Publications by authors named "Charles Pilette"

63 Publications

The Epithelial-Immune Crosstalk in Pulmonary Fibrosis.

Front Immunol 2021 19;12:631235. Epub 2021 May 19.

Pôle de pneumologie, O.R.L. et dermatologie, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Bruxelles, Belgium.

Interactions between the lung epithelium and the immune system involve a tight regulation to prevent inappropriate reactions and have been connected to several pulmonary diseases. Although the distal lung epithelium and local immunity have been implicated in the pathogenesis and disease course of idiopathic pulmonary fibrosis (IPF), consequences of their abnormal interplay remain less well known. Recent data suggests a two-way process, as illustrated by the influence of epithelial-derived periplakin on the immune landscape or the effect of macrophage-derived IL-17B on epithelial cells. Additionally, damage associated molecular patterns (DAMPs), released by damaged or dying (epithelial) cells, are augmented in IPF. Next to "sterile inflammation", pathogen-associated molecular patterns (PAMPs) are increased in IPF and have been linked with lung fibrosis, while outer membrane vesicles from bacteria are able to influence epithelial-macrophage crosstalk. Finally, the advent of high-throughput technologies such as microbiome-sequencing has allowed for the identification of a disease-specific microbial environment. In this review, we propose to discuss how the interplays between the altered distal airway and alveolar epithelium, the lung microbiome and immune cells may shape a pro-fibrotic environment. More specifically, it will highlight DAMPs-PAMPs pathways and the specificities of the IPF lung microbiome while discussing recent elements suggesting abnormal mucosal immunity in pulmonary fibrosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2021.631235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170303PMC
May 2021

Follow-up of functional exercise capacity in patients with COVID-19: It is improved by telerehabilitation.

Respir Med 2021 07 30;183:106438. Epub 2021 Apr 30.

Service de Pneumologie, Cliniques Universitaires Saint-Luc, Brussels, Belgium; Institut de Recherche Expérimentale et Clinique (IREC), Pôle de Pneumologie, ORL & Dermatologie, Université Catholique de Louvain, Brussels, Belgium; Secteur de Kinésithérapie et Ergothérapie, Cliniques Universitaires Saint-Luc, Brussels, Belgium. Electronic address:

Background: The impact of the COVID-19 pandemic on functional exercise capacity seemed quickly clinically evident. The objective of this study was to assess the functional exercise capacity of patients with severe COVID-19 and to evaluate the effect of a telerehabilitation program in the specific context of the COVID-19 pandemic.

Method: Patients hospitalized for severe or critical COVID-19 were recruited. The functional exercise capacity (1-min sit-to-stand test (STST)) was prospectively quantified at discharge. A telerehabilitation program was then proposed. A control group was composed with the patients refusing the program.

Results: At discharge, none of the 48 recruited patients had a STST higher than the 50th percentile and 77% of them were below the 2.5th percentile. SpO2 was 92.6 ± 3.0% after STST and 15 patients had oxygen desaturation. After 3-months of follow-up, the number of repetitions during STST significantly increased either in telerehabilitation (n = 14) (p < 0.001) or in control groups (n = 13) (p = 0.002) but only one patient had a result higher than the 50th percentile (in Telerehabilitation group) and 37% of them were still under the 2.5th percentile for this result. The improvement was significantly and clinically greater after the telerehabilitation program (p = 0.005). No adverse events were reported by the patients during the program.

Conclusions: Patients hospitalized for COVID-19 have a low functional exercise capacity at discharge and the recovery after three months is poor. The feasibility and the effect of a simple telerehabilitation program were verified, this program being able to substantially improve the functional recovery after three months.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.rmed.2021.106438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084600PMC
July 2021

Determinants of IgG antibodies kinetics after severe and critical COVID-19.

J Med Virol 2021 May 4. Epub 2021 May 4.

Division of Internal Medicine and Infectious Diseases, Cliniques Universitaires Saint-Luc, Brussels, Belgium.

The kinetics of IgG antibodies after coronavirus disease 2019 (COVID-19) remain poorly understood. We investigated factors influencing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG antibody levels and time to seronegativation during the follow-up of severe and critically ill patients. We retrospectively reviewed serological evaluations drawn during the follow-up of severe or critical laboratory-proven COVID-19 patients hospitalized at a large academic hospital. Specific IgG titers were measured using a chemiluminescent assay targeting anti-spike and anti-nucleocapsid protein IgG. The influence of time, demographic factors, clinical and paraclinical characteristics, and COVID-19 therapeutics on IgG levels were assessed through linear regression using a mixed-effect model, and delay until IgG negativation through a Weibull regression model. The cohort included 116 patients with a total of 154 IgG measurements drawn at a median of 79 days after diagnosis. IgG antibodies were increased with age (p = 0.005) and decreased significantly over time (p = 0.0002). Using elapsed time and age as covariates, we demonstrated higher IgG levels in patients with a higher body mass index (BMI) (p = 0.0026) and lower IgG levels in immunocompromised patients (p = 0.032). A high BMI was further found to delay and immunodeficiency to hasten significantly seronegativation, whereas no significant effect was observed with corticosteroids. These data highlight the waning over time of IgG antibodies after severe or critical COVID-19. Age, BMI, and immunosuppression also appear to influence the IgG kinetics, while short-term corticotherapy does not. Those data improve the understanding of SARS-CoV-2 serology while further research should determine the determinants of long-term seroprotection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jmv.27059DOI Listing
May 2021

Integrative respiratory follow-up of severe COVID-19 reveals common functional and lung imaging sequelae.

