Airway epithelium damage in acute respiratory distress syndrome.

BACKGROUND: The airway epithelium (AE) fulfils multiple functions to maintain pulmonary homeostasis, among which ensuring adequate barrier function, cell differentiation and polarization, and actively transporting immunoglobulin A (IgA), the predominant mucosal immunoglobulin in the airway lumen, via the polymeric immunoglobulin receptor (pIgR). Morphological changes of the airways have been reported in ARDS, while their detailed features, impact for mucosal immunity, and causative mechanisms remain unclear. Therefore, this study aimed to assess epithelial alterations in the distal airways of patients with ARDS. METHODS: We retrospectively analyzed lung tissue samples from ARDS patients and controls to investigate and quantify structural and functional changes in the small airways, using multiplex fluorescence immunostaining and computer-assisted quantification on whole tissue sections. Additionally, we measured markers of mucosal immunity, IgA and pIgR, alongside with other epithelial markers, in the serum and the broncho-alveolar lavage fluid (BALF) prospectively collected from ARDS patients and controls. RESULTS: Compared to controls, airways of ARDS were characterized by increased epithelial denudation (p = 0.0003) and diffuse epithelial infiltration by neutrophils (p = 0.0005). Quantitative evaluation of multiplex fluorescence immunostaining revealed a loss of ciliated cells (p = 0.0317) a trend towards decreased goblet cells (p = 0.056), and no change regarding cell progenitors (basal and club cells), indicating altered mucociliary differentiation. Increased epithelial permeability was also shown in ARDS with a significant decrease of tight (p < 0.0001) and adherens (p = 0.025) junctional proteins. Additionally, we observed a significant decrease of the expression of pIgR, (p < 0.0001), indicating impaired mucosal IgA immunity. Serum concentrations of secretory component (SC) and S-IgA were increased in ARDS (both p < 0.0001), along other lung-derived proteins (CC16, SP-D, sRAGE). However, their BALF concentrations remained unchanged, suggesting a spillover of airway and alveolar proteins through a damaged AE. CONCLUSION: The airway epithelium from patients with ARDS exhibits multifaceted alterations leading to altered mucociliary differentiation, compromised defense functions and increased permeability with pneumoproteinemia.

The intermittent intrapulmonary deflation technique for airway clearance in patients with cystic fibrosis: A randomized trial.

BACKGROUND: Cystic fibrosis (CF) is a muco-obstructive lung disease characterized by thick sputum with abnormal rheological properties. The intermittent intrapulmonary deflation (IID) is a new instrumental airway clearance technique (ACT) that aims to decrease the sputum viscoelastic properties. This study assessed the benefits of adding the IID technique to a conventional ACT in patients with CF hospitalized for intravenous antibiotic therapy. METHODS: Participants with CF accustomed to autogenic drainage (AD) as their standard ACT received, in a randomized order, a 30-min session of either AD alone or AD combined with IID (AD+IID). Sputum was collected during each ACT regimens and for a 24-hour period following both sessions. Sputum wet weight, dry weight, solids content and rheological properties were analyzed. Cough events occurring during and over 2 h post ACT were compared between both regimens. RESULTS: Seventeen patients with CF (aged 29 ± 11 years; FEV1%: 57.1 ± 20.1) were analysed. The sputum wet weight collected during AD alone was significantly higher than during AD+IID (8.11 ± 6.93 vs 5.40 ± 4.11 respectively, p = 0.01). The sputum rheological properties did not significantly differ between group. There were more cough episodes during AD alone compared to AD+IID (median [IQR]: 8 [5-15.5] vs 5 [3.5-11.0] respectively, p = 0.02). CONCLUSIONS: In participants with CF accustomed to AD, adding the IID technique in combination to AD does not confer a clear benefit on airway clearance in the short term. Clinical Trials register: NCT04157972.

One year effect of tezacaftor and ivacaftor on functional exercise capacity and muscle strength in people with cystic fibrosis.

