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See detailCysteinyl-leukotrienes contribute to sputum eosinophil chemotactic activity in asthmatics
Hemelaers, L.; Henket, Monique ULg; Sele, Jocelyne ULg et al

in Allergy (2006), 61(1), 136-139

Background: Cysteinyl-leukotrienes are lipid derived mediators involved in asthma. They are able to stimulate eosinophil chemotaxis in vitro. Induced sputum from asthmatics has been shown to contain ... [more ▼]

Background: Cysteinyl-leukotrienes are lipid derived mediators involved in asthma. They are able to stimulate eosinophil chemotaxis in vitro. Induced sputum from asthmatics has been shown to contain eosinophil chemotactic activity. The purpose of our study was to evaluate the contribution of cysteinyl-leukotrienes to sputum eosinophil chemotactic activity in asthmatics and to seek whether there might be differences between asthmatics free of inhaled corticosteroids vs those regularly receiving this treatment. Methods: Twenty-two patients (11 corticosteroid free, mean FEV1 99% predicted, 11 corticosteroid-treated, mean FEV1 77% predicted) recruited from our asthma clinic underwent a sputum induction. Sputum was processed according to standard procedure. Eosinophil chemotactic activity contained in the fluid phase was assessed using Boyden microchamber model and expressed as chemotaxis index (CI). Cysteinyl-leukotrienes were measured in sputum supernatant by ELISA and their role in sputum eosionophil chemotactic activity was evaluated by using montelukast, a selective antagonist of a cys-LT1 receptor. Results: Cysteinyl-leukotrienes were well detectable in sputum supernatants from both steroid-naive (247 +/- 42 pg/ml) and steroid-treated (228 +/- 26 pg/ml) asthmatics. Sputum eosinophil chemotactic activity was indiscriminately present in both corticosteroid-naive (CI: 2.61 +/- 0.22) and corticosteroid-treated (2.98 +/- 0.35) asthmatics. Montelukast (100 mu M) significantly inhibited the eosinophil chemotactic activity in both groups achieving a mean inhibition of 54.2 +/- 9.2% (P < 0.001) and 64.7 +/- 7.8% (P < 0.001) in steroid-naive and steroid-treated asthmatics respectively. Conclusion: Cysteinyl-leukotrienes actively participate in sputum eosinophil chemotactic activity found in asthmatics irrespective of whether they are or not under treatment with inhaled corticoids. [less ▲]

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See detailTableau clinique et mécanismes physiopathologiques des principales maladies inflammatoires chroniques des voies respiratoires du cheval
Mesnil, Claire ULg; Bureau, Fabrice ULg; Lekeux, Pierre ULg

in Annales de Médecine Vétérinaire (2006), 150(4), 227-240

The respiratory tract of the horse can be the seat of several chronic inflammatory diseases whose principal ones are the recurrent airway obstruction, the inflammatory airway disease, the summer pasture ... [more ▼]

The respiratory tract of the horse can be the seat of several chronic inflammatory diseases whose principal ones are the recurrent airway obstruction, the inflammatory airway disease, the summer pasture-associated obstructive pulmonary disease and the follicular pharyngitis. These diseases can have an important impact on horses’ health and on their sports performances. A good knowledge of their aetiologies and their physiopathological mechanisms would allow a better control of these affections. However, even if many studies were made on this subject, there are currently very few certainties as for the inflammatory mechanisms governing these diseases. This article aims to make an inventory of knowledge and deficiencies concerning these four chronic inflammatory diseases [less ▲]

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See detailInvasion intracellulaire des cellules non-phagocytaires par Staphylococcus aureus
Boulanger, Delphine; Bureau, Fabrice ULg; Lekeux, Pierre ULg

in Annales de Médecine Vétérinaire (2006), 150(1), 27-42

Intracellular invasion of Staphyloccocus aureus in nonphagocytic cells Staphylococcus aureus often causes chronic diseases. It is now believed that recurrence of these infections could be related to the ... [more ▼]

Intracellular invasion of Staphyloccocus aureus in nonphagocytic cells Staphylococcus aureus often causes chronic diseases. It is now believed that recurrence of these infections could be related to the ability of S. aureus to invade and persist within nonphagocytic cells. Adherence to eucaryotic cells is crucial for S. aureus to invade and persist within invasion and depends on interactions between bacterial fibronectin-binding proteins, fibronectin and the host cell fibronectin receptor, integrin alpha(5)beta(1). It is currently established that fibronectin acts as a bridging molecule. Penetration of S. aureus in host cells requires also activation of protein tyrosine kinases that mediate signal transduction and actin polymerization leading to cytoskeletal rearrangements. After internalization, S. aureus either remains in membrane-bound vacuoles or appears free in the cytoplasm. After bacterial proliferation, S. aureus induces host cell apoptosis or persist inside cells as small colony variants, which represent a less virulent subpopulation of S. aureus that grows slower. Although numerous in vitro and in vivo studies have demonstrated the ability of S. aureus to invade nonphagocytic cells, additional experiments have to be realized to understand the relevance of intracellular localization in vivo. [less ▲]

