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See detailControl of Allergen-Induced Inflammation and Hyperresponsiveness by the Metalloproteinase ADAMTS-12
Paulissen, Geneviève ULg; El Hour, Mehdi; Rocks, Natacha ULg et al

in Journal of Immunology (2012), 189

A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) constitute a family of endopeptidases related to matrix metalloproteinases. These proteinases have been largely implicated in tissue ... [more ▼]

A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) constitute a family of endopeptidases related to matrix metalloproteinases. These proteinases have been largely implicated in tissue remodeling associated with pathological processes. Among them, ADAMTS12 was identified as an asthma-associated gene in a human genome screening program. However, its functional implication in asthma is not yet documented. The present study aims at investigating potential ADAMTS-12 functions in experimental models of allergic airways disease. Two different in vivo protocols of allergen-induced airways disease were applied to the recently generated Adamts12-deficient mice and corresponding wild-type mice. In this study, we provide evidence for a protective effect of ADAMTS-12 against bronchial inflammation and hyperresponsiveness. In the absence of Adamts12, challenge with different allergens (OVA and house dust mite) led to exacerbated eosinophilic inflammation in the bronchoalveolar lavage fluid and in lung tissue, along with airway dysfunction assessed by increased airway responsiveness following methacholine exposure. Furthermore, mast cell counts and ST2 receptor and IL-33 levels were higher in the lungs of allergen-challenged Adamts12-deficient mice. The present study provides, to our knowledge, the first experimental evidence for a contribution of ADAMTS-12 as a key mediator in airways disease, interfering with immunological processes leading to inflammation and airway hyperresponsiveness. [less ▲]

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See detailCurcumin-cyclodextrin complexes potentiate gemcitabine effects in an orthotopic mouse model of lung cancer.
Rocks, Natacha ULg; Bekaert, Sandrine ULg; Coia, I et al

in British Journal of Cancer (2012), 107(7), 1083-92

Background:Overall clinical outcome for advanced lung cancer remains very disappointing despite recent advances in treatment. Curcumin has been reported as potentially active against cancer.Methods:Owing ... [more ▼]

Background:Overall clinical outcome for advanced lung cancer remains very disappointing despite recent advances in treatment. Curcumin has been reported as potentially active against cancer.Methods:Owing to poor curcumin solubility, we have used cyclodextrins (CD) as an excipient allowing a considerable increase of aqueous solubility and bioavailability of curcumin. The effects of solubilised curcumin have been evaluated in cell cultures as well as in an in vivo orthotopic lung tumour mouse model.Results:Cell proliferation was reduced while apoptosis rates were increased when lung epithelial tumour cells were cultured in the presence of curcumin-CD complexes. For in vivo experiments, cells were grafted into lungs of C57Bl/6 mice treated by an oral administration of a non-soluble form of curcumin, CDs alone or curcumin-CD complexes, combined or not with gemcitabine. The size of orthotopically implanted lung tumours was reduced upon curcumin complex administration as compared with treatments with placebo or non-solubilised curcumin. Moreover, curcumin potentiated the gemcitabine-mediated antitumour effects.Conclusion:Our data demonstrate that curcumin, when given orally in a CD-solubilised form, reduces lung tumour size in vivo. In vitro experiments show impaired tumour cell proliferation and increased cell apoptosis. Moreover, our data underline a potential additive effect of curcumin with gemcitabine thus providing an efficient therapeutic option for antilung cancer therapy. [less ▲]

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See detailNebulized Anti-IL-13 Monoclonal Antibody Fab' Fragment Reduces Allergen-Induced Asthma
Hacha, Jonathan ULg; Tomlinson, K; Maertens, Ludovic ULg et al

in American Journal of Respiratory Cell and Molecular Biology (2012), sous presse

Rationale: Interleukin-13 (IL-13) is a prototypic Th2 cytokine and a central mediator of the complex cascade of events leading to asthmatic phenotype. Indeed, IL-13 plays key roles in IgE synthesis ... [more ▼]