Background: The 1-min sit-to-stand test (1STST) is a practical tool to evaluate physical capacity. The aim of this study was to assess the impact of tezacaftor and ivacaftor on functional exercise capacity, muscle strength and symptoms in people with cystic fibrosis (PwCF). Methods: The assessments were performed during the first year of tezacaftor and ivacaftor using the 1STST, 6-min walk test (6MWT), MicroFET2 dynamometer®, CF Questionnaire-Revised (CFQ-R), Leicester Cough Questionnaire (LCQ). Forced expiratory volume in 1 s (FEV1), body mass index (BMI), pancreatic sufficiency status, genotype and microbiologic data were also collected. Results: Fifty-four PwCF participated to the study and took at least one dose of tezacaftor-ivacaftor. Mean age was 26y±10 (±SD), median BMI 20.9 kg/m2 (interquartile range) (19.4; 23.5) and mean FEV1 82 percent of predicted values (%PV) ± 21. Significant correlations were found at baseline between the 1STST and the 6MWT (r = 0.617, p < 0.0001), the quadriceps strength (r = 0.6556, p < 0.0001) and the FEV1 (r = 0.29, p = 0.03). After one year of treatment, the 1STST increased significantly in terms of number of repetitions (n) (median 50 versus 58.5, p < 0.0001), %PV (101.1 versus 115.2%PV, p = 0.0003) and n times weight in kg (2885 versus 3389nxkg, p < 0.0001). The 6MWT distance and quadriceps strength were not modified after treatment but during the 6MWT, oxygen desaturation decreased significantly. FEV1, BMI, CFQ-R, LCQ improved as previously demonstrated. Conclusion: After one year of tezacaftor and ivacaftor, the 1STST improves, suggesting that the 1STST seems more responsive than the 6MWT and the MicroFET2 dynamometer® to assess the effects of CFTR modulators.

Novel time-saving OGTT sparing HbA1c-HOMA2 based algorithm for the diagnosis of cystic fibrosis-related diabetes.

AIMS: The diagnosis of cystic fibrosis-related diabetes (CFRD) faces several challenges. We propose a novel screening algorithm to alleviate the burden of cystic fibrosis (CF). METHODS: Through a retrospective cross-sectional single-centre study, HbA1c and HOMA2 indices were assessed in multiple models as alternative diagnostic tools from OGTT data. We sought to establish specific thresholds for CFRD screening with oral glucose tolerance test (OGTT) as gold standard. We evaluated various straightforward or sequential approaches, in terms of diagnostic accuracy while also quantify the potential reduction in OGTTs through these different methods. RESULTS: HOMA indices were recovered in 72 patients. We devised a composite index that combines HbA1c and HOMA-B: Diabetes Predicting Index in cystic fibrosis (DIPIc) = (HbA1c(%) × 3.455) - (HOMA-B(%) ×  0.020) - 19.294. This index yields the highest screening accuracy according to receiver-operating characteristics curves. Using a stepwise algorithm that incorporates DIPIc decreases the requirement for annual OGTTs. A CFRD exclusion cutoff less than -1.7445 (sensitivity 98 %), in conjunction with a CFRD diagnostic threshold greater than 0.4543 (specificity 98 %) allows for 71 % OGTT sparing. CONCLUSION: The composite index DIPIc is a suitable, less invasive screening method for CFRD, which enables to avoid many OGTTs.

The memory of airway epithelium damage in smokers and COPD patients.

Chronic obstructive pulmonary disease (COPD), a devastating and irreversible lung disease, causes structural and functional defects in the bronchial epithelium, the (ir)reversibility of which remains unexplored in vitro. This study aimed to investigate the persistence of COPD-related epithelial defects in long-term airway epithelial cultures derived from non-smokers, smokers, and COPD patients. Barrier function, polarity, cell commitment, epithelial-to-mesenchymal transition, and inflammation were evaluated and compared with native epithelium characteristics. The role of inflammation was explored using cytokines. We show that barrier dysfunction, compromised polarity, and lineage abnormalities observed in smokers and COPD persisted for up to 10 wk. Goblet cell hyperplasia was associated with recent cigarette smoke exposure. Conversely, increased IL-8/CXCL-8 release and abnormal epithelial-to-mesenchymal transition diminished over time. These ex vivo observations matched surgical samples' abnormalities. Cytokine treatment induced COPD-like changes in control cultures and reactivated epithelial-to-mesenchymal transition in COPD cells. In conclusion, these findings suggest that the airway epithelium of smokers and COPD patients retains a multidimensional memory of its original state and previous cigarette smoke-induced injuries, maintaining these abnormalities for extended periods.

