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See detailSputum cytokines levels in patients undergoing hematopoietic SCT (HSCT) and comparison with healthy subjects and COPD: a pilot study
MOERMANS, Catherine ULg; BONNET, Christophe ULg; WILLEMS, Evelyne ULg et al

in Bone Marrow Transplantation (in press)

Patients undergoing hematopoietic stem cell transplantation (HSCT) display an airway neutrophilic inflammation before the transplantation that persists over the years. In this study, we have investigated ... [more ▼]

Patients undergoing hematopoietic stem cell transplantation (HSCT) display an airway neutrophilic inflammation before the transplantation that persists over the years. In this study, we have investigated the cytokine profile over a period of one year in sputum supernatant of patients who underwent HSCT. We have measured sputum supernatant levels of TNF-α, TGF-β1, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, IL-17, and IFN-γ in 49 HSCT patients and compared the results with those found in 40 COPD and 54 healthy subjects matched for age. Compared to healthy subjects, before the transplantation, HSCT patients exhibited raised levels of IL-6 (p<0.001) and IL-8 (p<0.05) while the other cytokines were generally poorly detectable. This picture was rather similar to what is seen in COPD even if cytokine levels were much greater in the latter with IL-8 being significantly greater in COPD than in HSCT patients (p<0.0001). In the 1 year following the transplantation, sputum IL-6 and IL-8 did not differ any longer compared to healthy subjects. Overall in HSCT patients, sputum IL-8 and IL-6 correlated with sputum neutrophil counts (r=0.4, p<0.0001; r=0.42, p<0.0001, respectively). In conclusion, sputum IL-6 and IL-8 may play a role in neutrophilic airway inflammation seen in patients undergoing HSCT. [less ▲]

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See detailImpact of co-transplantation of mesenchymal stem cells on lung function after unrelated allogeneic hematopoietic stem cell transplantation following non-myeloablative conditioning
MOERMANS, Catherine ULg; LECHANTEUR, Chantal ULg; BAUDOUX, Etienne ULg et al

in Transplantation (in press)

Background: In the context of hematopoietic stem cell transplantation (HSCT), mesenchymal stem cells (MSC) have been used to promote engraftment and prevent graft- versus-host-disease. However, in animal ... [more ▼]

Background: In the context of hematopoietic stem cell transplantation (HSCT), mesenchymal stem cells (MSC) have been used to promote engraftment and prevent graft- versus-host-disease. However, in animal models, MSC were shown to cause pulmonary alterations after systemic administration. The impact of MSC infusion on lung function has not been studied in humans. The objective of the study was to investigate the impact of MSC co-infusion on lung function and airway inflammation as well as on the incidence of pulmonary infections and cytomegalovirus (CMV) reactivation after HSCT. Methods: We have prospectively followed 30 patients who underwent unrelated HSCT with MSC co-infusion after non-myeloablative conditioning (NMA). Each patient underwent detailed lung function testing (FEV1, FVC, FEV1/FVC, RV, TLC, DLCO and KCO) and measurement of exhaled nitric oxide before HSCT and 3, 6 and 12 months posttransplant. The incidence of pulmonary infections and CMV reactivation were also monitored. This group was compared with another group of 28 patients who underwent the same type of transplantation but without MSC co-infusion. Results: Lung function tests did not show important modifications over time and did not differ between the MSC and control groups. There was a higher 1-year incidence of infection, particularly of fungal infections, in patients having received a MSC co-infusion. There was no difference between groups regarding the 1-year incidence of CMV reactivation. Conclusions: MSC co-infusion does not induce pulmonary deterioration 1 year after HSCT with NMA conditioning. MSC appear to be safe for the lung but close monitoring of pulmonary infections remains essential. [less ▲]

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See detailNovel association between vasoactive intestinal peptide and CRTH2 receptor in recruiting eosinophils: a possible biochemical mechanism for allergic eosinophilic inflammation of the airways.
EL SHAZLY, Amr ULg; Begon, Dominique ULg; KUSTERMANS, Gaëlle ULg et al

in Journal of Biological Chemistry (2013), 288(2), 1374-84

We explored the relation between vasoactive intestinal peptide (VIP), CRTH2, and eosinophil recruitment. It is shown that CRTH2 expression by eosinophils from allergic rhinitis (AR) patients and ... [more ▼]