Rationale: Interleukin-13 (IL-13) is a prototypic Th2 cytokine and a central mediator of the complex cascade of events leading to asthmatic phenotype. Indeed, IL-13 plays key roles in IgE synthesis, bronchial hyperresponsiveness, mucus hypersecretion, subepithelial fibrosis and eosinophil infiltration. Objectives: We assessed the potential efficacy of inhaled anti-IL-13 monoclonal antibody Fab' fragment on allergen-induced airway inflammation, hyperresponsiveness and remodeling in an experimental model of allergic asthma. Anti-IL-13 Fab' was administered to mice as a liquid aerosol generated by inExpose® inhalation system in a tower allowing a nose-only exposure. Methods: BALB/c mice were treated by PBS, anti-IL-13 Fab' or A33 Fab' fragment and subjected to ovalbumin (OVA) exposure for 1 and 5 weeks (short term (ST) and long term (LT) protocols). Measurements and Main Results: Our data demonstrate a significant anti-asthma effect following nebulization of anti-IL-13 Fab' in a model of asthma driven by allergen exposure as compared to saline and non-immune Fab fragments. In short and long terms protocols, administration of the anti-IL-13 Fab' by inhalation significantly decreased bronchial responsiveness to methacholine, BALF eosinophilia, inflammatory cell infiltration in lung tissue, and many features of airway remodeling. Levels of pro-inflammatory mediators and matrix metalloprotease levels were significantly lower in lung parenchyma of mice treated with anti-IL-13 Fab'. Conclusions: These data demonstrate that an inhaled anti-IL-13 Fab' significantly reduces airway inflammation, hyperresponsiveness and remodeling. Specific neutralization of IL-13 in the lungs using an inhaled anti-IL-13 Fab' could represent a novel and effective therapy for the treatment of asthma. [less ▲]

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See detailADAM-8, a metalloproteinase, drives acute allergen-induced airway inflammation
Paulissen, Geneviève ULg; Rocks, Natacha ULg; Guéders, Maud ULg et al

in European Journal of Immunology (2011), 41(2), 380-91

Asthma is a complex disease linked to various pathophysiological events including the activity of proteinases. The multifunctional A Disintegrin And Metalloproteinases (ADAMs) displaying the ability to ... [more ▼]

Asthma is a complex disease linked to various pathophysiological events including the activity of proteinases. The multifunctional A Disintegrin And Metalloproteinases (ADAMs) displaying the ability to cleave membrane-bound mediators or cytokines appear to be key mediators in various inflammatory processes. In the present study, we have investigated ADAM-8 expression and production in a mouse model of allergen-induced airway inflammation. In allergen-exposed animals, increased expression of ADAM-8 was found in the lung parenchyma and in dendritic cells purified from the lungs. The potential role of ADAM-8 in the development of allergen-induced airway inflammation was further investigated by the use of an anti-ADAM-8 antibody and ADAM-8 knock-out animals. We observed a decrease in allergen-induced acute inflammation both in BALF and the peribronchial area in anti-ADAM-8 antibody-treated mice and in ADAM-8 deficient mice (ADAM-8-/-) after allergen exposure. ADAM-8 depletion led to a significant decrease of the CD11c+ lung dendritic cells. We also report lower levels of CCL11 and CCL22 production in antibody-treated mice and ADAM-8-/- mice that might be explained by decreased eosinophilic inflammation and lower numbers of dendritic cells, respectively. In conclusion, ADAM-8 appears to favour allergen-induced acute airway inflammation by promoting dendritic cell recruitment and CCL11 and CCL22 production. [less ▲]

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See detailPotential Therapeutic Target Discovery by 2D-DIGE Proteomic Analysis in Mouse Models of Asthma
QUESADA CALVO, Florence ULg; Fillet, Marianne ULg; Renaut, Jenny et al

in Journal of Proteome Research (2011), 10(9), 4291-4301

As asthma physiopathology is complex and not fully understood to date; it is expected that new key mediators are still to be unveiled in this disease. The main objective of this study was to discover ... [more ▼]

