Netherlands

Effect of intravenous alpha-1-antitrypsin augmentation therapy on a proteinase-3-generated AαVal541 in deficient patients

Iris G. M. Schouten, Richard A. Mumford, Abraham C. van der Linden, Dirk Jan A. R. Moes, Pieter S. Hiemstra, Jan Stolk

Background. In alpha-1-antitrypsin deficiency (AATD), neutrophil serine proteases such as proteinase 3 (PR3) and elastase are insufficiently inhibited. A previous study in AATD patients showed a higher plasma level of the specific PR3-generated fibrinogen-derived footprint peptide AαVal541, compared to healthy controls (Newby et al, ERJ Open Res. 2019).
Aim and objectives. To analyse the course of AαVal541 in plasma over 4 weeks after a single iv dose of 240 mg/kg AAT in patients with genotype Z/Rare or Rare/Rare. 
Methods We developed a competitive immunoassay to measure AαVal541 in plasma. We assessed AaVal541 levels in healthy controls (n=20) and in patients before/after AAT augmentation (n=10).
Results. The average AαVal541 plasma level before treatment was 535.4 nM (range 46.9 - 4017.8 nM), and in all patients the level decreased within 1 day after receiving iv AAT. 
In the 5 patients who received AAT for the first time, the AαVal541 decreased to 42.0 nM (range 5.1 - 141.1 nM), 89.7% (SD 6.4%) of the baseline AαVal541 value. In the patients (n=5) who already received multiple infusions before, the AαVal541 decreased to 28.1 nM (range 21.9 - 38.0 nM), 68% (SD 13.8%) of baseline. In 9 of 10 patients, AαVal541 levels were reduced to the average level of healthy controls (27.9 nM ± 17.9 SD). At 7-14 days after treatment, AαVal541 levels started to increase again in all patients, reaching on average a level of 202.0 nM (range 15.3 - 1237.0 nM) at about 4 weeks after the AAT dose.
Conclusion. Fibrinopeptide AαVal541 may serve as a biochemical footprint to assess efficacy of in vivo inhibition of proteinase 3 activity in patients receiving intravenous AAT augmentation therapy. This opens opportunities for personalized tailored dosing.

Dutch Lung Congress

Effect of intravenous alpha-1-antitrypsin augmentation therapy onproteinase-3-generated AαVal541 in deficient patients

alpha-1-antitrypsin augmentation therapy

proteinase 3

alpha-1-antitrypsin deficiency

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Rationale. WNT/β-catenin signaling and particularly the WNT receptor FZD4 are downregulated in chronic obstructive pulmonary disease (COPD). FzM1, a negative allosteric modulator for FZD4, and FzM1.8, an allosteric agonist, can be used to assess the role of FZD4 in activating β-catenin-dependent transcription in COPD, and to investigate FZD4 as a potential therapeutic target in COPD.
Methods. We tested modulation of β-catenin-dependent transcription by FzM1 and FzM1.8 with a luciferase reporter assay (TOP/FOPflash assay) in A549 adenocarcinoma epithelial cells. Mouse organoids were obtained co-culturing EpCAM+ cells isolated from mice lungs and CCL206 mouse fibroblasts in Matrigel in a Transwell system. Organoids were treated with FzM1 and FzM1.8 every other day until day 14, when number and phenotype (alveolar, airway, bronchioalveolar) were assessed. Precision-cut lung slices (PCLS) were obtained from mice lungs filled with warm agarose and cut with a vibratome into slices that were treated with the ligands for 48 hours and 5 days. Gene expression of β-catenin target genes, proliferation and alveolar markers was assessed through qRT-PCR.
Results. TOP/FOPflash assay confirmed dose-dependent β-catenin inhibition by FzM1 and activation by FzM1.8. FzM1 caused a drastic and significant reduction in organoids number at day 14, while FzM1.8 did not have a significant effect on organoids number or phenotype. In PCLS we observed an increased expression of pro-SPC (alveolar type II) and T1α (alveolar type I) genes after treatment with FzM1.8 for 5 days, suggesting an effect on cell fate in the alveolar compartment.
Discussion. We confirmed that these compounds modulate FZD4 and β-catenin activity in in vitro and ex-vivo lung models. We show that blocking FZD4-dependent β-catenin activation impairs organoids formation, therefore FZD4 signaling may be vital to proliferation and differentiation of alveolar progenitor cells. Targeting FZD4 could be an important strategy to rescue tissue repair in COPD. Further experiments are needed to clarify the role of FZD4 activation with FzM1.8.