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See detailLa mammite bovine : de l’initiation à la résolution
Boutet, Philippe ULg; Bureau, Fabrice ULg; Lekeux, Pierre ULg

in Annales de Médecine Vétérinaire (2006), 150(1), 1-26

The bovine mastitis : from initiation to resolution The cure of a cow suffering from a bacterial mastitis relies on the balance between the eradication of the pathogen and the resolution of the ... [more ▼]

The bovine mastitis : from initiation to resolution The cure of a cow suffering from a bacterial mastitis relies on the balance between the eradication of the pathogen and the resolution of the inflammatory response, two processes that are essential to come back to a normal milk composition with low somatic cell count. The persistence of the inflammatory response, which main consequence is a reduction in milk yield, is a feature of chronic mastitis. This frequent disease depends on inappropriate host-pathogen interactions and is not yet well understood. This review resumes the main defence mechanisms of the bovine mammary gland, emphasizing the predominant roles played by the neutrophil, and brings some precisions on lipoxin implications in the resolution of inflammation. Reasons that may explain the persistence of the inflammatory reaction, a phenomenon found in the Staphylococcus aureus chronic mastitis, are also discussed. [less ▲]

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See detailNew trends in the diagnosis and treatment of recurrent inflammation in competition horses
Lekeux, Pierre ULg; Thomas, A.; Art, Tatiana ULg et al

in Pferdeheilkunde (2006)

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See detailProlactine triggers a pro-inflamatory response in bovine mammary epithelial cells
Boutet, Philippe ULg; Sulon, Joseph; Detilleux, Johann ULg et al

in Proceedings: 24th World Buiatrics Congress (2006)

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See detailEffect of Beclomethasone Dipropionate and Dexamethasone Isonicotinate on Lung Function, Bronchoalveolar Lavage Fluid Cytology, and Transcription Factor Expression in Airways of Horses with Recurrent Airway Obstruction
Couetil, L.; Art, Tatiana ULg; de Moffarts, Brieuc et al

in Journal of Veterinary Internal Medicine (2006), 20

Glucocorticoid (GC) therapy is recognized to be effective for the treatment of recurrent airway obstruction (RAO) in horses. Anti-inflammatory properties of GC are thought to be mediated by suppression of ... [more ▼]

Glucocorticoid (GC) therapy is recognized to be effective for the treatment of recurrent airway obstruction (RAO) in horses. Anti-inflammatory properties of GC are thought to be mediated by suppression of inflammatory gene expression via inhibition of transcription factors such as nuclear factor-kB (NF-kB) and activator protein-1 (AP-1). The purpose of this study was to evaluate the effect of low-dose inhaled beclomethasone dipropionate and injectable dexamethasone 21- isonicotinate on clinical signs, pulmonary function, airway cytology, and activity of NF-kB and AP-1 in bronchial cells of RAO-affected horses. Seven horses with RAO were exposed to moldy hay until they developed airway obstruction on 3 separate occasions. In a crossover design, they were then treated with a placebo (injection on day 1), inhaled beclomethasone (500 mg q12h for 10 days), or dexamethasone (0.06 mg/kg, IM on day 1) and monitored for 10 days. Pulmonary function, bronchoalveolar lavage fluid cytology, and NF-kB and AP-1 activity in bronchial brushing cells were measured before (day 1) and after treatment (day 10). Treatment with beclomethasone resulted in significantly improved pulmonary function of RAOaffected horses compared with placebo and dexamethasone treatments. However, none of the treatments had an effect on bronchoalveolar lavage fluid cytology or NF-kB and AP-1 activity. These findings reveal that, in a model of severe RAO, the benefits of low-dose inhaled beclomethasone on pulmonary function are not accompanied by a decrease in airway inflammatory cells or a suppression of transcription factors NF-kB and AP-1 DNA-binding activity. [less ▲]

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See detailDNA binding activity of transcription factors in bronchial cells of horses with recurrent airway obstruction.
Couetil, Laurent L; Art, Tatiana ULg; De Moffarts, Brieuc et al

in Veterinary Immunology and Immunopathology (2006), 113(1-2), 11-20

Horses with recurrent airway obstruction (RAO) present many similarities with human asthmatics including airway inflammation, hyperresponsiveness, reversible obstruction, and increased NF-kappaB ... [more ▼]