As asthma physiopathology is complex and not fully understood to date; it is expected that new key mediators are still to be unveiled in this disease. The main objective of this study was to discover potential new target proteins with a molecular weight >20 kDa by using two-dimensional differential in-gel electrophoresis (2D-DIGE) on lung parenchyma extracts from control or allergen-exposed mice (ovalbumin). Two different mouse models leading to the development of acute airway inflammation (5 days allergen exposure) and airway remodeling (10 weeks allergen exposure) were used. This experimental setting allowed the discrimination of 33 protein spots in the acute inflammation model and 31 spots in the remodeling model displaying a differential expression. Several proteins were then identified by MALDI-TOF/TOF MS. Among those differentially expressed proteins, PDIA6, GRP78, Annexin A6, hnRPA3, and Enolase display an increased expression in lung parenchyma from mice exposed to allergen for 5 days. Conversely, Apolipoprotein A1 was shown to be decreased after allergen exposure in the same model. Analysis on lung parenchyma of mice exposed to allergens for 10 weeks showed decreased calreticulin levels. Changes in the levels of those different mediators were confirmed by Western blot and immunohistochemical analysis. Interestingly, alveolar macrophages isolated from lungs in the acute inflammation model displayed enhanced levels of GRP78. Moreover, intratracheal instillation of anti-GRP78 siRNA in allergen-exposed animals led to a decrease in eosinophilic inflammation and bronchial hyperresponsiveness. This study unveils new mediators of potential importance that are up- and down-regulated in asthma. Among up-regulated mediators, GRP-78 appears as a potential new therapeutic target worthy of further investigations. [less ▲]

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See detailMMP-19 Deficiency Promotes Tenascin-C Accumulation and Allergen-induced Airway Inflammation.
Guéders, Maud ULg; Hirst, S.; Quesada Calvo, Florence ULg et al

in American Journal of Respiratory Cell and Molecular Biology (2010), 43(3), 286-95

Matrix metalloproteinases (MMPs) recently appeared as key regulators of inflammation, allowing recruitment and clearance of inflammatory cells and modifying the biological activity of many peptidic ... [more ▼]

Matrix metalloproteinases (MMPs) recently appeared as key regulators of inflammation, allowing recruitment and clearance of inflammatory cells and modifying the biological activity of many peptidic mediators by cleavage. MMP-19 is a newly described MMP and preferentially cleaves matrix proteins such as collagens and tenascin-C. The role of MMP-19 in asthma has not been described to date. The purpose of the present study was to assess MMP-19 expression in a murine asthma model and to address biological effects of MMP-19 deficiency in mice. Allergenexposed wild-type (WT) mice displayed an increased expression of MMP-19 mRNA and an increased number of MMP-19-positive cells in the lungs detected by immunohistochemistry. After allergen challenge of MMP-19 knockout (MMP-19-/-) mice, an exacerbated eosinophilic inflammation was detected in bronchoalveolar lavage fluid and bronchial tissue along with an increased airway responsiveness to methacholine. A shift towards increased Th2-driven inflammation in MMP-19-/- mice was demonstrated by 1) increased numbers of cells expressing the IL-33 receptor T1/ST2 in lung parenchyma, 2) increased IgG1 levels in serum and 3) higher levels of IL-13 and CCL11 in lung extracts. Tenascin-C was found accumulated in peribronchial areas of MMP-19-/- after allergen challenges as assessed by Western blot and immunohistochemistry analysis. We conclude that MMP-19 is a new mediator in asthma, preventing tenascin-C accumulation and directly or indirectly controlling Th2-driven airway eosinophilia and airway hyperreactivity. Our data suggest that MMP-19 might act on Th2 inflammation homeostasis through preventing tenascin protein accumulation. [less ▲]

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See detailNew asthma biomarkers: lessons from murine models of acute and chronic asthma.
Di Valentin, Emmanuel ULg; Crahay, Céline; Garbacki, Nancy ULg et al

in American Journal of Physiology - Lung Cellular and Molecular Physiology (2009), 296(2), 185-97

Many patients suffering from asthma are not fully controlled by currently available treatments, and some of them display an airway remodeling leading to exaggerated lung function decline. The aim of the ... [more ▼]

Many patients suffering from asthma are not fully controlled by currently available treatments, and some of them display an airway remodeling leading to exaggerated lung function decline. The aim of the present study was to unveil new mediators in asthma to better understand pathophysiology and propose or validate new potential therapeutic targets. A mouse model of asthma mimicking acute or chronic asthma disease was used to select genes undergoing a modulation in both acute and chronic conditions. Mice were exposed to ovalbumin or PBS for 1, 5, and 10 wk [short-, intermediate-, and long-term model (ST, IT, and LT)], and gene expression in the lung was studied using an Affymetrix 430 2.0 genome-wide microarray and further confirmed by RT-PCR and immunohistochemistry for selected targets. We report that 598, 1,406, and 117 genes were upregulated and 490, 153, 321 downregulated at ST, IT, and LT, respectively. Genes related to mucous secretion displayed a progressively amplified expression during the allergen exposure protocol, whereas genes corresponding to growth and differentiation factors, matrix metalloproteinases, and collagens were mainly upregulated at IT. By contrast, genes related to cell division were upregulated at ST and IT and were downregulated at LT. In this study, besides confirming that Arg1, Slc26a4, Ear11, and Mmp12 genes are highly modulated throughout the asthma pathology, we show for the first time that Agr2, Scin, and Cd209e genes are overexpressed throughout the allergen exposure and might therefore be considered as suitable new potential targets for the treatment of asthma. [less ▲]