Mucosal immune alterations at the early onset of tissue destruction in chronic obstructive pulmonary disease.

Rationale: COPD is characterized by chronic airway inflammation, small airways changes, with disappearance and obstruction, and also distal/alveolar destruction (emphysema). The chronology by which these three features evolve with altered mucosal immunity remains elusive. This study assessed the mucosal immune defense in human control and end-stage COPD lungs, by detailed microCT and RNA transcriptomic analysis of diversely affected zones. Methods: In 11 control (non-used donors) and 11 COPD (end-stage) explant frozen lungs, 4 cylinders/cores were processed per lung for microCT and tissue transcriptomics. MicroCT was used to quantify tissue percentage and alveolar surface density to classify the COPD cores in mild, moderate and severe alveolar destruction groups, as well as to quantify terminal bronchioles in each group. Transcriptomics of each core assessed fold changes in innate and adaptive cells and pathway enrichment score between control and COPD cores. Immunostainings of immune cells were performed for validation. Results: In mildly affected zones, decreased defensins and increased mucus production were observed, along CD8+ T cell accumulation and activation of the IgA pathway. In more severely affected zones, CD68+ myeloid antigen-presenting cells, CD4+ T cells and B cells, as well as MHCII and IgA pathway genes were upregulated. In contrast, terminal bronchioles were decreased in all COPD cores. Conclusion: Spatial investigation of end-stage COPD lungs show that mucosal defense dysregulation with decreased defensins and increased mucus and IgA responses, start concomitantly with CD8+ T-cell accumulation in mild emphysema zones, where terminal bronchioles are already decreased. In contrast, adaptive Th and B cell activation is observed in areas with more advanced tissue destruction. This study suggests that in COPD innate immune alterations occur early in the tissue destruction process, which affects both the alveoli and the terminal bronchioles, before the onset of an adaptive immune response.

Comparison of amikacin lung delivery between AKITA® and eFlow rapid® nebulizers in healthy controls and patients with CF: A randomized cross-over trial.

INTRODUCTION: Nebulization plays a key role in the treatment of cystic fibrosis. The Favorite function couple to jet nebulizers (AKITA®) emerged recently. The aim of this study was to assess the efficiency of the lung delivery by the AKITA® by comparing the urinary concentration of amikacin after nebulization with the AKITA® and the eFlow rapid®, in healthy subjects and patients with CF (PwCF). METHOD: The two samples (healthy subjects and PwCF) were randomized (cross-over 1:1) for two nebulizations (500 mg of amikacin diluted in 4 mL of normal saline solution), with the AKITA® and with the eFlow rapid®. The primary endpoint was the amount of urinary excretion of amikacin over 24 h. The constant of elimination (Ke) was calculated based on the maximal cumulative urinary amikacin excretion plotted over time. RESULTS: The total amount of urinary amikacin excretion was greater when AKITA® was used in PwCF (11.7 mg (8.2-14.1) vs 6.1 mg (3.7-13.3); p = 0.02) but not different in healthy subjects (14.5 mg (11.7-18.5) vs 12.4 mg (8.0-17.1); p = 0.12). The duration of the nebulization was always shorter with eFlow rapid® than with AKITA® (PwCF: 6.5 ± 0.6 min vs 9.2 ± 1.8 min; p = 0.001 - Healthy: 4.7 ± 1.3 min vs 9.7 ± 1.6 min; p = 0.03). The constant of elimination was similar between the two modalities in CF subjects (0.153 (0.071-0.205) vs 0.149 (0.041-0.182); p = 0.26) and in healthy subjects (0.166 (0.130-0.218) vs 0.167 (0.119-0.210), p = 0.25). CONCLUSION: the Favorite inhalation is better to deliver a specific amount of drug than a mesh nebulizer (eFlow rapid®) in PwCF but not in healthy subjects.

Epithelial-Mesenchymal Transition Mechanisms in Chronic Airway Diseases: A Common Process to Target?