Respir Med 2021 05 4;181:106383. Epub 2021 Apr 4.

Radiology Department, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Bruxelles, Belgium; Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Belgium.

Background: COVID-19 pandemic resulted in an unprecedented number of hospitalizations in general wards and intensive care units (ICU). Severe and critical COVID-19 patients suffer from extensive pneumonia; therefore, long-term respiratory sequelae may be expected.

Research Question: We conducted a cohort study to determine respiratory sequelae in patients with severe and critical COVID-19. We aimed at evaluating the proportion of patients with persisting respiratory symptoms and/or abnormalities in pulmonary function tests (PFT) or in lung imaging.

Study Design: and methods: This is a single center cohort study including COVID-19 survivors who underwent a three-month follow-up with clinical evaluation, PFT and lung high-resolution computed tomography (HRCT). All clinical, functional, and radiological data were centrally reviewed. Multiple linear regression analysis was performed to identify factors associated with residual lesions on HRCT.

Results: Full clinical evaluation, PFT and lung HRCT were available for central review in 126, 122 and 107 patients, respectively. At follow-up, 25% of patients complained from dyspnea and 35% from fatigue, lung diffusion capacity (DLCO) was decreased in 45%, 17% had HRCT abnormalities affecting more than 5% of their lung parenchyma while signs of fibrosis were found in 21%. In multiple linear regression model, number of days in ICU were related to the extent of persisting lesions on HRCT, while intubation was associated with signs of fibrosis at follow-up (P = 0.0005, Fisher's exact test). In contrast, the severity of lung imaging or PFT changes were not predictive of fatigue and dyspnea.

Interpretation: Although most hospitalized COVID-19 patients recover, a substantial proportion complains from persisting dyspnea and fatigue. Impairment of DLCO and signs suggestive of fibrosis are common but are not strictly related to long-lasting symptoms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.rmed.2021.106383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019490PMC
May 2021

Canonical WNT pathway is activated in the airway epithelium in chronic obstructive pulmonary disease.

EBioMedicine 2020 Nov 10;61:103034. Epub 2020 Oct 10.

Pole of Pneumology, ENT, and Dermatology, Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium; Department of Pneumology, Cliniques Universitaires Saint-Luc, Brussels, Belgium. Electronic address:

Background: Chronic obstructive pulmonary disease (COPD) is a devastating lung disease, mainly due to cigarette smoking, which represents the third cause of mortality worldwide. The mechanisms driving its epithelial salient features remain largely elusive. We aimed to evaluate the activation and the role of the canonical, β-catenin-dependant WNT pathway in the airway epithelium from COPD patients.

Methods: The WNT/β-catenin pathway was first assessed by WNT-targeted RNA sequencing of the air/liquid interface-reconstituted bronchial epithelium from COPD and control patients. Airway expression of total and active β-catenin was assessed in lung sections, as well as WNT components in laser-microdissected airway epithelium. Finally, we evaluated the role of WNT at the bronchial epithelial level by modulating the pathway in the reconstituted COPD epithelium.

Findings: We show that the WNT/β-catenin pathway is upregulated in the COPD airway epithelium as compared with that of non-smokers and control smokers, in targeted RNA-sequencing of in vitro reconstituted airway epithelium, and in situ in lung tissue and laser-microdissected epithelium. Extrinsic activation of this pathway in COPD-derived airway epithelium inhibited epithelial differentiation, polarity and barrier function, and induced TGF-β-related epithelial-to-mesenchymal transition (EMT). Conversely, canonical WNT inhibition increased ciliated cell numbers, epithelial polarity and barrier function, whilst inhibiting EMT, thus reversing COPD features.

Interpretation: In conclusion, the aberrant reactivation of the canonical WNT pathway in the adult airway epithelium recapitulates the diseased phenotype observed in COPD patients, suggesting that this pathway or its downstream effectors could represent a future therapeutic target.

Funding: This study was supported by the Fondation Mont-Godinne, the FNRS and the WELBIO.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2020.103034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559244PMC
November 2020

Lung immunoglobulin A immunity dysregulation in cystic fibrosis.

EBioMedicine 2020 Oct 11;60:102974. Epub 2020 Sep 11.