We explored the relation between vasoactive intestinal peptide (VIP), CRTH2, and eosinophil recruitment. It is shown that CRTH2 expression by eosinophils from allergic rhinitis (AR) patients and eosinophils cell line (Eol-1 cells) was up-regulated by VIP treatment. This was functional and resulted into exaggerated migratory response of cells against PGD2. Nasal challenge of AR patients resulted into significant increase of VIP contents in nasal secretion (ELISA), and the immunohistochemical studies of allergic nasal tissues, showed significant expression of VIP in association with intense eosinophil recruitment. Biochemical assays showed that VIP-induced eosinophils chemotaxis from AR patients and Eol-1 cells, was mediated through CRTH2 receptor. Cells migration against VIP was sensitive to protein kinase C (PKC) and protein kinase A (PKA) inhibition, but not to tyrosine kinase or P38 MAP-kinase inhibition, or calcium chelation. Western blot demonstrated a novel CRTH2 mediated cytosol to membrane translocation of PKC-epsilon, PKC-delta and PKA-alpha, gamma and IIalpha reg in Eol-1 cells upon stimulation with VIP. Confocal images and FACS demonstrated a strong association and co-localization between VIP peptide and CRTH2 molecules. Further, VIP induced PGD2 secretion from eosinophils. Our results demonstrate the first evidence of association between VIP and CRTH2 in recruiting eosinophils. [less ▲]

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See detailLung function and airway inflammation monitoring after hematopoietic stem cell transplantation.
Moermans, Catherine ULg; Poulet, Christophe ULg; HENKET, Monique ULg et al

in Respiratory Medicine (2013), 107

Background Induced sputum is a non-invasive method to investigate airway inflammation, which has been used to assess pulmonary inflammatory diseases. However, this procedure has not been studied in the ... [more ▼]

Background Induced sputum is a non-invasive method to investigate airway inflammation, which has been used to assess pulmonary inflammatory diseases. However, this procedure has not been studied in the context of hematopoietic stem cell transplantation (HSCT). Methods We monitored lung function in 182 patients who underwent HSCT and measured airway inflammation by sputum induction in 80 of them. We prospectively measured FEV1, FVC, DLCO, KCO, TLC, RV, exhaled nitric oxide (FeNO) as well as sputum cell counts before and 3, 6, 12, 24 and 36 months after HSCT. Results For the whole cohort there was a progressive decrease in TLC, which was significant after 3 years (p < 0.01). By contrast, there was no change in other lung functions parameters or in FeNO. Baseline sputum analysis revealed increased neutrophil counts in patients {Median (IQR): 63% (38–79)} compared to healthy subjects matched for age {Median (IQR): 49% (17–67), p < 0.001} but there was no significant change in any type of sputum cell counts over the three years. When comparing myeloablative (MA) vs non-myeloablative (NMA) conditioning, falls in FEV1, FVC and DLCO, and rise in RV and sputum neutrophils were more pronounced over the first year of observation in those receiving MA. Conclusions There was a progressive loss in lung function after HSCT, featuring a restrictive pattern. Myeloablative conditioning was associated with early rise of sputum neutrophils and greater alteration in lung function over the first year. [less ▲]

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See detailDistribution of sputum cellular phenotype in a large asthma cohort: predicting factors for eosinophilic vs neutrophilic inflammation.
SCHLEICH, FLorence ULg; Manise, Maïté ULg; Sele, Jocelyne et al

in BMC Pulmonary Medicine (2013), 13(1), 11

ABSTRACT: BACKGROUND: Phenotyping asthma according to airway inflammation allows identification of responders to targeted therapy. Induced sputum is technically demanding. We aimed to identify predictors ... [more ▼]

ABSTRACT: BACKGROUND: Phenotyping asthma according to airway inflammation allows identification of responders to targeted therapy. Induced sputum is technically demanding. We aimed to identify predictors of sputum inflammatory phenotypes according to easily available clinical characteristics. METHODS: This retrospective study was conducted in 508 asthmatics with successful sputum induction recruited from the University Asthma Clinic of Liege. Receiver-operating characteristic (ROC) curve and multiple logistic regression analysis were used to assess the relationship between sputum eosinophil or neutrophil count and a set of covariates. Equations predicting sputum eosinophils and neutrophils were then validated in an independent group of asthmatics. RESULTS: Eosinophilic (>=3%) and neutrophilic (>=76%) airway inflammation were observed in 46% and 18% of patients respectively. Predictors of sputum eosinophilia >=3% were high blood eosinophils, FENO and IgE level and low FEV1/FVC. The derived equation was validated with a Cohen's kappa coefficient of 0.59 (p < 0.0001). ROC curves showed a cut-off value of 220/mm3 (AUC = 0.79, p < 0.0001) or 3% (AUC = 0.81, p < 0.0001) for blood eosinophils to identify sputum eosinophilia >=3%. Independent predictors of sputum neutrophilia were advanced age and high FRC but not blood neutrophil count. CONCLUSION: Eosinophilic and paucigranulocytic asthma are the dominant inflammatory phenotypes. Blood eosinophils provide a practical alternative to predict sputum eosinophilia but sputum neutrophil count is poorly related to blood neutrophils. [less ▲]

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See detailDisturbed Cytokine Production at the Systemic Level in Difficult-to-Control Atopic Asthma: Evidence for Raised Interleukin-4 and Decreased Interferon-gamma Release following Lipopolysaccharide Stimulation.
MANISE, Maïté ULg; SCHLEICH, FLorence ULg; QUAEDVLIEG, Valérie ULg et al

in International Archives of Allergy & Immunology (2012), 158(1), 1-8

Background: Disturbed cytokine production is thought to govern inflammation in asthma, which, in its turn, may lead to uncontrolled disease. The aim of this study was to assess the relationship between ... [more ▼]