Epithelial-to-mesenchymal transition (EMT) is a reversible process, in which epithelial cells lose their epithelial traits and acquire a mesenchymal phenotype. This transformation has been described in different lung diseases, such as lung cancer, interstitial lung diseases, asthma, chronic obstructive pulmonary disease and other muco-obstructive lung diseases, such as cystic fibrosis and non-cystic fibrosis bronchiectasis. The exaggerated chronic inflammation typical of these pulmonary diseases can induce molecular reprogramming with subsequent self-sustaining aberrant and excessive profibrotic tissue repair. Over time this process leads to structural changes with progressive organ dysfunction and lung function impairment. Although having common signalling pathways, specific triggers and regulation mechanisms might be present in each disease. This review aims to describe the various mechanisms associated with fibrotic changes and airway remodelling involved in chronic airway diseases. Having better knowledge of the mechanisms underlying the EMT process may help us to identify specific targets and thus lead to the development of novel therapeutic strategies to prevent or limit the onset of irreversible structural changes.

Combined CFTR modulator therapies are linked with anabolic benefits and insulin-sparing in cystic fibrosis-related diabetes.

Aims: Combined CFTR modulator therapies have dramatically altered pulmonary outcomes in patients with cystic fibrosis (CF). Their impact on glucose metabolism requires further investigations. This study aims to evaluate insulin requirements after initiation of combined CFTR modulator therapy in patients with CF-related diabetes (CFRD) and HOMA indices changes in CF patients without diabetes. Methods: We retrospectively analyzed: 1) the effects of tezacaftor + ivacaftor and elexacaftor + tezacaftor + ivacaftor on FEV1, weight, BMI, HbA1c, and daily insulin dose, in 17 CFRD patients and 2) the impact of tezacaftor + ivacaftor on HOMA indices in 15 CF patients without diabetes. Results: Age was 37±12y in the CFRD group (70% men), 88% of whom were homozygous for F508del mutation. Diabetes duration was 15±10y. Median duration of combined CFTR modulator therapy was 16 months (IQR: 4) Thirteen patients received tezacaftor + ivacaftor, of whom 9 were switched to elexacaftor + tezacaftor + ivacaftor. Four patients received elexacaftor + tezacaftor + ivacaftor up front. A decrease in insulin needs was noticed in 88% of patients (0.85±0.3 vs 0.71±0.3U/kg/day; p = 0001). Total daily insulin dose decreased from 50±16 to 44±20U/day (p = 0.017). BMI improved (20.9 (IQR: 1.90) vs 22.1 kg/m2 (IQR: 3.70); p = 0.014). HbA1c went from 7.3±1.1 to 7.7±1.6% (p = 0.072). Median age was 22y (IQR: 11) in the CF group without diabetes (67% men), 93% of whom were homozygous for F508del mutation. Duration of combined CFTR modulator therapy was 10±5 months. HOMA-B changes were not significant (129.2 (IQR: 84.8) vs 103.5% (IQR: 66.3) nor were HOMA-S changes (from 94±64 to 95±49%). HOMA-BxS decreased from 112±45 to 104±29% (NS). BMI rose from 21.9±3 to 23.1±3.5 kg/m2 (p = 0.047). HbA1c was unchanged (5.0±0.5%). FEV1 improved in both groups (+11% and + 7% of predicted value; p < 0.001; p = 0.013). Conclusion: Combined CFTR modulator therapies are correlated with a decrease in insulin doses and positive effects on BMI and FEV1. HOMA indices did not change on tezacaftor + ivacaftor among CF patients without diabetes.

One-minute sit-to-stand test is practical to assess and follow the muscle weakness in cystic fibrosis.