Pole of Pneumology, ENT and Dermatology, Institute of Experimental & Clinical Research, Université catholique de Louvain (UCLouvain), Brussels, Belgium; Department of Pneumology, Cliniques universitaires Saint-Luc, Brussels, Belgium; Centre de référence pour la mucoviscidose, Cliniques universitaires Saint-Luc, Brussels, Belgium. Electronic address:

Background: In cystic fibrosis (CF), recurrent infections suggest impaired mucosal immunity but whether production of secretory immunoglobulin A (S-IgA) is impaired remains elusive. S-IgA is generated following polymeric immunoglobulin receptor (pIgR)-mediated transepithelial transport of dimeric (d-)IgA and represents a major defence through neutralisation of inhaled pathogens like Pseudomonas aeruginosa (Pa).

Methods: Human lung tissue (n = 74), human sputum (n = 118), primary human bronchial epithelial cells (HBEC) (cultured in air-liquid interface) (n = 19) and mouse lung tissue and bronchoalveolar lavage were studied for pIgR expression, IgA secretion and regulation.

Findings: Increased epithelial pIgR immunostaining was observed in CF lung explants, associated with more IgA-producing plasma cells, sputum and serum IgA, especially Pa-specific IgA. In contrast, pIgR and IgA transport were downregulated in F508del mice, CFTR-inhibited HBEC, and CF HBEC. Moreover, the unfolded protein response (UPR) due to F508del mutation, inhibited IgA transport in Calu-3 cells. Conversely, pIgR expression and IgA secretion were strongly upregulated following Pa lung infection in control and F508del mice, through an inflammatory host response involving interleukin-17.

Interpretation: A complex regulation of IgA secretion occurs in the CF lung, UPR induced by CFTR mutation/dysfunction inhibiting d-IgA transcytosis, and Pa infection unexpectedly unleashing this secretory defence mechanism.

Funding: This work was supported by the Forton's grant of the King Baudouin's Foundation, Belgium, the Fondazione Ricerca Fibrosi Cistica, Italy, and the Fonds National de la Recherche Scientifique, Belgium.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2020.102974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495088PMC
October 2020

Real-Life Study of Mepolizumab in Idiopathic Chronic Eosinophilic Pneumonia.

Lung 2020 04 12;198(2):355-360. Epub 2020 Feb 12.

Service de Pneumologie, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Avenue Hippocrate10 1200, Bruxelles, Belgium.

Introduction: Idiopathic chronic eosinophilic pneumonia (ICEP) is an orphan lung disease characterized by concomitant systemic and local eosinophilia, along with bilateral lung infiltrates. Symptoms include dyspnea of subacute/chronic onset, cough, and general systemic signs. Although all patients do respond to oral corticosteroids, relapse rate is very high, which highlights the need for alternative therapies in case of relapsing ICEP. Mepolizumab is a fully humanized antibody directed against interleukin 5, a key growth factor of eosinophils. In the present study, we retrospectively studied the effect of off-label use of mepolizumab for relapsing ICEP.

Materials And Methods: All data from patients treated with mepolizumab for relapsing ICEP were included in our database and diagnoses were reviewed. We analyzed the effect of treatment on relapse rate, oral corticosteroids (OCS) use, and lung lesions on high-resolution computed tomography (HRCT).

Results: We included ten patients in the final analysis, with a median follow-up of 9 months after initiation of mepolizumab. Beside its expected effect on circulating eosinophils, treatment with mepolizumab was associated with a significant reduction of annual rate of exacerbations and a reduced consumption of corticosteroids. We also observed a remission of lung lesions on follow-up HRCT.

Conclusions: In this open-label retrospective study, treatment of ICEP with mepolizumab was associated with a reduction of relapses, OCS use, and the disappearance of lung infiltrates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00408-020-00336-3DOI Listing
April 2020

Severe asthma: oral corticosteroid alternatives and the need for optimal referral pathways.

J Asthma 2021 Apr 11;58(4):448-458. Epub 2020 Jan 11.

Respiratory Division, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium.

Objective: Patients with severe asthma require high-dose inhaled corticosteroids, with or without add-on treatments, to maintain asthma control. Because symptom control remains unsatisfactory in some patients despite these therapies, maintenance therapy with oral corticosteroids (OCS) remains considered a treatment option by physicians. Besides physician-diagnosed exacerbations, many patients intermittently self-medicate with OCS during episodes of worsening symptoms or as a prevention of such episodes. However, long-term OCS use is associated with several comorbidities that may decrease health-related quality of life, worsen prognosis, and should ideally require monitoring and management. In this review, we discuss the adverse effects of OCS use, the OCS-sparing effect of biologics in severe asthma, and the need for optimal referral pathways to ensure the best outcomes for those at-risk asthma patients.

Data Sources: PubMed.

Study Selection: Studies with results on the OCS-sparing effect of biologics in adult severe asthma were selected.

Results: Chronic and intermittent OCS use in asthma is associated with considerable adverse effects in asthma. Omalizumab, mepolizumab, benralizumab, and dupilumab reduce the need for OCS in severe asthma, while also reducing the exacerbation rate and improving several patient-related outcomes.