Background: Disturbed cytokine production is thought to govern inflammation in asthma, which, in its turn, may lead to uncontrolled disease. The aim of this study was to assess the relationship between cytokine production from blood leucocytes and the level of asthma control. Methods: We compared the production of interleukin (IL)-4, IL-6, IL-10, interferon (IFN)-gamma and tumour necrosis factor-alpha from peripheral blood leucocytes in non-atopic healthy subjects (n = 22), atopic non-asthmatics (n = 10), well-controlled asthmatics [Juniper asthma control questionnaire (ACQ) score <1.5; n = 20] and patients with uncontrolled asthma despite inhaled or oral corticoids (ACQ score >/=1.5; n = 20). Fifty microlitres of peripheral blood was incubated for 24 h with RPMIc, lipopolysaccharide (LPS; 1 ng/ml) or phytohaemagglutinin (1 mug/ml), and cytokines were measured by immunotrapping (ELISA). Results: Both controlled and uncontrolled asthmatics as well as atopic non-asthmatics spontaneously produced more IL-4 than non-atopic healthy subjects (p < 0.001). IL-4 production induced by LPS was significantly greater (p < 0.05) in both asthma groups compared to atopic non-asthmatics and non-atopic healthy subjects. By contrast, IFN-gamma release induced by LPS was lower in uncontrolled asthmatics than in non-atopic healthy subjects (p < 0.05) and controlled asthmatics (p < 0.05). IL-10 release after LPS was greater in uncontrolled asthmatics than in atopic non-asthmatics (p < 0.05). No difference was observed regarding other cytokines. Conclusion: Blood cells from patients with difficult-to-control atopic asthma display highly skewed Th2 cytokine release following LPS stimulation. [less ▲]

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See detailDiagnostic value of neurotrophin expression in malignant pleural effusions
DUYSINX, Bernard ULg; PAULUS, Aurore ULg; HEINEN, Vincent ULg et al

in Experimental and Therapeutic Medicine (2011), 2(5), 941-946

Neurotrophins (NTs) modulate the growth of human malignancies, including lung cancers. Our prospective study evaluated the accuracy of pleural NTs [nerve growth factor, brain-derived neurotrophic factor ... [more ▼]

Neurotrophins (NTs) modulate the growth of human malignancies, including lung cancers. Our prospective study evaluated the accuracy of pleural NTs [nerve growth factor, brain-derived neurotrophic factor (BDNF), neurotrophin 3 (nT3) and 4 (nT4)] levels for differentiating benign from malignant pleural exudates. Levels of NTs were measured by ELISA in 170 patients with non-neutrophilic (<50%) exudative benign or malignant pleurisies diagnosed by pleuroscopy. Fifty-nine benign (9 infections and 50 inflammatory diseases) and 111 malignant (50 extrathoracic tumors, 51 lung cancers and 10 mesotheliomas) pleural exudates were diagnosed by thoracoscopy. Levels of BDNF were significantly higher in malignant than in benign effusions [17 pg/ml (0-367) vs. 8 pg/ml (0-51), p<0.05]. ROC analysis showed an area under the curve of 0.609 (p=0.012; best threshold 44 pg/ml). Pleural BDNF levels were significantly higher in pleural metastasis of pulmonary tumors and in mesothelioma than in pleural benign effusions. Finally, a higher proportion of pleural nT3 was detected in squamous cell lung carcinoma in comparison to that in non-squamous cell lung carcinoma (72.7 vs. 10%, p<0.0001). NTs and particularly BDNF may play a role in the pathogenesis of malignant pleural effusions. [less ▲]

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See detailIFN-gamma and TNF-alpha potentiate prostaglandin D2-induced human eosinophil chemotaxis through up-regulation of CRTH2 surface receptor.
EL SHAZLY, Amr ULg; MOONEN, Vincent ULg; MAWET, Marie et al

in International immunopharmacology (2011), 11(11), 1864-70

Prostaglandin D2 (PGD2) receptor CRTH2, is a pro-inflammatory molecule involved in eosinophil recruitment to the allergic airway. We investigated the expression of CRTH2 in eosinophil from allergic ... [more ▼]

