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: 4.32). 04/2005; 35(3):388-96. DOI: 10.1111/j.1365-2222.02193.x
Source: PubMed

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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    • "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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    British Journal of Pharmacology 05/2009; 157(3):334-41. DOI:10.1111/j.1476-5381.2009.00188.x · 4.99 Impact Factor
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    • "It has indeed been found that glucocorticosteroids can attenuate the fibrotic process involved in airway remodeling. In particular, using a mouse model of airway remodeling induced by repeated exposures to allergen challenge, McMillan et al. (2005) recently showed that BUD reduced subepithelial collagen deposition by interfering with TGF-b1 signaling via a decrease in the expression of phosphorylated Smad2, associated with the induction of its inhibitor Smad7. Moreover, it has been shown that glucocorticoid receptors are able to interact with Smad3, a TGF-b-activated DNA binding protein, thus inactivating its transcriptional function (Song et al., 1999). "
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    ABSTRACT: Transforming growth factor-beta1 (TGF-beta1) is crucially involved in the fibrotic events characterizing interstitial lung diseases (ILDs), as well as in the airway remodeling process typical of asthma. Within such a context, the aim of our study was to investigate, in primary cultures of normal and fibrotic human lung fibroblasts (HLFs), the effects of TGF-beta1 on mitogen-activated protein kinase (MAPK) phosphorylation, cell proliferation, and production of interleukins 6 (IL-6) and 11 (IL-11), in the presence or absence of a pretreatment with budesonide (BUD). MAPK phosphorylation was detected by Western blotting, cell viability and proliferation were evaluated using Trypan blue staining and [(3)H]-thymidine incorporation assay, respectively, and the release of IL-6 and IL-11 into cell culture supernatants was assessed by ELISA. TGF-beta1 (10 ng/ml) significantly stimulated MAPK phosphorylation (P < 0.01), and also enhanced cell proliferation as well as the secretion of both IL-6 and IL-11, which reached the highest increases at the 72nd h of cell exposure to this growth factor. All such effects were prevented by BUD (10(-8) M) and, with the exception of IL-6 release, also by a mixture of MAPK inhibitors. Therefore, our findings suggest that the fibrotic action exerted by TGF-beta1 in the lung is mediated at least in part by MAPK activation and by an increased synthesis of the profibrogenic cytokines IL-6 and IL-11; all these effects appear to be prevented by corticosteroids via inhibition of MAPK phosphorylation.
    Journal of Cellular Physiology 02/2007; 210(2):489-97. DOI:10.1002/jcp.20884 · 3.87 Impact Factor
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