Sophie Gohy

Imprinting of the COPD airway epithelium for dedifferentiation and mesenchymal transition

In chronic obstructive pulmonary disease (COPD), epithelial changes and subepithelial fibrosis are salient features in conducting airways. Epithelial-to-mesenchymal transition (EMT) has been recently suggested in COPD, but the mechanisms and relationship to peribronchial fibrosis remain unclear. We hypothesised that de-differentiation of the COPD respiratory epithelium through EMT could participate in airway fibrosis and thereby, in airway obstruction. Surgical lung tissue and primary broncho-epithelial cultures (in air–liquid interface (ALI)) from 104 patients were assessed for EMT markers. Cell cultures were also assayed for mesenchymal features and for the role of transforming growth factor (TGF)-β1. The bronchial epithelium from COPD patients showed increased vimentin and decreased ZO-1 and E-cadherin expression. Increased vimentin expression correlated with basement membrane thickening and airflow limitation. ALI broncho-epithelial cells from COPD patients also displayed EMT phenotype in up to 2 weeks of culture, were more spindle shaped and released more fibronectin. Targeting TGF-β1 during ALI differentiation prevented vimentin induction and fibronectin release. In COPD, the airway epithelium displays features of de-differentiation towards mesenchymal cells, which correlate with peribronchial fibrosis and airflow limitation, and which are partly due to a TGF-β1-driven epithelial reprogramming. The COPD airway epithelium is programmed for mesenchymal transition via a TGF-β1-dependent process http://ow.ly/LhIQb

Features of mesenchymal transition in the airway epithelium from chronic rhinosinusitis

Chronic rhinosinusitis (CRS) defines a group of disorders characterized by persistent inflammation of the sinonasal tract. Epithelial changes and structural remodelling are present, but whether epithelial differentiation is altered remains uncertain.

Polymeric immunoglobulin receptor down-regulation in chronic obstructive pulmonary disease. Persistence in the cultured epithelium and role of transforming growth factor-β.

RATIONALE The generation of protective secretory IgA relies on the epithelial polymeric immunoglobulin receptor (pIgR). pIgR expression is reduced in chronic obstructive pulmonary disease (COPD), but correlation to disease severity and underlying mechanisms remains unknown. OBJECTIVES To address the hypothesis that pIgR down-regulation in COPD concerns severe disease in relation to aberrant programming of the bronchial epithelium. METHODS Surgical lung tissue and primary bronchial epithelium (cultured in air-liquid interface, ALI) obtained from a large series of patients (n = 116) were studied for pIgR expression and regulation. MEASUREMENTS AND MAIN RESULTS pIgR immunostaining in the bronchial epithelium is decreased in severe COPD. In contrast, pIgR transcription was up-regulated in smokers with or without COPD. In ALI (vs. submerged) cultures, pIgR expression was strongly induced, whereas pIgR expression and IgA-transcytosis capacity were decreased in cultures from subjects with severe COPD as compared with control subjects. In addition, COPD cultures released more transforming growth factor-β1 (TGF-β1), reflecting increased epithelial TGF-β1 immunostaining in COPD lung tissue. Finally, besides inducing epithelial dedifferentiation, exogenous TGF-β1 dose-dependently inhibited pIgR production, whereas pIgR increased on blockade of TGF-β1 activity during ALI differentiation. CONCLUSIONS pIgR down-regulation in COPD correlates with disease severity, and the bronchial epithelium reconstituted in vitro from these patients retains its aberrant imprinting for pIgR expression. This study also links pIgR down-regulation to TGF-β-driven reprogramming of the bronchial epithelium, which results in impaired lung IgA immunity in patients with COPD.

Chronic inflammatory airway diseases: the central role of the epithelium revisited

The respiratory epithelium plays a critical role for the maintenance of airway integrity and defense against inhaled particles. Physical barrier provided by apical junctions and mucociliary clearance clears inhaled pathogens, allergens or toxics, to prevent continuous stimulation of adaptive immune responses. The “chemical barrier”, consisting of several anti‐microbial factors such as lysozyme and lactoferrin, constitutes another protective mechanism of the mucosae against external aggressions before adaptive immune response starts. The reconstruction of damaged respiratory epithelium is crucial to restore this barrier. This review examines the role of the airway epithelium through recent advances in health and chronic inflammatory diseases in the lower conducting airways (in asthma and chronic obstructive pulmonary disease). Better understanding of normal and altered epithelial functions continuously provides new insights into the physiopathology of chronic airway diseases and should help to identify new epithelial‐targeted therapies.