Conclusion: Targeted biologic therapies have revolutionized the treatment of uncontrolled severe asthma by reducing or even eliminating the need for OCS and improving other major outcomes. Novel agents are now rapidly increasing the therapeutic armamentarium, but additional efforts are needed to optimize referral pathways in order to ensure sustainable access to these therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/02770903.2019.1705335DOI Listing
April 2021

Altered generation of ciliated cells in chronic obstructive pulmonary disease.

Sci Rep 2019 11 29;9(1):17963. Epub 2019 Nov 29.

Université catholique de Louvain (UCL), Institute of Experimental & Clinical Research - Pole of Pneumology, ENT and Dermatology, Avenue Hippocrate 54/B1-54.04, B-1200, Brussels, Belgium.

In COPD, epithelial changes are prominent features in the airways, such as goblet cell hyperplasia and squamous metaplasia. In contrast, it remains unclear whether ciliated cells are reduced and which pathways dysregulate epithelial differentiation. We hypothesized that bronchial epithelial cell lineage specification is dysregulated in COPD because of an aberrant reprogramming through transforming growth factor (TGF)-β1. Surgical lung tissue from 81 COPD and 61 control (smokers and non-smokers) patients was assessed for bronchial epithelial cell phenotyping by immunohistochemistry, both in situ and in vitro in reconstituted air-liquid interface (ALI) cultures. The role of TGF-β1 was studied in vitro. COPD epithelium in large airways, when compared to controls, showed decreased β-tubulin IV + ciliated cells (4.4%, 2.5-8.8% versus 8.5%, 6.3-11.8% of surface staining, median and IQR, p = 0.0009) and increased MUC5AC + goblet cells (34.8%, 24.4-41.9% versus 10.3%, 5.1-17.6%, p < 0.0001). Both features were recapitulated in the ALI-cultured epithelium from COPD patients. Exogenous TGF-β1 reduced mucociliary differentiation while neutralizing TGF-β1 during ALI increased both specialized cell types. The COPD airway epithelium displays altered differentiation for ciliated cells, which recapitulates in vitro, at least in part through TGF-β1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-54292-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884487PMC
November 2019

Key role of the epithelium in chronic upper airways diseases.

Clin Exp Allergy 2020 02 6;50(2):135-146. Epub 2019 Dec 6.

Pole of Pneumology, ENT and Dermatology, Université catholique de Louvain (UCL), Brussels, Belgium.

The respiratory epithelium of the upper airways is a first-line defence against inhaled irritants, pathogens and allergens. It ensures a physical barrier provided by apical junctions and mucociliary clearance to avoid excessive activation of the immune system. The epithelium also forms a chemical and immunological barrier, extensively equipped to protect the airways against external aggressions before the adaptive immune system is required. Under normal circumstances, the epithelium is capable of recovering rapidly after damage. This manuscript reviews these main properties of the upper airway epithelium as well as its reported impairments in chronic inflammatory diseases. The knowledge on normal epithelial functions and their dysregulation in upper airway diseases should help to design new epithelial-targeted treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cea.13539DOI Listing
February 2020

Increased Expression and Activation of FAK in Small-Cell Lung Cancer Compared to Non-Small-Cell Lung Cancer.

Cancers (Basel) 2019 Oct 10;11(10). Epub 2019 Oct 10.

Pole of Pneumology, ENT, and Dermatology (PNEU), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCLouvain), 1200 Brussels, Belgium.

Introduction: Focal adhesion kinase (FAK) plays a crucial role in cancer development and progression. FAK is overexpressed and/or activated and associated with poor prognosis in various malignancies. However, in lung cancer, activated FAK expression and its prognostic value are unknown.

Methods: FAK and activated FAK (phospho-FAK Y397) expressions were analyzed by multiplex immunofluorescence staining in formalin-fixed paraffin-embedded tissues from 95 non-small-cell lung cancer (NSCLC) and 105 small-cell lung cancer (SCLC) patients, and 37 healthy donors. The FAK staining score was defined as the percentage (%) of FAK-stained tumor area multiplied by (×) FAK mean intensity and phospho-FAK staining score as the (% of phospho-FAK-stained area of low intensity × 1) + (% of phospho-FAK-stained area of medium intensity × 2) + (% of the phospho-FAK-stained area of high intensity × 3). FAK and phospho-FAK staining scores were compared between normal, NSCLC, and SCLC tissues. They were also tested for correlations with patient characteristics and clinical outcomes.

Results: The median follow-up time after the first treatment was 42.5 months and 6.4 months for NSCLC and SCLC patients, respectively. FAK and phospho-FAK staining scores were significantly higher in lung cancer than in normal lung and significantly higher in SCLC compared to NSCLC tissues ( < 0.01). Moreover, the ratio between phospho-FAK and FAK staining scores was significantly higher in SCLC than in NSCLC tissues ( < 0.01). However, FAK and activated FAK expression in lung cancer did not correlate with recurrence-free and overall survival in NSCLC and SCLC patients.