Prostaglandin D2 (PGD2) receptor CRTH2, is a pro-inflammatory molecule involved in eosinophil recruitment to the allergic airway. We investigated the expression of CRTH2 in eosinophil from allergic rhinitis patients (AR) and tested the modulatory role of several TH1 and TH2 cytokines closely related to the allergic immunological response, on the expression of CRTH2 receptor, utilizing human eosinophil cell line (Eol-1).The expression of CRTH2 was tested by immunohistochemistry and flow cytometry (FACS). Chemotaxis was performed in micro-chemotaxis chambers. It is shown that the expression of CRTH2 by eosinophils was significantly higher in the nasal tissue and peripheral blood of AR patients, when compared to control subjects. PGD2 exhibited a typical bell shape dose response in attracting eosinophil from AR patients with optimal activity at 10(-7)M. Eol-1 cell surface expression of CRTH2 was significantly up-regulated by 10ng/ml IFN-gamma and TNF-alpha. The percentage of Eol-1 cells expressing the receptor increased by IFN-gamma and TNF-alpha from 12.74%+/-2.66 to 55%+/-8 and 33.8%+/-9.4, respectively. PGD2-induced Eol-1 chemotaxis was not blocked by SB203580, H-89 Dihydrochloride, Bisindo-lylmaleimide, or Genistein. PGD2-induced Eol-1 chemotaxis was potentiated by IFN-gamma and TNF-alpha without changing the signal transduction pathway. Correlation of our results to peripheral blood eosinophils from allergic rhinitis patients confirmed that 3hour pretreatment of eosinophils by 10ng/ml IFN-gamma and TNF-alpha, increased the mean fluorescence intensity (MFI) of CRTH2 from 8.23 to 9.68 and 9.38, respectively, and potentiated PGD2-induced eosinophil chemotaxis. Our results demonstrate a novel synergism between PGD2, IFN-gamma and TNF-alpha, in eosinophil chemotaxis. [less ▲]

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See detail2B4 (CD244) is involved in eosinophil adhesion and chemotaxis, and its surface expression is increased in allergic rhinitis after challenge.
El-Shazly, Armel; HENKET, Monique ULg; Lefèbvre, Philippe ULg et al

in International Journal of Immunopathology and Pharmacology (2011), 24(4), 949-60

A role for the subtypes of CD2 Ig superfamily receptors has been recently demonstrated in eosinophilic inflammation in experimental asthma and atopic asthmatics. We investigated the functions of 2B4 ... [more ▼]

A role for the subtypes of CD2 Ig superfamily receptors has been recently demonstrated in eosinophilic inflammation in experimental asthma and atopic asthmatics. We investigated the functions of 2B4 (CD244) molecules in eosinophil adhesion and chemotaxis, and correlated the results to the pathophysiology of allergic rhinitis (AR). Herein, we show that agonistic stimulation of 2B4 by C1.7, the anti-human 2B4 functional grade purified antibody, resulted in significant increase of eosinophils and eosinophil cell line (Eol-1 cells) adhesion to collagen type IV, and random migration. These functions were associated with tyrosine kinase phosphorylation of several protein residues of low molecular weight. Flow cytometry (FACS) experiments demonstrated that Eol-1 cells, normal peripheral blood eosinophils and eosinophils from AR patients, express surface 2B4 molecules. In vitro AR model demonstrated that the CC-chemokine receptor CCR3 stimulation by eotaxin induced significant increase in the expression of surface 2B4 in eosinophils and Eol-1 cells. Immunofluorescence confocal microscopy images showed that eotaxin induces also redistribution of 2B4 molecules towards the pseudopods in eosinophils and Eol-1 cells, changing their shape. Blocking of 2B4 molecules by the corresponding neutralizing antibody inhibited eotaxin induced Eol-1-adhesion, chemotaxis and the cytoskeleton changes. Pretreatment of Eol-1 cells with 1 microM genistein blocked eotaxin-induced Eol-1 adhesion, chemotaxis and 2B4 up-regulated expression. In vivo correlation demonstrated the expression of 2B4 molecules in eosinophils from AR patients to be significantly increased, after nasal provocation challenge. These results identify a novel role for 2B4 molecules in eosinophil functional migratory response and may point to a novel tyrosine kinase-mediated ligation between CCR3 receptor and 2B4 co-receptor in eosinophil chemotaxis. If so, then 2B4 molecules would be a novel target for therapeutic modalities in diseases characterized by eosinophilia such as AR. [less ▲]

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See detailLocal and systemic cellular inflammation and cytokine release in chronic obstructive pulmonary disease.
Moermans, Catherine ULg; HEINEN, Vincent ULg; NGUYEN DANG, Delphine ULg et al

in Cytokine (2011), 56(2), 298-304

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic airway inflammatory disease caused by repeated exposure to noxious gases or particles. It is now recognized that the disease also ... [more ▼]