Granulomatous meningitis due to rheumatoid arthritis.

Meningoencephalitis is a rare but aggressive complication of rheumatoid arthritis (RA). The most common complications of RA occur in the severe and chronic stages of the disease. Only a few cases have been reported in the literature. The symptoms are usually nonspecific, and arthralgia may be missing. Brain MRI and CSF analysis are useful to guide the diagnosis. However, a biopsy is required to demonstrate the existence of granulomatous lesions and the lack of mycobacterium infection. Early detection is essential to prevent neurological complications. Treatment consists of intravenous high doses of corticoid followed by oral tapered doses associated with immunosuppressive therapy. The present case is remarkable by the presence of granulomatous lesions in the lung and meninges and the dramatic improvement after immunosuppressive therapy.

Airway Epithelium Dysfunction in Cystic Fibrosis and COPD

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.

Variability of gait speed during six minutes walking test in COPD and cystic fibrosis patients.

BACKGROUND Recently, gait speed reached an increasing importance in the management of respiratory patients. The aim of this retrospective study was to compare walking speed and physiological adaptations during the 6MWT in COPD and CF patients. METHODS 6MWT performed by COPD and CF patients were retrospectively reviewed. Global and sequential walking speeds were measured on six minutes and every sequence of two minutes respectively. Heart rate, oxygen saturation and dyspnea were analyzed. RESULTS 78 and 246 tests from CF and COPD patients were reviewed respectively. FEV1 (52.3 vs 56.2% pred) and FVC (72.5 vs 73.8% pred) were similar between both diseases. However, 6MWT in patients with CF were characterized by significantly higher heart rate, global walking speed and walking distance (+68%) while dyspnea evolutions and the proportions of patients presenting walking speed decline over the 6min were significantly lower. CONCLUSION Walking speed and cardio-respiratory parameters evolution during 6MWT differ between COPD and CF patients.

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

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‐&bgr; mediates the IL‐4/IL‐13 effect on the pIgR, with a partial contribution of upregulated transforming growth factor‐&agr;/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.

DRESS syndrome in a patient with cystic fibrosis: A case report

Drug reaction with eosinophilia and systemic symptom (DRESS) syndrome is a rare and severe side‐effect, mainly described after intake of anticonvulsants, allopurinol, or antibiotics. It usually begins within 2 months after drug introduction. Symptoms include cutaneous rash, hematologic abnormalities, and internal organ involvement and the diagnosis might be challenging. This case report illustrates for the first time this life‐threatening complication in a patient with cystic fibrosis (CF). In this case, withdrawal of the offending drug was sufficient for full recovery. Clinicians involved in CF care should be aware of DRESS syndrome, as they commonly prescribe several potentially culprit drugs. Pediatr Pulmonol. 2017;52:E18–E21.

Comparison of the RGM medium and the mycobacterial growth indicator tube automated system for isolation of non-tuberculous mycobacteria from sputum samples of cystic fibrosis patients in Belgium

Purpose Pulmonary infections due to non-tuberculous mycobacteria (NTM) are an emerging issue in the cystic fibrosis (CF) population. Due to bacterial and fungal overgrowth, isolation of mycobacteria from the sputum samples of these patients remains challenging. RGM medium, a novel agar-based culture medium was evaluated for the isolation of NTM from sputum samples of CF patients. Methodology Sputum samples were inoculated onto RGM medium and conventional Mycobacterial Growth Indicator Tube (MGIT™, Becton Dickinson, USA). Agar plates were incubated at 35 °C and growth was recorded once a week during 42 days. We compared the yield of the two media. Results 217 samples were obtained from 124 CF patients. 20 samples (13 patients) had a positive culture for NTM. 79/217 (36.4%) MGIT had to be discontinued due to contamination compared to 18/217 (8.3%) for RGM. We reported equivalent NTM detection performances for RGM and MGIT (P = 0.579): these media enabled the isolation of 15 and 12 NTM strains respectively. Conclusion RGM medium increases the proportion of interpretable results and the number of NTM cultured. Taking into account the non-inferiority compared to conventional methods and ease of use of RGM medium, we estimate that this test can replace current approaches for the screening of NTM among people with CF. Additionally, RGM provides semi-quantitative results (number of colonies) and information on the morphology of colonies, which may be clinically relevant information.