Two novel allosteric ligands of FZD4 regulate the WNT/β-catenin pathway in COPD

The main site of replication of the causative agent of the Coronavirus Disease 2019 (COVID 19), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the human airway epithelium. In this study, we used well-differentiated primary human bronchial and tracheal epithelial cells (PBEC/PTEC) cultured at air-liquid interface (ALI) to study SARS-CoV-2 infection biology and pathogenesis. We validated our infection model by measuring SARS-CoV-2 replication kinetics and related antiviral and inflammatory responses. Similar replication kinetics were found in cultures from individual donors and mixed donors, which also displayed upregulation of antiviral and inflammatory cytokines. To investigate the impact of cellular composition/maturation on SARS-CoV-2 infection, we either varied the culture time or treated cultures with IL-13 or DAPT (Notch signaling inhibitor) to modulate differentiation. We found that viral replication and the percentage of infected cells increased with cell culture duration, which was in line with changes of total number of ciliated and goblet cells with prolonged cell culture time. The predominant target cells were ciliated and goblet cells in both ALI-PTEC and ALI-PBEC. However, no relation with epithelial expression of SARS-CoV-2 cell entry genes was found. Furthermore, increased numbers of ciliated cells following DAPT treatment, and goblet cells after IL-13 treatment could not fully explain the differences in infection observed. In conclusion, our results identify epithelial maturation/differentiation level as a contributing factor to airway epithelial susceptibility to SARS-CoV-2.

This study was supported in part by a COVID-19 MKMD grant from ZonMw and Proefdiervrij (grant #114025007)


Effects of cellular composition/maturation on SARS-CoV-2 infection in cultured primary human airway epithelial cells

Respiratory syncytial virus (RSV) during infancy is associated with subsequent childhood asthma symptoms. In addition, RSV infections can cause asthma exacerbations by infecting the epithelial layer of the airways, which induces an innate and adaptive immune response. The type-I interferon antiviral response by the epithelial cells induced by RSV infection has been shown to be reduced in asthma in most - but not all - studies. However, the molecular mechanisms that cause this difference between the healthy and asthmatic bronchial epithelium in response to viral infection are not completely understood. In this study, we investigated the transcriptional response of primary bronchial epithelial cells (PBECs) from asthma patients and healthy donors to RSV infection. The PBECs obtained from bronchial brushes were cultured at air-liquid interface conditions for 3 weeks followed by infection with RSV, UV-inactivated RSV or control suspension. Three days after infection, cells were processed for bulk or single-cell RNA sequencing. Transepithelial electrical resistance measurements showed that the barrier function of PBECs from healthy donors is superior to that of PBECs from asthma patients. In the bulk transcriptomic data, a pro-inflammatory response to RSV was observed in both conditions, but was stronger for the healthy PBECs. Cell type deconvolution on the bulk RNA-sequencing data revealed an increase in proportion of ciliated cells (p=0,023) and a decrease in basal cells (p=0,047) after RSV infection in asthma, but not in healthy PBECs. To further analyze the response to RSV infection in a cell-type specific fashion, we performed single-cell RNA sequencing, which revealed the presence of a strong NF-kB response from the basal and secretory cells, which was reduced in PBECs from asthma patients. Our results highlight that the response to RSV infection is altered in the bronchial epithelial cells in asthma, with a reduced inflammatory response and a shift in cell-type composition after viral infection.

PBECs from asthma patients display a shift in cell-type composition and a reduced inflammatory response to RSV infection

Background: Recently, an mHealth intervention has been developed to support patients with COPD in exacerbation-related self-management: the Copilot app. Health care providers (HCPs) are important stakeholders as they are the ones who have to provide the app to patients, personalize the app, and review the app. The aim of this study is to evaluate the perceived feasibility of the Copilot app in the daily practice of HCPs.
Methods: A multimethods design was used to investigate how HCPs experience working with the app and perceive the feasibility of the app in their daily practice. HCPs were observed while performing tasks in the app and asked to think aloud. The System Usability Scale was used to investigate the usability of the app, and semistructured interviews were conducted to explore the feasibility of the app. The study was conducted in primary, secondary, and tertiary care settings in the Netherlands from February 2019 to September 2019.
Results: In total, 14 HCPs participated in this study—8 nurses, 5 physicians, and 1 physician assistant. The HCPs found the app acceptable to use. The expected key benefits of the app were an increased insight into patient symptoms, more structured patient conversations, and more tailored self-management support. The app especially fits within the available time and workflow of nurses. The use of the app will be influenced by the autonomy of the professional, the focus of the organization on eHealth, costs associated with the app, and compatibility with the current systems used. Most HCPs expressed that there are conditions that must be met to be able to use the app. The app can be integrated into primary, secondary, and tertiary health care settings. 
Conclusions: This early-stage feasibility study shows that the Copilot app is feasible to use in the daily practice of HCPs. The app was considered to best fit the role of the nurses. The app will be less feasible for those organizations in which many conditions need to be met to use the app. This study provides a new approach to evaluate the perceived feasibility of mHealth interventions at an early stage.