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic airway inflammatory disease caused by repeated exposure to noxious gases or particles. It is now recognized that the disease also features systemic inflammation. The purpose of our study was to compare airway and systemic inflammation in COPD to that seen in healthy subjects and to relate the inflammation with the disease severity. METHODS: Ninety-five COPD patients, encompassing the whole severity spectrum of the disease, were recruited from our outpatient clinic and rehabilitation center and compared to 33 healthy subjects. Induced sputum and blood samples were obtained for measurement of inflammatory cell count. Interleukin (IL)-4, IL-6, IL-10, TNF-alpha and IFN-gamma produced by 24h sputum and blood cell cultures were measured. RESULTS: Compared to healthy subjects, COPD exhibited a prominent airway neutrophilic inflammation associated with a marked IL-10, IL-6 and TNF-alpha release deficiency that contrasted with a raised IFN-gamma production. Neutrophilic inflammation was also prominent at blood level together with raised production of IFN-gamma, IL-10 and TNF-alpha. Furthermore, sputum neutrophilia correlated with disease severity assessed by GOLD stages. Likewise the extent of TNF-alpha release from blood cells also positively correlated with the disease severity but negatively with that of sputum cell culture. Blood release of TNF-alpha and IL-6 negatively correlated with body mass index. Altogether, our results showed a significant relationship between cellular marker in blood and sputum but poor relationship between local and systemic release of cytokines. CONCLUSIONS: COPD is characterized by prominent neutrophilic inflammation and raised IFN-gamma production at both bronchial and systemic level. Overproduction of TNF-alpha at systemic level correlates with disease severity and inversely with body mass index. [less ▲]

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See detailCytokine production from sputum cells and blood leukocytes in asthmatics according to disease severity.
Manise, Maïté ULg; Schleich, FLorence ULg; Gusbin, Natacha ULg et al

in Allergy (2010), 65(7), 889-96

BACKGROUND: Although mild to moderate asthma is known to be Th2 driven, cytokines produced in refractory asthma might not fit the classical Th2 pattern. METHODS: The aim of our study was to assess the ... [more ▼]

BACKGROUND: Although mild to moderate asthma is known to be Th2 driven, cytokines produced in refractory asthma might not fit the classical Th2 pattern. METHODS: The aim of our study was to assess the cytokine production by sputum and blood cells from 15 refractory asthmatics (American Thoracic Society Criteria) compared to 15 mild untreated and 17 moderate treated asthmatics and 22 healthy subjects. Spontaneous production of interleukin (IL)-4, IL-6, IL-10, interferon-gamma, and tumor necrosis factor alpha was measured by immunotrapping after 24 h sputum or blood cell culture. RESULTS: Moderate and refractory asthmatics were both characterized by a lower production of IL-6 from their airway cells compared to healthy subjects. However, the difference was no longer significant when expressing the results per gram of sputum. No significant difference between the three groups was found regarding other cytokines. As for cytokine production from blood, the three groups of asthmatics exhibited raised production of IL-4 when compared to healthy subjects, and this was true when results were expressed per blood volume or after normalization for total leukocyte cell count. Moderate asthmatics exhibited greater production of IL-10 when compared to refractory asthmatics and healthy subjects when results were normalized for total leukocyte cell count. CONCLUSIONS: Sputum cells from moderate and refractory asthmatics release less IL-6. While the systemic overproduction of IL-4 was observed through the all spectrum of asthma severity, moderate asthmatics exhibited greater systemic IL-10 production compared to refractory asthmatics. [less ▲]

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See detailAssociation between asthma control and bronchial hyperresponsiveness and airways inflammation: a cross-sectional study in daily practice.
Quaedvlieg, Valérie ULg; Sele, Jocelyne ULg; Henket, Monique ULg et al

in Clinical & Experimental Allergy : Journal of the British Society for Allergy & Clinical Immunology (2009), 39

Summary Background The primary end-point in the management of asthma is to obtain optimal control. The aim of this study was to assess the relationships between the markers of airway inflammation (sputum ... [more ▼]

Summary Background The primary end-point in the management of asthma is to obtain optimal control. The aim of this study was to assess the relationships between the markers of airway inflammation (sputum eosinophilia and exhaled nitric oxide), bronchial hyperresponsiveness (BHR) and asthma control. Methods One hundred and thirty-four patients were recruited from our asthma clinic between January 2004 and September 2005 [mean age: 42 years, mean forced expiratory volume in 1 s (FEV(1)): 86% predicted]. Eighty-six of them were treated by inhaled corticosteroids, 99 were atopic and 23 were current smokers. They all underwent detailed investigations including fractional-exhaled nitric oxide (FE(NO)) measurement, sputum induction and methacholine challenge when FEV(1) was >70% predicted, and filled in a validated asthma control questionnaire (ACQ6 Juniper). Results When dividing patients into the three groups according to their level of asthma control determined by ACQ [well-controlled asthma (ACQ score </=0.75), borderline (0.75<ACQ score <1.5) and uncontrolled asthma (ACQ score >/=1.5)], it appeared that uncontrolled asthmatics had a greater BHR to methacholine and sputum eosinophilia than controlled asthma (P<0.05, P<0.001, respectively). By contrast, we failed to show significant differences in the FE(NO) levels between the groups. With receiver-operating characteristic curves for differentiating uncontrolled (ACQ>/=1.5) from controlled and borderline (ACQ<1.5) asthma, sputum eosinophilia and methacholine responsiveness were found to be more accurate than FE(NO) (area under the curve: 0.72, 0.72 and 0.59, respectively). Conclusion In a broad spectrum of asthmatics encountered in clinical practice, sputum eosinophilia and methacholine bronchial hyperresponsiveness, but not FE(NO), are associated with uncontrolled asthma. [less ▲]