Conclusions: Total FAK and activated FAK expressions are significantly higher in lung cancer than in normal lung, and significantly higher in SCLC compared to NSCLC, but are not prognostic biomarkers in this study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers11101526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827365PMC
October 2019

Vitamin D Modulates the Response of Bronchial Epithelial Cells Exposed to Cigarette Smoke Extract.

Nutrients 2019 Sep 6;11(9). Epub 2019 Sep 6.

Lab of Respiratory Diseases, CHROMETA, KU Leuven, 3000 Leuven, Belgium.

In chronic obstructive pulmonary disease (COPD), the bronchial epithelium is the first immune barrier that is triggered by cigarette smoke. Although vitamin D (vitD) has proven anti-inflammatory and antimicrobial effects in alveolar macrophages, little is known about the direct role of vitD on cigarette smoke-exposed bronchial epithelial cells. We examined the effects of vitD on a human bronchial epithelial cell line (16HBE) and on air-liquid culture of primary bronchial epithelial cells (PBEC) of COPD patients and controls exposed for 24 h to cigarette smoke extract (CSE). VitD decreased CSE-induced IL-8 secretion by 16HBE cells, but not by PBEC. VitD significantly increased the expression of the antimicrobial peptide cathelicidin in 16HBE and PBEC of both COPD subjects and controls. VitD did not affect epithelial to mesenchymal transition or epithelial MMP-9 expression and was not able to restore impaired wound healing by CSE in 16HBE cells. VitD increased the expression of its own catabolic enzyme CYP24A1 thereby maintaining its negative feedback. In conclusion, vitD supplementation may potentially reduce infectious exacerbations in COPD by the upregulation of cathelicidin in the bronchial epithelium.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu11092138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770037PMC
September 2019

Variability in total serum IgE over 1 year in severe asthmatics.

Allergy Asthma Clin Immunol 2019 29;15:20. Epub 2019 Mar 29.

6Novartis Pharma, Medialaan 40, 1800 Vilvoorde, Belgium.

Background: Immunoglobulin E (IgE) is the treatment target of omalizumab, a monoclonal antibody indicated in the treatment of severe allergic asthma. Long-term variability of serum total IgE (sIgE) in asthmatics remains poorly documented.

Methods: In this prospective study, sIgE levels were measured over 1 year at 7 time points in 41 severe asthmatics treated with high-dose of inhaled corticosteroids and long-acting β agonists. 33 patients were atopic based on at least one positive RAST to common aeroallergens. Patients were divided into three groups according to their baseline sIgE level: low (< 76 IU/mL; n = 10), intermediate (76-700 IU/mL; n = 20) or high (> 700 IU/mL; n = 11). Patients also completed the six-item Juniper Asthma Control Questionnaire (ACQ). The sIgE variability and factors predictive for this variability were studied, as well as ACQ outcomes.

Results: The variation in sIgE level was mostly the consequence of between patient-variability, which represented 96%, 71% and 96% of the total variability in the low, intermediate and high sIgE subgroups, respectively. The residual within-patient variability was therefore limited. In 10/41 patients, sIgE levels increased or decreased, for at least one visit, beyond the predefined range of the subgroups to which they were assigned (< 76 IU/mL; 76-700 IU/mL; > 700 IU/mL). There was a significant but weak correlation between sIgE and ACQ score over all time points (r = 0.15, p = 0.02), but sIgE failed to associate with severe exacerbation. sIgE decreased by 3% with any additional year of age for the whole group (p = 0.01) and increased by 5% per one unit of allergen exposure score in atopic patients (p = 0.002).

Conclusion: In severe asthmatics, limited within-patient variability of sIgE levels was observed over 1 year as opposed to marked between-subject variability. sIgE decreases with age. Variation in sIgE weakly associates with asthma control but not with exacerbation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13223-019-0331-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441212PMC
March 2019

Health literacy among asthma patients and treatment expectations: results of a Belgian survey.

Acta Clin Belg 2020 Apr 14;75(2):141-148. Epub 2019 Jan 14.

Department of Respiratory Medicine, Ghent University Hospital, Gent, Belgium.

: Non-adherence to asthma medication can lead to lower disease control and asthma exacerbations that may be fatal. This survey assessed the attitude and expectations of Belgian asthma patients towards their treatment.: This cross-sectional survey was conducted between June 2015 and February 2016 in 70 Belgian pharmacies. Participants completing the survey had to be ≥15 years, diagnosed with asthma, and on inhaled corticosteroid-based treatment. The analysis included 80 completed questionnaires.: Participants comprehended well that controller drugs are intended to prevent the occurrence of asthma symptoms and complications, and their long-term daily use should be maintained. Twenty seven percent of participants indicated fear of side effects concerning long-term daily use of a controller inhaler. Participants had a good understanding that quick-relief drugs are intended to (quickly) relieve asthma symptoms and do not need to be used on a systematic, daily basis. Out of 73 participants on long-term controller drugs, 33 (45%) were 'non-adherent' (used less frequently than prescribed). Suboptimal adherence to maintenance treatment appeared to increase nightly awakenings and the risk of restrictions in activities due to asthma. Out of 54 participants with available quick-relief drug adherence data, 18 (33%) were non-adherent (used their quick-relief drug more frequently than prescribed).: This survey confirms suboptimal adherence to maintenance controller therapy and overuse of short-acting reliever medications among Belgian patients, which affects asthma control and quality of life. A substantial proportion of patients expressed fear about their chronic therapy, indicating the need for patient education about their disease and its management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17843286.2018.1564543DOI Listing
April 2020

Therapeutic Potential of Focal Adhesion Kinase Inhibition in Small Cell Lung Cancer.