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See detailBiomarker discovery in asthma-related inflammation and remodeling.
Quesada Calvo, Florence ULg; Fillet, Marianne ULg; De Seny, Dominique ULg et al

in Proteomics (2009), 9(8), 2163-2170

Asthma is a complex inflammatory disease of airways. A network of reciprocal interactions between inflammatory cells, peptidic mediators, extracellular matrix components, and proteases is thought to be ... [more ▼]

Asthma is a complex inflammatory disease of airways. A network of reciprocal interactions between inflammatory cells, peptidic mediators, extracellular matrix components, and proteases is thought to be involved in the installation and maintenance of asthma-related airway inflammation and remodeling. To date, new proteic mediators displaying significant activity in the pathophysiology of asthma are still to be unveiled. The main objective of this study was to uncover potential target proteins by using surface-enhanced laser desorption/ionization-time of flight-mass spectrometry (SELDI-TOF-MS) on lung samples from mouse models of allergen-induced airway inflammation and remodeling. In this model, we pointed out several protein or peptide peaks that were preferentially expressed in diseased mice as compared to controls. We report the identification of different five proteins: found inflammatory zone 1 or RELM (FIZZ-1), calcyclin (S100A6), clara cell secretory protein 10 (CC10), Ubiquitin, and Histone H4. [less ▲]

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See detailRole of ADAM and ADAMTS metalloproteinases in airway diseases
Paulissen, Geneviève ULg; Rocks, Natacha ULg; Guéders, Maud ULg et al

in Respiratory Research (2009), 10(1), 127

Lungs are exposed to the outside environment and therefore to toxic and infectious agents or allergens. This may lead to permanent activation of innate immune response elements. A Disintegrin And ... [more ▼]

Lungs are exposed to the outside environment and therefore to toxic and infectious agents or allergens. This may lead to permanent activation of innate immune response elements. A Disintegrin And Metalloproteinases (ADAMs) and ADAMs with Thrombospondin motifs (ADAMTS) are proteinases closely related to Matrix Metalloproteinases (MMPs). These multifaceted molecules bear metalloproteinase and disintegrin domains endowing them with features of both proteinases and adhesion molecules. Proteinases of the ADAM family are associated to various physiological and pathological processes and display a wide spectrum of biological effects encompassing cell fusion, cell adhesion, "shedding process", cleavage of various substrates from the extracellular matrix, growth factors or cytokines... This review will focus on the putative roles of ADAM/ADAMTS proteinases in airway diseases such as asthma and COPD. [less ▲]

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See detailComparison of acute inflammatory and chronic structural asthma-like responses between C57BL/6 and BALB/c mice
Van Hove, C. L.; Maes, T.; Cataldo, Didier ULg et al

in International Archives of Allergy & Immunology (2009), 149(3), 195-207

BACKGROUND: The interactions between airway responsiveness, structural remodelling and inflammation in allergic asthma remain poorly understood. Prolonged challenge with inhaled allergen is necessary to ... [more ▼]

BACKGROUND: The interactions between airway responsiveness, structural remodelling and inflammation in allergic asthma remain poorly understood. Prolonged challenge with inhaled allergen is necessary to replicate many of the features of airway wall remodelling in mice. In both mice and humans, genetic differences can have a profound influence on allergy, inflammation, airway responsiveness and structural changes. METHODS: The aim of this study was to provide a comparative analysis of allergen-induced airway changes in sensitized BALB/c and C57BL/6 mice that were exposed to inhaled allergen for 2 ('acute'), 6 or 9 weeks ('chronic'). Inflammation, remodelling and responsiveness were analyzed. RESULTS: Both strains developed a Th-2-driven airway inflammation with allergen-specific IgE, airway eosinophilia and goblet cell hyperplasia upon 2 weeks of allergen inhalation. This was accompanied by a significant increase in airway smooth muscle mass and hyperresponsiveness in BALB/c but not in C57BL/6 mice. However, airway eosinophilia was more pronounced in the C57BL/6 strain. Chronic allergen exposure (6 or 9 weeks) resulted in an increase in airway smooth muscle mass as well as subepithelial collagen and fibronectin deposition in both strains. The emergence of these structural changes paralleled the disappearance of inflammation in both C57BL/6 and BALB/c mice and loss of hyperresponsiveness in the BALB/c strain. TGF-beta(1 )was accordingly elevated in both strains. CONCLUSION: Airway inflammation, remodelling and hyperresponsiveness are closely intertwined processes. Genetic background influences several aspects of the acute allergic phenotype. Chronic allergen exposure induces a marked airway remodelling that parallels a decreased inflammation, which was largely comparable between the two strains. [less ▲]