BACKGROUND: Quadriceps muscle weakness and reduced exercise tolerance are prevalent and associated with a worse prognosis in patients with cystic fibrosis (CF). The one-minute sit-to-stand test (1STST) has been proposed to evaluate functional exercise capacity and quadriceps strength. RESEARCH QUESTION: The aim of the study was to verify the relationship between the 1STST and the maximal isometric voluntary contraction of the quadriceps (MVCQ) evaluated by the dynamometer in stable patients with CF and to evaluate the impact of intravenous (IV) antibiotherapy. METHODS: Dynamometer and 1STST were performed in stable patients with CF at a routine visit, the admission and the discharge of an IV antibiotherapy. Patients wore an activity monitor during 72 h during IV treatment. RESULTS AND SIGNIFICANCE: 51 stable patients with CF at a routine visit and 30 treated with IV antibiotherapy were recruited. In stable patients, the 1STST was reduced to a mean of 2101 nxkg (657-SD), representing a median of 79% (7; 142-min; max)) of the predicted values (%PV) as well as the MVCQ to 78.64 N-m (23.21; 170.34), representing 57%PV (26). The 1STST was correlated to MVCQ (r = 0.536; p < 0.0001) and lung function (r = 0.508; p = 0.0001). Over the IV antibiotherapy course, the 1STST improves significantly like lung function and body mass index while a positive trend for MVCQ was observed. The gain of 1STST was correlated to the change in MVCQ (r = 0.441; p = 0.02) and was significantly higher in hospitalized patients versus home therapy. The 1STST is a good alternative to the dynamometer to evaluate and assess muscular weakness for the routine visit and IV antibiotherapy.

Sweat Proteomics in Cystic Fibrosis: Discovering Companion Biomarkers for Precision Medicine and Therapeutic Development.

In clinical routine, the diagnosis of cystic fibrosis (CF) is still challenging regardless of international consensus on diagnosis guidelines and tests. For decades, the classical Gibson and Cooke test measuring sweat chloride concentration has been a keystone, yet, it may provide normal or equivocal results. As of now, despite the combination of sweat testing, CFTR genotyping, and CFTR functional testing, a small fraction (1-2%) of inconclusive diagnoses are reported and justifies the search for new CF biomarkers. More importantly, in the context of precision medicine, with a view to early diagnosis, better prognosis, appropriate clinical follow-up, and new therapeutic development, discovering companion biomarkers of CF severity and phenotypic rescue are of utmost interest. To date, previous sweat proteomic studies have already documented disease-specific variations of sweat proteins (e.g., in schizophrenia and tuberculosis). In the current study, sweat samples from 28 healthy control subjects and 14 patients with CF were analyzed by nanoUHPLC-Q-Orbitrap-based shotgun proteomics, to look for CF-associated changes in sweat protein composition and abundance. A total of 1057 proteins were identified and quantified at an individual level, by a shotgun label-free approach. Notwithstanding similar proteome composition, enrichment, and functional annotations, control and CF samples featured distinct quantitative proteome profiles significantly correlated with CF, accounting for the respective inter-individual variabilities of control and CF sweat. All in all: (i) 402 sweat proteins were differentially abundant between controls and patients with CF, (ii) 68 proteins varied in abundance between F508del homozygous patients and patients with another genotype, (iii) 71 proteins were differentially abundant according to the pancreatic function, and iv) 54 proteins changed in abundance depending on the lung function. The functional annotation of pathophysiological biomarkers highlighted eccrine gland cell perturbations in: (i) protein biosynthesis and trafficking, (ii) CFTR proteostasis and membrane stability, and (iii) cell-cell adherence, membrane integrity, and cytoskeleton crosstalk. Cytoskeleton-related biomarkers were of utmost interest because of the consistency between variations observed here in CF sweat and variations previously documented in other CF tissues. From a clinical stance, nine candidate biomarkers of CF diagnosis (CUTA, ARG1, EZR, AGA, FLNA, MAN1A1, MIA3, LFNG, SIAE) and seven candidate biomarkers of CF severity (ARG1, GPT, MDH2, EML4 (F508del homozygous), MGAT1 (pancreatic insufficiency), IGJ, TOLLIP (lung function impairment)) were deemed suitable for further verification.

Prevalence and characteristics of cystic fibrosis liver disease: a study highlighting the lack of histological diagnosis.

