Therapeutic administration of Budesonide ameliorates allergen-induced airway remodelling.
ABSTRACT Airway inflammation and remodelling are important pathophysiologic features of chronic asthma. Although current steroid use demonstrates anti-inflammatory activity, there are limited effects on the structural changes in the lung tissue.
We have used a mouse model of prolonged allergen challenge that exhibits many of the salient features of airway remodelling in order to investigate the anti-remodelling effects of Budesonide.
Treatment was administered therapeutically, with dosing starting after the onset of established eosinophilic airway inflammation and hyper-reactivity.
Budesonide administration reduced airway hyper-reactivity and leukocyte infiltration in association with a decrease in production of the Th2 mediators, IL-4, IL-13 and eotaxin-1. A reduction in peribronchiolar collagen deposition and mucus production was observed. Moreover, our data show for the first time that, Budesonide treatment regulated active transforming growth factor (TGF)-beta signalling with a reduction in the expression of pSmad 2 and the concomitant up-regulation of Smad 7 in lung tissue sections.
Therefore, we have determined that administration of Budesonide modulates the progression of airway remodelling following prolonged allergen challenge via regulation of inflammation and active TGF-beta signalling.
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ABSTRACT: Although CSs (corticosteroids) demonstrate potent effects in the control of airway inflammation in asthma, many patients continue to experience symptoms and AHR (airway hyper-responsiveness) despite optimal treatment with these agents, probably due to progressive airway remodelling. Identifying novel therapies that can target airway remodelling and/or airway reactivity may improve symptom control in these patients. We have demonstrated previously that the anti-fibrotic hormone RLN (relaxin) can reverse airway remodelling (epithelial thickening and subepithelial fibrosis) and AHR in a murine model of AAD (allergic airways disease). In the present study, we compared the effects of RLN with a CS (methylprednisolone) on airway remodelling and AHR when administered independently or in combination in the mouse AAD model. Female mice at 6-8 weeks of age were sensitized and challenged to OVA (ovalbumin) over a 9-week period and treated with methylprednisolone, RLN, a combination of both treatments or vehicle controls. Methylprednisolone was administered intraperitoneally on the same day as nebulization for 6 weeks, whereas recombinant human RLN-2 was administered via subcutaneously implanted osmotic mini-pumps from weeks 9-11. RLN or methylprednisolone alone were both able to significantly decrease subepithelial thickness and total lung collagen deposition; whereas RLN but not methylprednisolone significantly decreased epithelial thickness and AHR. Additionally, combination therapy with CS and RLN more effectively reduced subepithelial collagen thickness than either therapy alone. These findings demonstrate that RLN can modulate a broader range of airway remodelling changes and AHR than methylprednisolone and the combination of both treatments offers enhanced control of subepithelial fibrosis.Clinical Science 07/2012; 124(1):41-51. · 4.86 Impact Factor
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ABSTRACT: Aims. Compare the effects of montelukast or dexamethasone in distal lung parenchyma and airway walls of guinea pigs (GP) with chronic allergic inflammation. Methods. GP have inhaled ovalbumin (OVA group-2x/week/4weeks). After the 4th inhalation, GP were treated with montelukast or dexamethasone. After 72 hours of the 7th inhalation, GP were anesthetised, and lungs were removed and submitted to histopathological evaluation. Results. Montelukast and dexamethasone treatments reduced the number of eosinophils in airway wall and distal lung parenchyma compared to OVA group (P < 0.05). On distal parenchyma, both treatments were effective in reducing RANTES, NF- κ B, and fibronectin positive cells compared to OVA group (P < 0.001). Montelukast was more effective in reducing eotaxin positive cells on distal parenchyma compared to dexamethasone treatment (P < 0.001), while there was a more expressive reduction of IGF-I positive cells in OVA-D group (P < 0.001). On airway walls, montelukast and dexamethasone were effective in reducing IGF-I, RANTES, and fibronectin positive cells compared to OVA group (P < 0.05). Dexamethasone was more effective in reducing the number of eotaxin and NF- κ B positive cells than Montelukast (P < 0.05). Conclusions. In this animal model, both treatments were effective in modulating allergic inflammation and remodeling distal lung parenchyma and airway wall, contributing to a better control of the inflammatory response.BioMed research international. 01/2013; 2013:523761.
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ABSTRACT: KCa3.1 has been suggested to be involved in regulating cell activation, proliferation and migration in multiple cell types including airway inflammatory and structural cells. However, the contribution of KCa3.1 to airway inflammation and remodeling and subsequent airway hyperresponsiveness (AHR) in allergic asthma remains to be explored. The main purpose of this study was to elucidate the roles of the KCa3.1 and potential therapeutic value of KCa3.1 blockers in chronic allergic asthma. Using real-time PCR, Western blot, and/or immunohistochemical analyses, we explored the precise role of KCa3.1 in bronchus of allergic mice and asthmatic human bronchial smooth muscle cells (BSMCs). We found that KCa3.1 mRNA and protein expression were elevated in the bronchus of allergic mice, and double labeling revealed that up-regulation occurred primarily in airway SMCs. TRAM-34, a KCa3.1 blocker, dose-dependently inhibited the generation and maintenance of OVA-induced airway inflammation associated with increased Th2-type cytokines and decreased Th1-type cytokine as well as subepithelial extracellular matrix deposition, goblet cell hyperplasia and AHR in mouse model of asthma. Moreover, pharmacological blockade and gene silencing of KCa3.1, which elevated evidently after mitogen stimulation, suppressed asthmatic human BSMCs proliferation and migration and arrested the cell cycle at the G0/G1 phase. Additionally, KCa3.1 activator 1-EBIO-induced membrane hyperpolarization and intracellular calcium increase in asthmatic human BSMCs were attenuated by TRAM-34. We demonstrate for the first time that an important role for KCa3.1 in the pathogenesis of airway inflammation and remodeling in allergic asthma and suggest that KCa3.1 blockers may represent a promising therapeutic strategy for asthma.American Journal of Respiratory Cell and Molecular Biology 03/2013; · 4.15 Impact Factor