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See detailMouse models of asthma: a comparison between C57BL/6 and BALB/c strains regarding bronchial responsiveness, inflammation, and cytokine production
Guéders, Maud ULg; Paulissen, Geneviève ULg; Crahay, Céline et al

in Inflammation Research (2009), 58(12), 845-54

Objective Animal models of asthma mimic major features of human disease. Since the genetic background of experimental animals might affect hyperresponsiveness and inflammation, we studied its potential ... [more ▼]

Objective Animal models of asthma mimic major features of human disease. Since the genetic background of experimental animals might affect hyperresponsiveness and inflammation, we studied its potential influence and the mechanisms leading to differences in strains. Methods We applied a mouse model of allergic asthma to BALB/c and C57BL/6 mice. Results BALB/c mice displayed greater levels of airway reactivity to methacholine than C57BL/6 mice. Moreover, BALB/c mice exhibited higher numbers of mast cells in lung tissue when compared to C57BL/6. On the contrary, eosinophil and neutrophil counts in bronchoalveolar lavage fluid (BALF) as well as peribronchial eosinophilia were greater in C57BL/6. IL (Interleukin)-4, IL-5, IL-13, and CCL11 levels measured in whole-lung extracts were higher in BALB/c, while, in sharp contrast, CCL11 and CCL5 levels were higher in BALF of C57BL/6 mice. Conclusions We observed phenotypic differences between C57BL/6 and BALB/c mice in an asthma model with different distributions of pro-inflammatory cytokines and inflammatory cells. [less ▲]

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See detailEmerging Roles of ADAM and ADAMTS Metalloproteinases in Cancer
Rocks, Natacha ULg; Paulissen, Geneviève ULg; El Hour, Mehdi ULg et al

in Biochimie (2008), 90(2), 369-79

A disintegrin and metalloproteinases (ADAMs) are a recently discovered family of proteins that share the metalloproteinase domain with matrix metalloproteinases (MMPs). Among this family, structural ... [more ▼]

A disintegrin and metalloproteinases (ADAMs) are a recently discovered family of proteins that share the metalloproteinase domain with matrix metalloproteinases (MMPs). Among this family, structural features distinguish the membrane-anchored ADAMs and the secreted ADAMs with thrombospondin motifs referred to as ADAMTSs. By acting on a large panel of membrane-associated and extracellular substrates, they control several cell functions such as adhesion, fusion, migration and proliferation. The current review addresses the contribution of these proteinases in the positive and negative regulation of cancer progression as mainly mediated by the regulation of growth factor activities and integrin functions. [less ▲]

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See detailthe metalloproteinase ADAM-12 regulates bronchial epithelial cell proliferation and apoptosis.
Rocks, Natacha ULg; Estrella, C.; Paulissen, Geneviève ULg et al

in Cell Proliferation (2008), 41(6), 988-1001

Objectives: The ADAMs (a disintegrin and metalloproteinase) enzymes compose a family of membrane-bound proteins characterized by their multi-domain structure and ADAM-12 expression is elevated in human ... [more ▼]