BACKGROUND AND AIMS: Cystic fibrosis liver disease (CFLD) is the third leading cause of death in patients with cystic fibrosis (CF). We aim to determine the prevalence of CFLD in a cohort of adult patients with CF and to characterise liver involvement in this population highlighting the importance of histological diagnosis. METHODS: We retrospectively studied a cohort of patients with CF. Inclusion criteria were age ≥ 18 and minimum 1 year of follow-up. We excluded lung transplant patients. CFLD was defined as having 2 out of 3 criteria: persistent elevation of transaminases and/or gamma-glutamyltransferase; abnormal ultrasound; and abnormal transient elastography. Non-invasive fibrosis biomarkers were calculated in CFLD patients. Adult-onset CFLD (Ad-CFLD) was defined as CFLD ≥18 years. Severe CFLD (s-CFLD) was defined as CFLD with cirrhosis and/or portal hypertension. RESULTS: We included 113 patients. Median age was 29 years, 58 were male. Forty patients had CFLD. Median age at CFLD diagnosis was 10 years. Twenty-one patients had s-CFLD. Two s-CFLD patients had nodular regenerative hyperplasia, 1 had hepatocellular carcinoma and 4 underwent liver transplantation. Six patients had ad-CFLD. Both CFLD and s-CFLD groups were compared to a non-CFLD group. The CFLD group had significantly more males (p = 0.034). S-CFLD group had worse pulmonary function (p = 0.015). CONCLUSION: Thirty five percent of adult patients with CF, mainly males, had CFLD. Nineteen percent had s-CFLD and had worse pulmonary function. With recent reports unravelling different pathophysiological mechanisms in CFLD, we believe it is important to better characterise liver involvement using liver biopsy.

Secretory Immunoglobulin A Immunity in Chronic Obstructive Respiratory Diseases.

Chronic obstructive pulmonary disease (COPD), asthma and cystic fibrosis (CF) are distinct respiratory diseases that share features such as the obstruction of small airways and disease flare-ups that are called exacerbations and are often caused by infections. Along the airway epithelium, immunoglobulin (Ig) A contributes to first line mucosal protection against inhaled particles and pathogens. Dimeric IgA produced by mucosal plasma cells is transported towards the apical pole of airway epithelial cells by the polymeric Ig receptor (pIgR), where it is released as secretory IgA. Secretory IgA mediates immune exclusion and promotes the clearance of pathogens from the airway surface by inhibiting their adherence to the epithelium. In this review, we summarize the current knowledge regarding alterations of the IgA/pIgR system observed in those major obstructive airway diseases and discuss their implication for disease pathogenesis.

The Role of IgA in Chronic Upper Airway Disease: Friend or Foe?

Chronic upper airway inflammation is amongst the most prevalent chronic disease entities in the Western world with prevalence around 30% (rhinitis) and 11% (rhinosinusitis). Chronic rhinitis and rhinosinusitis may severely impair the quality of life, leading to a significant socio-economic burden. It becomes more and more clear that the respiratory mucosa which forms a physiological as well as chemical barrier for inhaled particles, plays a key role in maintaining homeostasis and driving disease. In a healthy state, the mucosal immune system provides protection against pathogens as well as maintains a tolerance toward non-harmful commensal microbes and benign environmental substances such as allergens. One of the most important players of the mucosal immune system is immunoglobulin (Ig) A, which is well-studied in gut research where it has emerged as a key factor in creating tolerance to potential food allergens and maintaining a healthy microbiome. Although, it is very likely that IgA plays a similar role at the level of the respiratory epithelium, very little research has been performed on the role of this protein in the airways, especially in chronic upper airway diseases. This review summarizes what is known about IgA in upper airway homeostasis, as well as in rhinitis and rhinosinusitis, including current and possible new treatments that may interfere with the IgA system. By doing so, we identify unmet needs in exploring the different roles of IgA in the upper airways required to find new biomarkers or therapeutic options for treating chronic rhinitis and rhinosinusitis.

Needle-free iontophoresis-driven ß-adrenergic sweat rate test.