Mol Cancer Ther 2019 01 23;18(1):17-27. Epub 2018 Oct 23.

Institut de Recherche Expérimentale et Clinique (IREC), Pôle de Pneumologie, ORL et Dermatologie (PNEU), Université catholique de Louvain (UCL), Brussels, Belgium.

Small cell lung cancer (SCLC) has a poor prognosis. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase regulating cell proliferation, survival, migration, and invasion, which is overexpressed and/or activated in several cancers, including SCLC. We wanted to determine whether FAK contributes to SCLC aggressive behavior. We first evaluated the effect of FAK small-molecule inhibitor PF-573,228 in NCI-H82, NCI-H146, NCI-H196, and NCI-H446 SCLC cell lines. PF-573,228 (0.1-5 μmol/L) inhibited FAK activity by decreasing phospho-FAK (Tyr397), without modifying total FAK expression. PF-573,228 decreased proliferation, decreased DNA synthesis, induced cell-cycle arrest in G-M phases, and increased apoptosis in all cell lines. PF-573,228 also decreased motility in adherent cell lines. To make sure that these effects were not off-target, we then used a genetic method to inhibit FAK in NCI-H82 and NCI-H446, namely stable transduction with FAK shRNA and/or FAK-related nonkinase (FRNK), a splice variant lacking the N-terminal and kinase domains. Although FAK shRNA transduction decreased total and phospho-FAK (Tyr397) expression, it did not affect proliferation, DNA synthesis, or progression through cell cycle. However, restoration of FAK-targeting (FAT) domain (attached to focal adhesion complex where it inhibits pro-proliferative proteins such as Rac-1) by FRNK transduction inhibited proliferation, DNA synthesis, and induced apoptosis. Moreover, although FAK shRNA transduction increased active Rac1 level, FRNK reexpression in cells previously transduced with FAK shRNA decreased it. Therefore, FAK appears important in SCLC biology and targeting its kinase domain may have a therapeutic potential, while targeting its FAT domain should be avoided to prevent Rac1-mediated protumoral activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-18-0328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318062PMC
January 2019

Increased IgA Expression in Lung Lymphoid Follicles in Severe Chronic Obstructive Pulmonary Disease.

Am J Respir Crit Care Med 2019 03;199(5):592-602

1 Pôle de Pneumologie, ORL & Dermatologie.

Rationale: Accumulation of B cells and lymphoid follicles (LFs) has been described in chronic obstructive pulmonary disease (COPD) airways, but the functional status of lung B cells remains poorly known.

Objectives: To characterize LFs for expression of IgA, the main mucosal antibody.

Methods: The presence of B cells and LFs, including intrafollicular IgA expression, were determined in the lung from patients with COPD (n = 37) versus control subjects (n = 34) by immunohistochemistry. We also evaluated follicular IgA responses in the lungs from mice infected with Pseudomonas aeruginosa (PAO1) (n = 10 per group) and in smoking mice.

Measurements And Main Results: Whereas in smokers B-cell numbers slightly increased, robust increases in B-cell and LF numbers (mainly in distal airways) were only observed in severe COPD. Most follicular B cells were IgM (70-80%), but IgA (and not IgG) B-cell numbers were increased in LFs from severe COPD compared with control subjects (twofold, 44.7% vs. 25.2%), and this was significant in distal but not proximal airways. Follicular IgA response was also observed in PAO1-infected mouse lungs, but not after smoke exposure. Moreover, follicular IgA expression associated with expression of IL-21, which was very potent to activate immunoglobulin production in vitro.

Conclusions: This study shows that IgA production occurs in peribronchiolar LFs from severe COPD, where IL-21-producing T cells are present, and presumably represents a feature of exacerbated mucosal adaptive immune responses against microbial and/or self-antigens.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.201802-0352OCDOI Listing
March 2019

Urgent need for pragmatic trial platforms in severe asthma.

Lancet Respir Med 2018 08;6(8):581-583

Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium; Departments of Epidemiology and Respiratory Medicine, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2213-2600(18)30291-1DOI Listing
August 2018

Reply to Upham: The Bronchial Epithelial Secretory IgA System in Asthma.

Am J Respir Crit Care Med 2018 11;198(9):1236-1238

1 Université Catholique de Louvain Brussels, Belgium.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.201806-1128LEDOI Listing
November 2018

Airway Epithelium Dysfunction in Cystic Fibrosis and COPD.