Objectives: The ADAMs (a disintegrin and metalloproteinase) enzymes compose a family of membrane-bound proteins characterized by their multi-domain structure and ADAM-12 expression is elevated in human non-small cell lung cancers. The aim of this study was to investigate the roles played by ADAM-12 in critical steps of bronchial cell transformation during carcinogenesis. Materials and methods: To assess the role of ADAM-12 in tumorigenicity, BEAS-2B cells were transfected with a plasmid encoding human full-length ADAM-12 cDNA, and then the effects of ADAM-12 overexpression on cell behaviour were explored. Treatment of clones with heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) neutralizing antibodies as well as an EGFR inhibitor allowed the dissection of mechanisms regulating cell proliferation and apoptosis. Results: Overexpression of ADAM-12 in BEAS-2B cells promoted cell proliferation. ADAM-12 overexpressing clones produced higher quantities of HB-EGF in their culture medium which may rely on membrane-bound HB-EGF shedding by ADAM-12. Targeting HB-EGF activity with a neutralizing antibody abrogated enhanced cell proliferation in the ADAM-12 overexpressing clones. In sharp contrast, targeting of amphiregulin, EGF or transforming growth factor-α failed to influence cell proliferation; moreover, ADAM-12 transfectants were resistant to etoposide-induced apoptosis and the use of a neutralizing antibody against HB-EGF activity restored rates of apoptosis to be similar to controls. Conclusions: ADAM-12 contributes to enhancing HB-EGF shedding from plasma membranes leading to increased cell proliferation and reduced apoptosis in this bronchial epithelial cell line. [less ▲]

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See detailA novel formulation of inhaled doxycycline reduces allergen-induced inflammation, hyperresponsiveness and remodeling by matrix metalloproteinases and cytokines modulation in a mouse model of asthma
Guéders, Maud ULg; Bertholet, P.; Perin, Fabienne ULg et al

in Biochemical Pharmacology (2008), 75(2), 514-26

Background In this study, we assess the effectiveness of inhaled doxycycline, a tetracycline antibiotic displaying matrix metalloproteinases (MMP) inhibitory effects to prevent allergen-induced ... [more ▼]

Background In this study, we assess the effectiveness of inhaled doxycycline, a tetracycline antibiotic displaying matrix metalloproteinases (MMP) inhibitory effects to prevent allergen-induced inflammation, hyperresponsiveness and remodeling. MMPs play key roles in the complex cascade of events leading to asthmatic phenotype. Methods Doxycycline was administered by aerosols by the mean of a novel formulation as a complex with hydroxypropyl-gamma-cyclodextrin (HP-gamma-CD) used as an excipient. BALB/c mice (n = 16–24 in each group) were sensitized and exposed to aerosolized ovalbumin (OVA) from day 21 to 27 (short-term exposure protocol) or 5 days/odd weeks from day 22 to 96 (long-term exposure protocol). Results In the short-term exposure model, inhaled doxycycline decreased allergen-induced eosinophilic inflammation in bronchoalveolar lavage (BAL) and in peribronchial areas, as well as airway hyperresponsiveness. In lung tissue, exposure to doxycycline via inhaled route induced a fourfold increase in IL-10 levels, a twofold decrease in IL-5, IL-13 levels and diminished MMP-related proteolysis and the proportion of activated MMP-9 as compared to placebo. In the long-term exposure model, inhaled doxycycline significantly decreased the extent of glandular hyperplasia, airway wall thickening, smooth muscle hyperplasia and subepithelial collagen deposition which are well recognized features of airway remodeling. Conclusion Doxycycline administered by aerosols decreases the allergen-induced airway inflammation and hyperresponsiveness and inhibits the development of bronchial remodeling in a mouse model of asthma by modulation of cytokines production and MMP activity. [less ▲]

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See detailADAMTS-1 metalloproteinase induces a stromal reaction and propotes tumor development in mice.
Rocks, Natacha ULg; Paulissen, Geneviève ULg; Quesada Calvo, Florence ULg et al

in Cancer Research (2008), 68(22), 9541-50

ADAMTS-1 (a disintegrin and metalloproteinase with thrombospondin motifs), the first described member of the ADAMTS family, is differentially expressed in various tumors. However, its exact role in tumor ... [more ▼]