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See detailLeukotriene B4 Contributes to Exhaled Breath Condensate and Sputum Neutrophil Chemotaxis in COPD.
Corhay, Jean-Louis ULg; Henket, Monique ULg; Nguyen Dang, Delphine ULg et al

in CHEST (2009), 136(4), 1047-1054

Background Neutrophils have been implicated in the pathogenesis of COPD. Several chemoattractants for neutrophils have been measured in exhaled breath condensate (EBC) and induced-sputum (IS) from ... [more ▼]

Background Neutrophils have been implicated in the pathogenesis of COPD. Several chemoattractants for neutrophils have been measured in exhaled breath condensate (EBC) and induced-sputum (IS) from patients with COPD. Objectives The aims of this study were to compare EBC and IS supernatant neutrophil chemotactic activity from ex-smoking COPD and healthy ex-smokers, and to assess the contribution of LTB(4) to this activity. Methods 34 COPD were compared to 24 controls. EBC and IS chemotactic activity for neutrophils were assessed by using Boyden microchambers. Chemotactic index (CI) was used to evaluate cell migration. LTB(4) was measured by a specific enzyme immunoassay. Contribution of LTB4 to EBC and sputum neutrophil chemotaxis was assessed by an LTB(4) receptor antagonist (U-75302: Cayman Chemical Company, Ann Arbor, MI, USA). Results EBC and IS from both COPD and healthy subjects displayed significant neutrophil chemotactic activity but this activity was raised in COPD compared to healthy subjects. Chemotactic activity contained in sputum, however, failed to correlate with that in EBC. In COPD there was a significant correlation between EBC neutrophil chemotactic activity and sputum neutrophil counts. LTB(4) levels were raised in EBC, but not in sputum, from COPD as compared to healthy subjects. LTB(4) receptor antagonist (2.5 10(-4) M) reduced by 44.6% and by 44.4% chemotactic activity contained in EBC and sputum respectively. Conclusions EBC and IS from COPD patients have a raised neutrophil chemotactic activity to which LTB4 contributes. [less ▲]

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See detailDiagnostic value of interleukine-6, transforming growth factor-beta 1 and vascular endothelial growth factor in malignant pleural effusions.
Duysinx, Bernard ULg; Corhay, Jean-Louis ULg; Hubin, Laurent et al

in Respiratory Medicine (2008), 102(12), 1708-14

STUDY OBJECTIVES: We evaluate the accuracy of pleural interleukine-6 (IL-6), transforming growth factor-beta 1 (TGF-beta1), and vascular endothelial growth factor (VEGF) levels for differentiating benign ... [more ▼]

STUDY OBJECTIVES: We evaluate the accuracy of pleural interleukine-6 (IL-6), transforming growth factor-beta 1 (TGF-beta1), and vascular endothelial growth factor (VEGF) levels for differentiating benign from malignant pleural exudates. PATIENTS AND METHODS: Levels of IL-6, TGF-beta1, and VEGF were measured by ELISA in 103 patients with non neutrophilic (<50%) exudative pleurisy including both benign and malignant effusions. Pleurisies were split into benign and malignant according to the pathological diagnosis. RESULTS: Thirty-nine benign (seven infections; 32 inflammatory diseases) and 64 malignant (34 extrathoracic tumors; 25 lung cancers; five mesotheliomas) pleural exudates were diagnosed by thoracoscopy. Pleural reticulo-monocyte count, protein Light's ratio and lactic dehydrogenase Light's ratio were significantly higher in malignant than in benign effusions (p<0.05, p<0.001 and p<0.001, respectively). The median (range) level of VEGF was significantly higher in malignant than in benign effusions (664.50 pg/ml [10-40,143] vs 349 pg/ml [10-8888]) (p<0.05). VEGF levels correlated with pleural LDH (r=0.41, p<0.0001), glucose (r=-0.30, p<0.01) and red cell count (r=0.57, p<0.0001). No significant difference was found between malignant and benign effusions with respect to IL-6 (26.8 ng/ml [1.8-421] vs 18.4 ng/ml [0.45-400], respectively) and TGF-beta1 (1079 pg/ml [18-6206] vs 1123 pg/ml [34-5447]) levels. ROC analysis between benign and malignant pleurisies for VEGF showed an area under the curve of 619 (p=0.03) with a value of 382 pg/ml as the best threshold for distinguishing benign from malignant effusions. CONCLUSIONS: Malignant effusions may enhance the release of VEGF in pleural space and its measurement may help in the diagnosis of malignant effusion. [less ▲]

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See detailGranulocyte chemotactic activity in exhaled breath condensate of healthy subjects and patients with COPD
Corhay, Jean-Louis ULg; Hemelaers; Henket, Monique ULg et al

in CHEST (2007), 131(6), 1672-1677

Background. Several chemoattractants have been measured in exhaled breath condensate (EBC) from patients with COPD. The aim of this study was to compare the eosinophil. and neutrophil chemotactic activity ... [more ▼]