Mediators Inflamm 2018 8;2018:1309746. Epub 2018 Apr 8.

Lung Biology Group, Department of Clinical Microbiology, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Dublin, Ireland.

Cystic fibrosis is a genetic disease caused by mutations in the CFTR gene, whereas chronic obstructive pulmonary disease (COPD) is mainly caused by environmental factors (mostly cigarette smoking) on a genetically susceptible background. Although the etiology and pathogenesis of these diseases are different, both are associated with progressive airflow obstruction, airway neutrophilic inflammation, and recurrent exacerbations, suggesting common mechanisms. The airway epithelium plays a crucial role in maintaining normal airway functions. Major molecular and morphologic changes occur in the airway epithelium in both CF and COPD, and growing evidence suggests that airway epithelial dysfunction is involved in disease initiation and progression in both diseases. Structural and functional abnormalities in both airway and alveolar epithelium have a relevant impact on alteration of host defences, immune/inflammatory response, and the repair process leading to progressive lung damage and impaired lung function. In this review, we address the evidence for a critical role of dysfunctional airway epithelial cells in chronic airway inflammation and remodelling in CF and COPD, highlighting the common mechanisms involved in the epithelial dysfunction as well as the similarities and differences of the two diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2018/1309746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911336PMC
October 2018

Bronchial Epithelial IgA Secretion Is Impaired in Asthma. Role of IL-4/IL-13.

Am J Respir Crit Care Med 2018 06;197(11):1396-1409

1 Pôle de Pneumologie, ORL, et Dermatologie and.

Rationale: Asthma is associated with increased lung IgE production, but whether the secretory IgA system is affected in this disease remains unknown.

Objectives: We explored mucosal IgA transport in human asthma and its potential regulation by T-helper cell type 2 inflammation.

Methods: Bronchial biopsies from asthma and control subjects were assayed for bronchial epithelial polymeric immunoglobulin receptor (pIgR) expression and correlated to T-helper cell type 2 biomarkers. Bronchial epithelium reconstituted in vitro from these subjects, on culture in air-liquid interface, was assayed for pIgR expression and regulation by IL-4/IL-13.

Measurements And Main Results: Downregulation of pIgR protein was observed in the bronchial epithelium from patients with asthma (P = 0.0002 vs. control subjects). This epithelial defect was not observed ex vivo in the cultured epithelium from patients with asthma. Exogenous IL-13 and IL-4 could inhibit pIgR expression and IgA transcytosis. Mechanistic experiments showed that autocrine transforming growth factor-β mediates the IL-4/IL-13 effect on the pIgR, with a partial contribution of upregulated transforming growth factor-α/epidermal growth factor receptor.

Conclusions: This study shows impaired bronchial epithelial pIgR expression in asthma, presumably affecting secretory IgA-mediated frontline defense as a result of type 2 immune activation of the transforming growth factor pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.201703-0561OCDOI Listing
June 2018

Aberrant epithelial differentiation by cigarette smoke dysregulates respiratory host defence.

Eur Respir J 2018 04 26;51(4). Epub 2018 Apr 26.

Dept of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands.

It is currently unknown how cigarette smoke-induced airway remodelling affects highly expressed respiratory epithelial defence proteins and thereby mucosal host defence.Localisation of a selected set of highly expressed respiratory epithelial host defence proteins was assessed in well-differentiated primary bronchial epithelial cell (PBEC) cultures. Next, PBEC were cultured at the air-liquid interface, and during differentiation for 2-3 weeks exposed daily to whole cigarette smoke. Gene expression, protein levels and epithelial cell markers were subsequently assessed. In addition, functional activities and persistence of the cigarette smoke-induced effects upon cessation were determined.Expression of the polymeric immunoglobulin receptor, secretory leukocyte protease inhibitor and long and short PLUNC (palate, lung and nasal epithelium clone protein) was restricted to luminal cells and exposure of differentiating PBECs to cigarette smoke resulted in a selective reduction of the expression of these luminal cell-restricted respiratory host defence proteins compared to controls. This reduced expression was a consequence of cigarette smoke-impaired end-stage differentiation of epithelial cells, and accompanied by a significant decreased transepithelial transport of IgA and bacterial killing.These findings shed new light on the importance of airway epithelial cell differentiation in respiratory host defence and could provide an additional explanation for the increased susceptibility of smokers and patients with chronic obstructive pulmonary disease to respiratory infections.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/13993003.01009-2017DOI Listing
April 2018

The integrated stress response system in cardiovascular disease.

Drug Discov Today 2018 04 27;23(4):920-929. Epub 2018 Feb 27.

INSERM UMR_S 999, Université Paris-Sud and Université Paris-Saclay, Le Plessis-Robinson, France. Electronic address:

The integrated stress response system represents an ancillary, extremely conserved signalling pathway present in virtually all eukaryotic cells, which plays an important part in the pathophysiology of several disorders such as cancer and neurodegeneration. However, its role in the cardiovascular system remains largely elusive. Hence, this review aims to acknowledge recent findings regarding the action of the eIF2α kinases in the cardiovascular system and their role in the pathophysiology of related disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.drudis.2018.02.008DOI Listing
April 2018

Lung lymphoid neogenesis in cystic fibrosis: a model of adaptive responses to bacteria?