OBJECTIVES: Two CFTR-dependent ß-adrenergic sweat rate tests applying intradermal drug injections were reported to better define diagnosis and efficacy of CFTR-directed therapies. The aim of this work was to develop and test a needle-free image-based test and to provide an accurate analysis of the responses. METHODS: The modified method was conducted by applying two successive iontophoresis sessions using the Macroduct device. Efficiency of drug delivery was tested by evaporimetry. Cholinergically stimulated sweating was evoked by pilocarpine iontophoresis. ß-adrenergically stimulated sweating was obtained by iontophoresis of isoproterenol and aminophylline in the presence of atropine and ascorbic acid. A nonlinear mixed-effects (NLME) approach was applied to model volumes of sweat and subject-specific effects displaying inter- and intra-subject variability. RESULTS: Iontophoresis provided successful transdermal delivery of all drugs, including almost neutral isoproterenol and aminophylline. Pilocarpine was used at a concentration ∼130-times lower than that used in the classical Gibson and Cooke sweat test. Addition of ascorbic acid lowered the pH of the solution, made it stable, prevented isoproterenol degradation and promoted drug iontophoresis. Maximal secretory capacity and kinetic rate of ß-adrenergic responses were blunted in CF. A cutoff of 5.2 minutes for ET50, the time to reach the half maximal secretion, discriminated CF from controls with a 100% sensitivity and specificity. Heterozygous showed an apparently reduced kinetic rate and a preserved secretory capacity. CONCLUSION: We tested a safe, well-tolerated needle-free image-based sweat test potentially applicable in children. Modelling responses by NLME allowed evaluating metrics of CFTR-dependent effects reflecting secretory capacity and kinetic rate.

Immunoglobulin A Mucosal Immunity and Altered Respiratory Epithelium in Cystic Fibrosis.

The respiratory epithelium represents the first chemical, immune, and physical barrier against inhaled noxious materials, particularly pathogens in cystic fibrosis. Local mucus thickening, altered mucociliary clearance, and reduced pH due to CFTR protein dysfunction favor bacterial overgrowth and excessive inflammation. We aimed in this review to summarize respiratory mucosal alterations within the epithelium and current knowledge on local immunity linked to immunoglobulin A in patients with cystic fibrosis.

How to manage cigarette smoking in kidney transplant candidates and recipients?

Tobacco smoking is a frequent problem affecting many kidney transplant (KT) candidates and recipients. The negative impact of active smoking on KT outcomes has been demonstrated. Consequently, most guidelines strongly recommend quitting smoking before considering kidney transplantation. However, nicotine addiction is a complex multifactorial disease and only 3-5% of the patients who try to quit by themselves achieve prolonged abstinence. Smoking cessation programmes (SCPs) have proven their efficacy in the general population to increase the rate of quitting and should therefore be proposed to all smoking KT candidates and recipients. Nevertheless, SCPs have not been evaluated in the KT field and not all KT centres have easy access to these programmes. In this work, we aim to review the current knowledge on the subject and provide an overview of the available interventions to help smoking patients quit. We detail non-pharmaceutical and pharmaceutical approaches and discuss their use in KT candidates and recipients.

Loss of ciliated cells and altered airway epithelial integrity in cystic fibrosis.

BACKGROUND: In cystic fibrosis, the respiratory epithelium is the target tissue of both the genetic abnormality of the disease and of external aggressions, notably by pathogens (Pseudomonas aeruginosa). A detailed characterisation of the cystic fibrosis bronchial epithelium is however lacking, as most previous studies focused on the nasal epithelium or on cell lines. This study aimed to characterise the abnormal phenotype and epithelial-to-mesenchymal transition in cystic fibrosis bronchial epithelium and to evaluate in cell cultures whether abnormalities persist ex vivo. METHODS: Explant lung tissues (n = 44) were assessed for bronchial epithelial cell phenotyping by immunostaining. Human bronchial epithelial cells were derived from basal cells isolated from cystic fibrosis patients or control donors and cultured in air-liquid interface for 2, 4 or 6 weeks. RESULTS: Enhanced mucin 5AC and decreased ß-tubulin expression were observed in cystic fibrosis airways reflecting a decreased ciliated/goblet cell ratio, associated with increased number of vimentin-positive cells, indicating epithelial-to-mesenchymal transition process. These features were recapitulated in vitro, in cystic fibrosis-derived reconstituted epithelium. However, they were not induced by CFTR inhibition or Pseudomonas infection, and most abnormalities tended to disappear in long-term culture (6 weeks) except for increased fibronectin release, an epithelial-to-mesenchymal transition marker. CONCLUSIONS: This study provides new insights into airway epithelial changes in cystic fibrosis, which are imprinted through an acquired mechanism that we could not relate to CFTR function.