Background. Several chemoattractants have been measured in exhaled breath condensate (EBC) from patients with COPD. The aim of this study was to compare the eosinophil. and neutrophil chemotactic activity contained in EBC from healthy subjects and patients with COPD. Methods: EBC collected using a commercially available condenser (EcoScreen; Erich Jaeger Viasys; Hoechberg, Germany) was compared in 45 COPD patients and 65 healthy subjects. EBC chemotactic activity for eosinophils and neutrophils was assessed using microchambers (Boyden; Neuro Probe; Cabin John, MD). Chemotactic index (CI) was used to evaluate cell migration. Results: EBC from patients with COPD (C1, 2.21 +/- 0.16 [mean +/- SEM]) and healthy subjects (CI, 1.67 +/- 0.11) displayed significant neutrophil chemotactic activity (p < 0.0001 for both), which was however higher in patients with COPD (p < 0.001). Healthy smokers had a significantly raised C1 for neutrophils by comparison with healthy nonsmokers (p < 0.01) and ex-smokers (p < 0.05). Ukewise, current COPD smokers tended to have greater neutrophil C1 than COPD who stopped smoking (p = 0.08). COPD ex-smokers had raised chemotactic activity by comparison with healthy ex-smokers (p < 0.05). Anti-interleuldn-8 (10(-6) g/mL) antibodies reduced neutrophil chemotactic activity by 35.2% (p < 0.05). EBC also contained significant eosinophil chemotactic activity in healthy subjects (CI, 1.68 0.09; p < 0.0001) and patients with COPD (CI, 1.23 +/- 0.07; p < 0.01), with a significantly lower CI in patients with COPD as compared to healthy subjects (p < 0.001). Smoking did not influence eosinophil chemotactic activity in healthy subjects or patients with COPD. Conclusions: Current smoking favors neutrophil chemotactic activity. As compared to healthy subjects, EBC from patients with COPD displays a skewed chemotactic activity toward neutrophils vs eosinophils. [less ▲]

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See detailDifferences in local versus systemic TNF alpha production in COPD: inhibitory effect of hyaluronan on LPS induced blood cell TNF alpha release
Dentener, M. A.; Louis, Renaud ULg; Cloots, R. H. E. et al

in Thorax (2006), 61(6), 478-484

Background: Chronic obstructive pulmonary disease (COPD) is characterised by both airway inflammation and systemic changes. To elucidate the relationship between local and systemic inflammation, tumour ... [more ▼]

Background: Chronic obstructive pulmonary disease (COPD) is characterised by both airway inflammation and systemic changes. To elucidate the relationship between local and systemic inflammation, tumour necrosis factor alpha (TNF alpha) production by sputum cells and blood cells of patients with COPD and controls was compared and the effect of the extracellular matrix compound hyaluronan (HA) on TNF alpha release was studied. Methods: Four study groups were included: 10 steroid free COPD patients, 8 steroid treated patients, 10 healthy smokers, and 11 healthy non-smokers. Sputum cells and blood were incubated for 24 hours with or without lipopolysaccharide (LPS) in the absence or presence of HA (122 kDa or HMW fragment). TNF alpha was measured by ELISA. Results: Sputum cells produced spontaneously high levels of TNF alpha but were unresponsive to LPS. Sputum cells from COPD patients (both steroid free and steroid treated) produced significantly less TNF alpha than cells from healthy non-smoking subjects (p = 0.017 and p = 0.001, respectively). In contrast, blood cells produced TNF alpha only in response to LPS. No differences were observed in TNF alpha production by blood cells between the patient groups and the control groups. HA (both fragments) partially blocked LPS (1 ng/ml) induced TNF alpha release by blood cells from all study groups, whereas TNF alpha production by sputum cells was not influenced by HA. Conclusion: These data indicate a difference between local and systemic TNFa production. Sputum cells of patients with COPD produced less TNFa than controls, which could contribute to impaired local defence. An inhibitory effect of HA on TNF alpha release in blood cells was observed which was similar in both patients and controls. [less ▲]

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See detailCytokine production from sputum cells in eosinophilic versus non-eosinophilic asthmatics
Quaedvlieg, Valérie ULg; Henket, Monique ULg; Sele, Jocelyne ULg et al

in Clinical & Experimental Immunology (2006), 143(1), 161-166

The inflammatory pathways involved in asthma are more complex than the sole Th2-mediated eosinophilic airway inflammation. Different phenotypes of asthma have been recently highlighted and are probably ... [more ▼]

