Therapeutic administration of Budesonide ameliorates allergen-induced airway remodelling
Leukocyte Biology Section, Division of Biomedical Sciences, Faculty of Medicine Imperial College, London SW7 2AZ, UK. Clinical & Experimental Allergy
(Impact Factor: 4.77).
04/2005; 35(3):388-96. DOI: 10.1111/j.1365-2222.02193.x
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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Available from: Fernanda D Lopes
- "Corticosteroids can cause the induction of eosinophils apoptosis by the mechanism known as programmed cell death, acting as a target therapy in asthmatic patients . McMillan et al.  showed in mice chronically exposed to ovalbumin that chronic administration of budesonide was able to decrease airway hyperreactivity, as well as leukocyte infiltration, and decreased production of Th2 mediators such as interleukin 4 (IL-4), interleukin 12 (IL-12), and eotaxin-1. "
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Compare the effects of montelukast or dexamethasone in distal lung parenchyma and airway walls of guinea pigs (GP) with chronic allergic inflammation.
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.
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).
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.
09/2013; 2013(6):523761. DOI:10.1155/2013/523761
Available from: ncbi.nlm.nih.gov
- "However, none of the available drugs today significantly affects or reverses the airway wall remodelling. On the contrary, there is evidence that glucocorticoids may worsen airway remodelling under certain conditions in humans at least in vitro (Chakir et al., 2003; de Kluijver et al., 2005; Goulet et al., 2007), but not in animal models (McMillan et al., 2005). Such species-specific differences may be explained by a feedback mechanism between collagens and glucocorticoid signalling (Bonacci et al., 2003; Goulet et al., 2007). "
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ABSTRACT: The asthma prevalence was increasing over the past two decades worldwide. Allergic asthma, caused by inhaled allergens of different origin or by food, is mediated by inflammatory mechanisms. The action of non-allergic asthma, induced by cold air, humidity, temperature or exercise, is not well understood. Asthma affects up to 15% of the population and is treated with anti-inflammatory and muscle relaxing drugs which allow symptom control. Asthma was first defined as a malfunction of the airway smooth muscle, later as an imbalanced immune response of the lung. Recent studies placed the airway smooth muscle again into the focus. Here we summarize the molecular biological basis of the deregulated function of the human airway smooth muscle cell as a cause or important contributor to the pathology of asthma. In the asthmatic human airway smooth muscle cells, there is: (i) a deregulation of cell differentiation due to low levels of maturation-regulating transcription factors such as CCAAT/enhancer binding proteins and peroxisome proliferator-activated receptors, thereby reducing the cells threshold to proliferate and to secrete pro-inflammatory cytokines under certain conditions; (ii) a higher basal energy turnover that is due to increased number and activity of mitochondria; and (iii) a modified feedback mechanism between cells and the extracellular matrix they are embedded in. All these cellular pathologies are linked to each other and to the innate immune response of the lung, but the sequence of events is unclear and needs further investigation. However, these findings may present the basis for the development of novel curative asthma drugs.
British Journal of Pharmacology 05/2009; 157(3):334-41. DOI:10.1111/j.1476-5381.2009.00188.x · 4.84 Impact Factor
Available from: Andrzej M Fal
- "These findings suggest that TGF-β1 in the epithelium might exert a different role from the one it exerts in the ECM, as these correlations were not seen regarding submucosal TGF-β1 immunoreactivity. In the present study the other agent making the interpretation difficult could be the corticosteroid therapy introduced in LSA-group, as the influence of ICS on TGF-β1 expression is not clear [3, 21, 24]. "
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ABSTRACT: Chronic inflammation in asthmatic airways leads to bronchial hyper-responsiveness (BHR) and the development of structural changes. Important features of remodeling include the formation of subepithelial fibrosis due to increased collagen deposition in the reticular basement membrane. Transforming growth factor (TGF)-beta might be a central mediator of tissue fibrosis and remodeling.
Immunohistochemistry was used to measure collagen III deposition and TGF-beta(1) expression in biopsies from patients with long-standing asthma treated with inhaled corticosteroids, patients with recently diagnosed asthma, and control subjects. Computer-assisted image analysis was used to evaluate total basement membrane (TBM) thickness.
Asthmatics, particularly those with long-standing asthma, had thicker TBMs than healthy subjects. Collagen III deposition was comparable in the studied groups. BHR was not correlated with features of mucosal inflammation and was lower in steroid-treated patients with long-standing asthma than in subjects with newly diagnosed asthma untreated with steroids. Epithelial TGF-beta(1) expression negatively correlated with collagen III deposition and TBM thickness.
The study showed that TBM thickness, but not collagen III deposition, could be a differentiating marker of asthmatics of different disease duration and treatment. The lack of correlation between BHR and features of mucosal inflammation suggests the complexity of BHR development. Corticosteroids can reduce BHR in asthmatics, but it seems to be less effective in reducing subepithelial fibrosis. The role of epithelial TGF-beta(1) needs to be further investigated since the possibility that it plays a protective and anti-inflammatory role in asthmatic airways cannot be excluded.
Archivum Immunologiae et Therapiae Experimentalis 01/2009; 56(6):401-8. DOI:10.1007/s00005-008-0044-z · 3.18 Impact Factor
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