ADAMTS-1 (a disintegrin and metalloproteinase with thrombospondin motifs), the first described member of the ADAMTS family, is differentially expressed in various tumors. However, its exact role in tumor development and progression is still unclear. The aim of this study was to investigate the effects of ADAMTS-1 transfection in a bronchial epithelial tumor cell line (BZR) and its potential to modulate tumor development. ADAMTS-1 overexpression did not affect in vitro cell properties such as (a) proliferation in two-dimensional culture, (b) proliferation in three-dimensional culture, (c) anchorageindependent growth in soft agar, (d) cell migration and invasion in modified Boyden chamber assay, (e) angiogenesis in the aortic ring assay, and (f) cell apoptosis. In contrast, ADAMTS-1 stable transfection in BZR cells accelerated the in vivo tumor growth after s.c. injection into severe combined immunodeficient mice. It also promoted a stromal reaction characterized by myofibroblast infiltration and excessive matrix deposition. These features are, however, not observed in tumors derived from cells overexpressing a catalytically inactive mutant of ADAMTS-1. Conditioned media from ADAMTS-1–overexpressing cells display a potent chemotactic activity toward fibroblasts. ADAMTS-1 overexpression in tumors was associated with increased production of matrix metalloproteinase-13, fibronectin, transforming growth factor B (TGF-B), and interleukin-1B (IL-1B). Neutralizing antibodies against TGF-B and IL-1B blocked the chemotactic effect of medium conditioned by ADAMTS-1–expressing cells on fibroblasts, showing the contribution of these factors in ADAMTS-1–induced stromal reaction. In conclusion, we propose a new paradigm for catalytically active ADAMTS-1 contribution to tumor development, which consists of the recruitment of fibroblasts involved in tumor growth and tumor-associated stroma remodeling. [less ▲]

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See detailContribution of cyclodextrins in the developement of different pharmaceutical formulations of a nex matrix metalloproteinase inhibitor
Evrard, Brigitte ULg; Bertholet, Pascal; Guéders, Maud ULg et al

in Journal of Inclusion Phenomena and Molecular Recognition in Chemistry (2007), 57(1-4), 303-308

Ro 28-2653 is a new synthetic inhibitor of matrix metalloproteinases. The ability of these enzymes to degrade various components of the extracellular matrix seems to play a major role in tumors ... [more ▼]

Ro 28-2653 is a new synthetic inhibitor of matrix metalloproteinases. The ability of these enzymes to degrade various components of the extracellular matrix seems to play a major role in tumors progression and is potentially effective against bronchial remodeling in asthma and BPCO. Ro 28-2653 is very poorly soluble in water. This low solubility estimated at about 0.56 lg/ml in water at 25 C gives rise to difficulties in pharmaceutical formulation of oral, injectable or <br />nebulizable solutions. The purpose of our study is to prepare and to characterize inclusion complexes between Ro 28-2653 and cyclodextrins and to investigate the biopharmaceutical repercussion of the inclusion of the active substance.The complex formation was investigated by phase solubility studies. 1H-NMR spectroscopy and molecular modeling studies were carried out to elucidate the structure of the inclusion <br />complex between Ro 28-2653 and cyclodextrin. Oral, intravenous and nebulizable solutions of Ro 28-2653 were developed with cyclodextrin. The in vivo studies were performed on healthy sheep for the pharmacokinetic evaluation of the oral and intravenous formulations while the nebulization of the complex solution was studied by using an asthma model in mouse. [less ▲]

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See detailExpression of a disintegrin and metalloprotease (ADAM and ADAMTS) enzymes in human non-small-cell lung carcinomas (NSCLC)
Rocks, Natacha ULg; Paulissen, Geneviève ULg; Quesada Calvo, Florence ULg et al

in British Journal of Cancer (2006), 94(5), 724-730

A Disintegrin and Metalloprotease (ADAM) are transmembrane proteases displaying multiple functions. ADAM with ThromboSpondin-like motifs (ADAMTS) are secreted proteases characterised by thrombospondin (TS ... [more ▼]

A Disintegrin and Metalloprotease (ADAM) are transmembrane proteases displaying multiple functions. ADAM with ThromboSpondin-like motifs (ADAMTS) are secreted proteases characterised by thrombospondin (TS) motifs in their C-terminal domain. The aim of this work was to evaluate the expression pattern of ADAMs and ADAMTS in non small cell lung carcinomas (NSCLC) and to investigate the possible correlation between their expression and cancer progression. Reverse transcriptase-polymerase chain reaction (RT-PCR), Western blot and immunohistochemical analyses were performed on NSCLC samples and corresponding nondiseased tissue fragments. Among the ADAMs evaluated (ADAM-8, -9, -10, -12, -15, -17, ADAMTS-1, TS-2 and TS-12), a modulation of ADAM-12 and ADAMTS-1 mRNA expression was observed. Amounts of ADAM-12 mRNA transcripts were increased in tumour tissues as compared to the corresponding controls. In sharp contrast, ADAMTS-1 mRNA levels were significantly lower in tumour tissues when compared to corresponding nondiseased lung. These results were corroborated at the protein level by Western blot and immunohistochemistry. A positive correlation was observed between the mRNA levels of ADAM-12 and those of two vascular endothelial growth factor (VEGF)-A isoforms (VEGF-A(165) and VEGF-A(121)). Taken together, these results providing evidence for an overexpression of ADAM-12 and a lower expression of ADAMTS-1 in non-small-cell lung cancer suggest that these proteases play different functions in cancer progression. [less ▲]