The inflammatory pathways involved in asthma are more complex than the sole Th2-mediated eosinophilic airway inflammation. Different phenotypes of asthma have been recently highlighted and are probably underlied by different immunological profiles. The aim of the study was to assess cytokine production from sputum cells in eosinophilic versus non-eosinophilic asthmatics. Induced sputum was obtained from 48 consecutive stable mild to moderate asthmatics (20 eosinophilic asthmatics, 28 non-eosinophilic asthmatics) and 31 healthy subjects. Cytokine released from sputum cells were measured by a home-made two-step sandwich immunoassay. Cytokines investigated were interleukin (IL)-4, IL-6, IL-10, tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma. Sputum cells from eosinophilic asthmatics produced more IL-4 than those from both healthy subjects (P < 0.05) and non-eosinophilic asthmatics (P < 0.05). Conversely, sputum cells from eosinophilic asthma were found to release lower amounts of TNF-alpha than those from healthy subjects (P < 0.05). The group of non-eosinophilic asthmatics did not distinguish from healthy subjects with respect to any cytokines measured. Sputum cells from asthmatics exhibiting eosinophilic airway inflammation release more IL-4 and less TNF-alpha than those of healthy subjects. By contrast, non-eosinophilic asthmatics did not distinguish from healthy subjects by abnormal cytokine release from their sputum cells. [less ▲]

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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 detailNebulised salbutamol administered during sputum induction improves bronchoprotection in patients with asthma
Delvaux, Muriel ULg; Henket, Monique ULg; Lau, L. et al

in Thorax (2004), 59(2), 111-115

Background: Inhalation of hypertonic or even isotonic saline during sputum induction may cause bronchospasm in susceptible patients with asthma, despite premedication with 400 mug inhaled salbutamol ... [more ▼]

Background: Inhalation of hypertonic or even isotonic saline during sputum induction may cause bronchospasm in susceptible patients with asthma, despite premedication with 400 mug inhaled salbutamol delivered by pressurised metered dose inhaler (pMDI). The bronchoprotection afforded by additional inhaled salbutamol administered through the ultrasonic nebuliser during sputum induction was investigated. Methods: Twenty patients with moderate to severe asthma underwent sputum induction by inhaling saline 4.5% (or 0.9% if post-bronchodilation forced expiratory volume in 1 second (FEV1) <65% predicted) for 10 minutes according to two protocols given 1 week apart in random order. At visit A the patients received 400 mg salbutamol administered through a pMDI + spacer 20 minutes before induction while at visit B the premedication was supplemented by 1500 mg nebulised salbutamol inhaled throughout the induction procedure. Both the investigator and the patients were blind to the nebulised solution used. FEV1 was recorded during sputum induction at 1, 3, 5, and 10 minutes. Sputum cell counts and histamine, tryptase and albumin levels in the supernatants were determined. Results: The mean (SE) maximal reduction in FEV1 over the 10 minute period of sputum induction was 11.7 (2.8)% at visit A, which was significantly greater than at visit B (2.6 (1.2)%; mean difference 9% (95% CI 2.7 to 15.4), p < 0.01). Total and differential sputum cell counts as well as albumin, tryptase, and histamine levels did not differ between the two visits. Conclusion: The addition of inhaled salbutamol through an ultrasonic nebuliser markedly improves bronchoprotection against saline induced bronchoconstriction in patients with moderate to severe asthma undergoing sputum induction without affecting cell counts and inflammatory markers. [less ▲]

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See detailCytokine production from sputum cells after allergenic challenge in IgE-mediated asthma
Bettiol, Jeanne; Sele, Jocelyne ULg; Henket, Monique ULg et al

in Allergy (2002), 57(12), 1145-1150

Background: Th2 cytokine production from airway cells is thought to govern the eosinophilic airways in ammation in allergic asthma. Induced sputum has become a widely used technique to assess airways in ... [more ▼]

Background: Th2 cytokine production from airway cells is thought to govern the eosinophilic airways in ammation in allergic asthma. Induced sputum has become a widely used technique to assess airways in ammation. Methods: By applying the technique of induced sputum to collect airways cells, we have assessed the spontaneous production of a set of cytokines, including interleukin-4, 6, 10, interferon-gamma and tumour necrosis factor-alpha 6 h after a bronchial allergenic hallenge with Dermatophagoides pteronyssinus (Dpt) in 12 sensitized asthmatics and compared the results obtained after inhalation of saline as control. A group of eight healthy non-allergic subjects was enrolled to control for any non-specific effect of Dpt. Cytokines were measured by a dynamic immunoassay during a 24-h sputum cell culture. Results: Allergen challenge in sensitized asthmatics caused an acute and a late bronchospasm together with a rise in sputum eosinophil counts. Afterwards allergen sputum cells from allergic asthmatics displayed a rise in their production of IL-4 (P < 0.01), IL-6 (P < 0.05) and IL- 10 (P < 0.05) when compared to saline. By this time sputum generation of IL- 4 in atopic asthmatics was greater than in healthy subjects (P < 0.001). Furthermore, in allergic asthmatics there was a strong correlation between the rise in interleukin-4 production from sputum cells and the rise in sputum eosinophils (r = 0.87, P < 0.001). Conclusions: Sputum cell culture is a useful model to assess cytokine production in allergic asthmatics who show a marked up-regulation of Th2 cytokines following acute allergen exposure. The rise in sputum eosinophil count following allergen challenge strongly correlates with the rise in IL-4 generation from sputum cells. [less ▲]

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