone and drug combination resulted in high inhibition rate. Collagen synthesis in EBF was rather hampered by dexamethasone than by ?-agonists. Collectively, the expression of ?2-adrenoceptor subtype in EBF and the anti-proliferative effect of clenbuterol suggest that ?2-adrenoceptors are growth inhibitory and anti-fibrotic in EBF. These ?2-agonist effects in EBF were synergistically enhanced by dexamethasone, providing the additive effects of glucocorticoids to counteract airway remodelling and morbidity of asthma and RAO.

PMID: 25128704 [PubMed – as supplied by publisher]

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Hesperidin-3′-o-methylether is more potent than hesperidin in phosphodiesterase inhibition and suppression of ovalbumin-induced airway hyperresponsiveness.

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]

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Restoration of Corticosteroid Sensitivity by p38 Mitogen Activated Protein Kinase Inhibition in Peripheral Blood Mononuclear Cells from Severe Asthma.

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Restoration of Corticosteroid Sensitivity by p38 Mitogen Activated Protein Kinase Inhibition in Peripheral Blood Mononuclear Cells from Severe Asthma.

PLoS One. 2012;7(7):e41582

Authors: Mercado N, Hakim A, Kobayashi Y, Meah S, Usmani OS, Chung KF, Barnes PJ, Ito K

Abstract
BACKGROUND: Severe asthma accounts for a small number of asthmatics but represents a disproportionate cost to health care systems. The underlying mechanism in severe asthma remains unknown but several mechanisms are likely to be involved because of a very heterogeneous profile. We investigated the effects of a p38MAPK inhibitor in corticosteroid sensitivity in peripheral blood mononuclear cells (PBMCs) from severe asthmatics and the profile of its responders.
METHODOLOGY/PRINCIPAL FINDINGS: Corticosteroid sensitivity was determined by measuring dexamethasone inhibition of CD3/28 and TNF-? induced IL-8 production in PBMCs by using ELISA. PBMCs from severe asthmatics were relatively less sensitive to dexamethasone (Dex) as compared to those of non-severe asthmatics and healthy volunteers. The IC(50) values of Dex negatively correlated with decreased glucocorticoid receptor (GR) nuclear translocation assessed using immunocytochemistry (r?=?-0.65; p<0.0005) and with decreased FEV(1) (% predicted) (r?=?0.6; p<0.0005). A p38?/? inhibitor (SB203580) restored Dex-sensitivity in a subpopulation of severe asthma that was characterized by a defective GR nuclear translocation, clinically by lower FEV(1) and higher use of oral prednisolone. We also found that SB203580 partially inhibited GR phosphorylation at serine 226, resulting in increased GR nuclear translocation in IL-2/IL-4 treated corticosteroid insensitive U937s.
CONCLUSIONS/SIGNIFICANCE: p38MAPK?/? is involved in defective GR nuclear translocation due to phosphorylation at Ser226 and this will be a useful biomarker to identify responders to p38MAPK?/? inhibitor in the future.

PMID: 22911818 [PubMed – in process]

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