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See detailMatrix metalloproteinases (MMPs) and tissue inhibitors of MMPs in the respiratory tract: Potential implications in asthma and other lung diseases
Guéders, Maud ULg; Foidart, Jean-Michel ULg; Noël, Agnès ULg et al

in European Journal of Pharmacology (2006), 533(1-3), 133-144

In healthy lung, Matrix Metalloproteinases (MMPs) and their physiological inhibitors, tissue inhibitors of matrix metalloproteinases (TIMPs), are produced in the respiratory tract by a panel of different ... [more ▼]

In healthy lung, Matrix Metalloproteinases (MMPs) and their physiological inhibitors, tissue inhibitors of matrix metalloproteinases (TIMPs), are produced in the respiratory tract by a panel of different structural cells. These activities are mandatory for many physiological processes including development, wound healing and cell trafficking. Deregulation of proteolytic-antiproteolytic network and inappropriate secretion of various MMPs by stimulated structural or inflammatory cells is thought to take part to pathophysiology of numerous lung diseases including asthma, chronic obstructive pulmonary disease (COPD), lung fibrosis and lung cancer. Cytokines and growth factors are involved in these inflammatory processes and some of those mediators interact directly with MMPs and TIMPs leading either to a regulation of their expression or changes in their biological activities by proteolytic cleavage. In turn, cytokines and growth factors modulate secretion of MMPs establishing a complex network of reciprocal interactions. Every MMP seem to play a rather specific role and some variations of their expression are observed in different lung diseases. The precise role of these enzymes and their inhibitors is now studied in depth as they could represent relevant therapeutic targets for many diseases. Indeed, MMP inhibition can lead either to a decrease of the intensity of a pathological process or, in the contrary for some of them, to an increase of disease severity. In this review, we focus on the role played by MMPs and TIMPs in asthma and we provide an overview of their potential roles in COPD, lung fibrosis and lung cancer, with a special emphasis on loops including MMPs and cytokines and growth factors relevant in these diseases. [less ▲]

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See detailEvaluation of the pulmonary inflammation and bronchial hyperresponsiveness in healthy mice induced by inhaled cyclodextrins
Guéders, Maud ULg; Bertholet, P.; Barillaro, Valery et al

in Journal of inclusion Phenomena and Macrocyclic Chesmistry (2005)

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See detailMatrix metalloproteinase-12 and cathepsin D expression in pulmonary macrophages and dendritic cells of cigarette smoke-exposed mice
Bracke, K.; Cataldo, Didier ULg; Maes, T. et al

in International Archives of Allergy & Immunology (2005), 138(2), 169-179

An imbalance between proteinases and their inhibitors is believed to play an essential role in the development of chronic obstructive pulmonary disease ( COPD) and pulmonary emphysema. COPD is mainly ... [more ▼]

An imbalance between proteinases and their inhibitors is believed to play an essential role in the development of chronic obstructive pulmonary disease ( COPD) and pulmonary emphysema. COPD is mainly caused by cigarette smoking, and is characterized by an increase in inflammatory cells in small airways and lung parenchyma. We examined the mRNA expression of several proteinases in lungs of mice exposed to cigarette smoke or control air. After 1, 3 and 6 months' smoke exposure there was a significant increase of matrix metalloproteinase (MMP)-12 and Cathepsin D mRNA, compared to air-exposed mice. To determine the cellular origin of MMP-12 and Cathepsin D, we isolated dendritic cells (DCs) and macrophages from the lungs of mice. There was an increase in MMP-12 mRNA after smoke exposure in both macrophage and DC populations, whereas Cathepsin D was predominantly expressed in macrophages. Immunohistochemistry clearly revealed the expression of Cathepsin D protein in alveolar macrophages of cigarette smoke-exposed mice, in contrast to air-exposed littermates. Western blots on lung tissue demonstrated an increase of MMP-12 protein in cigarette smoke- exposed animals. These results indicate that cigarette smoke increases the expression of MMP-12 and Cathepsin D in the lungs of mice, and that not only macrophages but also DCs produce MMP-12. Copyright (C) 2005 S. Karger AG, Basel. [less ▲]

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