Eur Respir J 2017 04 26;49(4). Epub 2017 Apr 26.

Institute of Experimental and Clinical Research - Pole of Pneumology, ENT and Dermatology, Université catholique de Louvain (UCL), Brussels, Belgium

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/13993003.00380-2017DOI Listing
April 2017

A Belgian survey on the diagnosis of asthma-COPD overlap syndrome.

Int J Chron Obstruct Pulmon Dis 2017 13;12:601-613. Epub 2017 Feb 13.

Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium.

Introduction: Patients with chronic airway disease may present features of both asthma and COPD, commonly referred to as asthma-COPD overlap syndrome (ACOS). Recommendations on their diagnosis are diffuse and inconsistent. This survey aimed to identify consensus on criteria for diagnosing ACOS.

Methods: A Belgian expert panel developed a survey on ACOS diagnosis, which was completed by 87 pulmonologists. Answers chosen by ≥70% of survey respondents were considered as useful criteria for ACOS diagnosis. The two most frequently selected answers were considered as major criteria, others as minor criteria. The expert panel proposed a minimal requirement of two major criteria and one minor criterion for ACOS diagnosis. Respondents were also asked which criteria are important for considering inhaled corticosteroids prescription in a COPD patient.

Results: To diagnose ACOS in COPD patients, major criteria were "high degree of variability in airway obstruction over time (change in forced expiratory volume in 1 second ≥400 mL)" and "high degree of response to bronchodilators (>200 mL and ≥12% predicted above baseline)". Minor criteria were "personal/family history of atopy and/or IgE sensitivity to ≥1 airborne allergen", "elevated blood/sputum eosinophil levels and/or increased fractional exhaled nitric oxide", "diagnosis of asthma <40 years of age"; "symptom variability", and "age (in favor of asthma)". To diagnose ACOS in asthma patients, major criteria were "persistence of airflow obstruction over time (forced expiratory volume in 1 second/forced vital capacity ratio <0.7)" and "exposure to noxious particles/gases, with ≥10 pack-years for (ex-)smokers"; minor criteria were "lack of response on acute bronchodilator test"; "reduced diffusion capacity"; "limited variability in airway obstruction"; "age >40 years"; "emphysema on chest computed tomography scan".

Conclusion: Specific criteria were identified that may guide physicians to a more uniform diagnostic approach for ACOS in COPD or asthma patients. These criteria are largely similar to those used to prescribe inhaled corticosteroids in COPD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/COPD.S124459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5315206PMC
August 2017

Interleukin-1α induced release of interleukin-8 by human bronchial epithelial cells in vitro: assessing mechanisms and possible treatment options.

Transpl Int 2017 Apr 2;30(4):388-397. Epub 2017 Mar 2.

Lung Transplant Unit, Department of Clinical and Experimental Medicine, Division of Respiratory Disease, KU Leuven, Leuven, Belgium.

Survival after lung transplantation is hampered by chronic lung allograft dysfunction (CLAD). Persistently elevated BAL-neutrophilia is observed in some patients despite treatment with azithromycin, which may be induced by IL-1α. Our aim is to establish an in vitro model, assess mechanistic pathways and test different therapeutic strategies of IL-1α-induced release of IL-8 by human bronchial epithelial cells. Bronchial epithelial cells (16HBE) were stimulated with IL-1α with or without azithromycin or dexamethasone. IL-8 protein was analyzed in cell supernatant. Different MAP kinases (p38, JNK, ERK , Iκβ) and targets known to be involved in tumor formation (PI3K, Akt) were investigated. Finally, different treatment options were tested for their potential inhibitory effect. IL-1α induced IL-8 in bronchial epithelial cells, which was dose-dependently inhibited by dexamethasone but not by azithromycin. IL-1α induced p38 and Akt phosphorylation, but activation of these MAPK was not inhibited by dexamethasone. JNK, ERK , Iκβ and PI3K were not activated. None of the tested drugs reduced the IL-1α induced IL-8 production. We established an in vitro model wherein steroids inhibit the IL-1α-induced IL-8 production, while azithromycin was ineffective. Despite using this simple in vitro model, we could not identify a new treatment option for azithromycin-resistant airway neutrophilia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/tri.12915DOI Listing
April 2017

Interleukin-1α: a key player for epithelial-to-mesenchymal signalling in COPD?

Eur Respir J 2016 08;48(2):301-4

Institut de Recherche Expérimentale et Clinique, Pôle de Pneumologie, ORL et Dermatologie, Université Catholique de Louvain, Brussels, Belgium Cliniques Universitaires Saint-Luc, Service de Pneumologie, Brussels, Belgium

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/13993003.01180-2016DOI Listing
August 2016