Horses with recurrent airway obstruction (RAO) present many similarities with human asthmatics including airway inflammation, hyperresponsiveness, reversible obstruction, and increased NF-kappaB expression. Studies in experimental asthma models have shown that transcriptions factors such as activator protein-1 (AP-1), GATA-3, cyclic AMP response element binding protein (CREB) and CAAT/enhancer binding protein (C/EBP) may also play an important role in airway inflammation. The purpose of this study was to measure DNA binding activity of these transcription factors in the airways of horses with RAO and to compare it to pulmonary function and bronchoalveolar lavage fluid (BALF) cytology. Seven horses with RAO and six control animals were studied during a moldy hay challenge and after 2 months at pasture. Pulmonary function, BALF cytology and transcription factors' activities in bronchial brushings were measured during hay and pasture exposures. During moldy hay challenge, RAO-affected horses developed severe airway obstruction and inflammation and a significantly higher airway AP-1 binding activity than in controls. After 2 months on pasture, pulmonary function and airway AP-1 binding activity were not different between RAO and control horses. The DNA binding activity of CREB in airways of RAO-affected horses increased significantly after 2 months at pasture and became higher than in controls. A significant positive correlation was detected between AP-1 binding activity and indicators of airway obstruction and inflammation. Airway GATA-3, CEBP and CREB binding activities were negatively correlated with indices of airway obstruction. However, contrarily to CREB binding activity, GATA-3 and CEBP binding activities were not different between RAO and control horses and were unaffected by changes in environment. These data support the view that AP-1 and CREB play a role in modulating airway inflammation in horses with RAO [less ▲]

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See detailIdentification de gènes d'intérêt pour le traitement du cheval poussif
Ramery, Eve ULg; Closset, Rodrigue; Salinas, Emmanuelle et al

in Proceedings: AVEF, Versailles, France (2006)

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See detailG1 checkpoint failure and increased tumor susceptibility in mice lacking the novel p53 target Ptprv.
Doumont, Gilles; Martoriati, Alain; Beekman, Chantal et al

in EMBO Journal (2005), 24(17), 3093-3103

In response to DNA damage, p53 activates a G1 cell cycle checkpoint, in part through induction of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1). Here we report the identification of a new direct ... [more ▼]

In response to DNA damage, p53 activates a G1 cell cycle checkpoint, in part through induction of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1). Here we report the identification of a new direct p53 target, Ptprv (or ESP), encoding a transmembrane tyrosine phosphatase. Ptprv transcription is dramatically and preferentially increased in cultured cells undergoing p53-dependent cell cycle arrest, but not in cells undergoing p53-mediated apoptosis. This observation was further confirmed in vivo using a Ptprv null-reporter mouse line. A p53-responsive element is present in the Ptprv promoter and p53 is recruited to this site in vivo. Importantly, while p53-dependent apoptosis is intact in mice lacking Ptprv, Ptprv-null fibroblasts and epithelial cells of the small intestine are defective in G1 checkpoint control. Thus, Ptprv is a new direct p53 target and a key mediator of p53-induced cell cycle arrest. Finally, Ptprv loss enhances the formation of epidermal papillomas after exposure to chemical carcinogens, suggesting that Ptprv acts to suppress tumor formation in vivo. [less ▲]

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See detailL’apoptose du neutrophile
Fievez, Laurence ULg; Seumois, G.; Lekeux, Pierre ULg et al

in Annales de Médecine Vétérinaire (2005), 149

Regulation of the neutrophil life span by apoptosis provides a fine balance between their function as effector cells of host defence and a safe turnover of these potentially harmful cells. Apoptosis is ... [more ▼]

Regulation of the neutrophil life span by apoptosis provides a fine balance between their function as effector cells of host defence and a safe turnover of these potentially harmful cells. Apoptosis is thus necessary to keep cellular homeostasis under physiologic conditions. Alterations of neutrophil apoptosis are associated with diseases such as bacterial and autoimmune inflammatory diseases where neutrophil apoptosis is delayed. Excessive production of survival factors is often observed in such inflammatory responses and neutrophil survival can be increased several fold. Cytokines withdrawal, as it occurs in the resolution phase of inflammation, leads to the induction of neutrophil apoptosis. Recent studies have shown the involvement of members of the Bcl-2 protein family and caspases in the regulation and execution of neutrophil apoptosis. Cell surface receptors and protein kinases also play critical roles in transducing the signals that result in neutrophil apoptosis or extended survival. The aim of this review is to summarise the principal molecular mechanisms and components of neutrophil apoptosis [less ▲]

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See detailPrincipes des microdamiers à ADN et applications potentielles en sciences vétérinaires
Thomas, A.; Closset, Jean ULg; Bureau, Fabrice ULg et al

in Annales de Médecine Vétérinaire (2005), 149

Microarray technology is a miniaturized biotechnological tool with potential applications for study and analysis of multiple molecular compounds as proteins, lipids, carbohydrates or nucleic acids. The ... [more ▼]

Microarray technology is a miniaturized biotechnological tool with potential applications for study and analysis of multiple molecular compounds as proteins, lipids, carbohydrates or nucleic acids. The nucleic acids microarray technology focuses interest of scientists for fifteen years because of its huge potential as regard to the scientific research, clinical diagnosis, and development of new drugs. Only DNA microarrays are investigated in this paper. Born from the conjunction of micro-electronics, biochemistry, molecular biology, and image processing, microarrays allow to analyse several thousands of genetic information simultaneously. Thanks to this new tool, it is possible in parallel to identify, to even proportion, a considerable number of nucleic acid sequences contained in a biological sample (blood, biopsy, water, food, etc). This article proposes, after having considered the operating mode of the microarrays, to understand their quality standards as well as their advantages and disadvantages. The two following parts are devoted to the place the microarrays occupy in scientific research and in the establishment of a clinical diagnosis. Finally the last part evaluates prospects the microarrays offer in veterinary sciences. [less ▲]

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See detailLe controle de la transcription genique en tant que nouvelle cible therapeutique dans le traitement de l'asthme
Desmet, Christophe ULg; Louis, Renaud ULg; Lekeux, Pierre ULg et al

in Revue Médicale de Liège (2005), 60(10), 789-795

The recent advances in the knowledge of the molecular mechanisms underlying asthma have lead to a significant improvement of the current treatments of the disease and opened new perspectives for the ... [more ▼]

The recent advances in the knowledge of the molecular mechanisms underlying asthma have lead to a significant improvement of the current treatments of the disease and opened new perspectives for the development of therapeutic alternatives to inhaled corticosteroids. The selective targeting of transcription factors controlling the expression of the genes implicated in the pathogenesis of asthma is one of these privileged strategies. This review aims at describing the most promising new therapeutic targets in the control of asthmatic inflammation at the gene transcription level. [less ▲]

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See detailProstaglandin D2 affects the differentiation and functions of human dendritic cells: impact on the T cell response.
Gosset, Philippe; Pichavant, Muriel; Faveeuw, Christelle et al

in European Journal of Immunology (2005), 35(5), 1491-1500

The local environment in which dendritic cells (DC) differentiate is important for the acquisition of their immunostimulatory properties. Since prostaglandin D(2) (PGD(2)), a major prostanoid produced ... [more ▼]

The local environment in which dendritic cells (DC) differentiate is important for the acquisition of their immunostimulatory properties. Since prostaglandin D(2) (PGD(2)), a major prostanoid produced during inflammatory reactions, is involved in the control of immune responses, its effect on the differentiation and functions of human monocyte-derived dendritic cells (MDDC) was studied. We show that DC differentiated in the presence of PGD(2) (PG/DC) have an unusual phenotype, with modifications in the expression of molecules involved in antigen (Ag) capture and presentation, leading to higher endocytic and Ag-processing activities. However, under conditions that necessitated Ag processing and presentation, PG/DC have an impaired ability to stimulate naive T cells, whereas superAg-pulsed DC efficiently promote their proliferation. Upon lipopolysaccharide or TNF-alpha/IL-1beta stimulation, PG/DC phenotypically mature but produce abnormal amounts of immunoregulatory cytokines (decreased IL-12p70/IL-10 ratio). Moreover, mature PG/DC fail to up-regulate the chemokine receptor CCR7 and show an impaired migration towards its ligand CCL19. Finally, PG/DC favor the differentiation of naive T cells toward Th2 cells, an effect dependent on IL-10 and inducible costimulator ligand expression by DC. Most of the herein described effects of PGD(2) on MDDC can be reproduced, usually with a higher efficacy, with a selective D prostanoid receptor (DP)1, but not DP2, agonist. Taken as a whole, these results demonstrate that PGD(2) impacts DC differentiation and functions, and extend the concept that it exerts important roles in immunity [less ▲]

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See detailPro-inflammatory properties for thiazolidinediones.
Desmet, Christophe ULg; Warzée, Barbara ULg; Gosset, Philippe et al

in Biochemical Pharmacology (2005), 69(2), 255-265

Thiazolidinediones (TZDs) are pharmacological ligands of the peroxisome proliferator-activated receptor (PPAR)-gamma that are extensively used in the treatment of type II diabetes. Recently, an anti ... [more ▼]

Thiazolidinediones (TZDs) are pharmacological ligands of the peroxisome proliferator-activated receptor (PPAR)-gamma that are extensively used in the treatment of type II diabetes. Recently, an anti-inflammatory potential for TZDs has been suggested, based on observations that these compounds may inhibit pro-inflammatory cytokine expression in vitro and may attenuate the inflammatory response in vivo. Here, we show that the TZDs rosiglitazone (RSG) and troglitazone (TRO) do not inhibit the inflammatory response to tumor necrosis factor (TNF)-alpha in various epithelial cell types. On the contrary, both RSG and TRO significantly potentiated TNF-alpha-induced production of granulocyte/macrophage-colony-stimulating factor, interleukin (IL)-6 and/or IL-8 in these cells. This increase in pro-inflammatory cytokine expression was functionally significant as supernatants from cells co-treated with TNF-alpha and TZDs displayed increased neutrophil pro-survival activity when compared with supernatants from cells treated with TNF-alpha alone. Additionally, it was shown that TZDs enhance cytokine expression at the transcriptional level, but that the pro-inflammatory effects of TZDs are independent on PPARgamma, nuclear factor kappaB or mitogen-activated protein kinase activation. Our study shows that TZDs may potentiate the inflammatory response in epithelial cells, a previously unappreciated effect of these compounds [less ▲]

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See detailSTAT5 promotes granulocyte survival during inflammation
Fievez, Laurence ULg; Desmet, Christophe ULg; Seumois, G. et al

in Proceedings: The American Thoracic Society (2005)

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See detailSelective inhibition of AP-1 activity in airway immune cells ameliorates experimental asthma
Desmet, Christophe ULg; Gosset, P.; Garzé, V. et al

in Proceedings: The American Thoracic Society (2005)

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See detailTreatment of experimental asthma by decoy-mediated local inhibition of activator protein-1
Desmet, Christophe ULg; Gosset, P.; Henry, E. et al

in American Journal of Respiratory & Critical Care Medicine (2005), 172(6), 671-678

Rationale: Asthma is associated with increased expression of a typical array of genes involved in immune and inflammatory responses, including those encoding the prototypic Th2 cytokines interleukin (IL ... [more ▼]

Rationale: Asthma is associated with increased expression of a typical array of genes involved in immune and inflammatory responses, including those encoding the prototypic Th2 cytokines interleukin (IL) 4, IL-5, and IL-13. Most of these genes contain binding sites for activator protein-1 (AP-1) within their promoter and are therefore believed to depend on AP-1 for their expression, suggesting that this transcription factor could be of particular importance in asthma pathophysiology. Objective: To clarify the role of AP-1 in the effector phase of pulmonary allergy. Methods: Ovalbumin (OVA)-sensitized mice were intratracheally given decoy oligodeoxyribonucleotides (ODNs) specifically directed to AP-1 or scrambled control ODNs before challenge with aerosolized OVA. Twenty-four hours after the last OVA challenge, airway hyperresponsiveness was measured and allergic airway inflammation was evaluated quantitatively. AP-1 decoys were localized using flow cytometry and immunohistochemistry. AP-1 activity in the lung was assessed using electrophoretic mobility shift assay. Measurements and Main Results: Intratracheally delivered AP-1 decoys efficiently targeted airway immune cells, thus precluding AP-1 activation on OVA challenge. Decoy-mediated local inhibition of AP-1 resulted in significant attenuation of all the pathophysiologic features of experimental asthma-namely, eosinophilic airway inflammation, airway hyperresponsiveness, mucous cell hyperplasia, production of allergen-specific immunoglobulins, and synthesis of IL-4, IL-5, and IL-13. Scrambled control ODNs had no detectable effects. Conclusions: Our results reveal a key role for AP-1 in the effector phase of pulmonary allergy and indicate that specific AP-1 inhibition in the airways may have therapeutic value in the control of established asthma. [less ▲]

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See detailNouvelles approches du traitement des affections respiratoires du bétail
Lekeux, Pierre ULg; Bureau, Fabrice ULg

in Point Vétérinaire (2005), 252

Devant des affections surtout polyfactorielles, l’ère du “tout antibiotique” semble révolue, comme l’illustrent certaines pistes actuelles de recherche.

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