Early-Stage Feasibility of a Mobile Health Intervention (Copilot) to Enhance Exacerbation-Related Self-Management in Patients With Chronic Obstructive Pulmonary Disease: Multimethods Approach

Sarcoidosis is a systemic granulomatous disease, mostly affecting lungs and lymph nodes. While in some patients disease activity resolves spontaneously, others have a more progressive disease course and require immunosuppressive therapy. Unfortunately, efficacy of therapy varies greatly between patients due to partial understanding of pathobiology and lack of specific biomarkers. Various markers like ACE, sIL-2R, T-cell subsets and monocytes have been evaluated in sarcoidosis over the past decades. However, a prospective study addressing the predictive value with regard to treatment response is lacking.
The PREDMETH study offers a unique opportunity to study existing and new biological markers, gain insights in disease pathogenesis and provide translational results for tailored treatment in sarcoidosis. 

The PREDMETH study is a national study, initiated by the Erasmus MC and St. Antonius Hospital and designed in collaboration with the sarcoidosis patient association. In this study efficacy and side-effects of methotrexate as first-line treatment option is compared with prednisone. Data and blood samples are collected at baseline, 4, 16, 24 weeks, and 1 and 2 years. 
To discover and validate markers that predict response to therapy absolute values at baseline of markers ACE and sIL-2R, monocyte and T-cell subsets and protein content of extracellular vesicles will be compared between responders and non-responders. To improve understanding of pathogenesis of sarcoidosis and response to therapy, changes in markers before and on treatment will be studied over time. Finally, all data will be combined to build a model for tailored treatment advice and pathophysiological response in sarcoidosis. 

This unique study combines clinical and fundamental research. We expect to provide new fundamental insights in markers for therapeutic response and cellular processes in the pathogenesis of sarcoidosis. Most importantly, this study holds promise to produce validated biomarkers that predict response to treatment and pave the way to tailored treatment in sarcoidosis.




Study design of the PREDMETH study: evaluation of immunological biomarkers that predict treatment response in pulmonary sarcoidosis

Rationale
IL-33 and its receptor IL-1RL1 are important asthma genes. T helper-2 (TH2) cells present in asthmatic airway wall contribute to chronic inflammation and epithelial remodeling. TH2 cells express IL-1RL1 and respond to IL-33 by increased cytokine production upon stimulation. We aimed to test the extent of the IL-33-driven modification of Th2 cell activation, and whether the asthma-susceptibility alleles of IL1RL affect this response. 
Methods
CD4+ T cells isolated from PBMCs of 16 healthy donors and 16 asthma patients, stratified for IL-1RL1 high and low risk-genotypes, were differentiated into TH2 cells in vitro, and re-stimulated by CD3/CD28-crosslinking in presence or absence of 100 ng/mL rhIL-33. Gene expression was assessed by RNA-sequencing, and subsequently analyzed using limma in R comparing high and low risk genotype and asthma versus controls. Membrane bound IL1-RL1-b protein levels were determined using FACS.
Results
Presence of IL-33 during CD3/CD28 stimulation of TH2 effector cells in vitro results in extensive changes in gene expression, affecting up to 40% of the transcriptomic changes induced by TH2 cell activation. The fold change in gene expression induced by IL-33 was significantly higher in TH2 cells carrying the IL-1RL1 risk haplotype compared to the IL-1RL protective haplotype. However, the identity of the IL-33 regulated genes was not different between the IL-1RL1 haplotype groups. In addition, significant differences in IL-33 regulated genes were observed between Th2 cells derived from healthy controls and asthma patients. At the protein level, the change in TH2 cells expressing the transmembrane IL-1RL1 receptor was higher in asthma patients than in controls . 
Conclusions
The asthma-associated IL-1RL1 haplotype strongly increases the sensitivity of TH2 effector cell for IL-33-mediated regulation of gene expression, while disease status also has an independent effect. IL-33 in the airway wall will contribute to chronic inflammation maintained by TH2 effector cells mainly in patients with asthma carrying the IL-1RL1 asthma risk alleles. 


Enhanced IL-33 response in differentiated human TH2 cells carrying the IL-1RL1 asthma risk genotype

Introduction
Cystic Fibrosis (CF) is a severe inherited disorder caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) chloride channel, resulting in a severe muco-obstructive lung disease. It is proposed that potentiation of airway epithelial fluid secretion by the alternative chloride channel TMEM16A may act as therapy for all individuals with CF, independent of their mutation type. Therefore, we aimed to design a TMEM16A-dependent fluid secretion assay using nasal organoids from individuals with CF.

Methods
Nasal organoids from individuals with CF were derived from nasal brushing. Organoid culture conditions were optimized for TMEM16A-dependent fluid secretion with the cytokine IL-4. This was validated by qPCR, western blot, an organoid swelling assay using chemical inhibitors, and with CRISPR gene knock-out organoids. 

Results
IL-4 enhanced TMEM16A mRNA and protein expression in CF nasal organoids. Furthermore, IL-4 treatment increased nasal organoid swelling, induced by the TMEM16A activator ATP. This was inhibited by the chemical TMEM16A inhibitors ani9 and niclosamide. 

Conclusion
A TMEM16A-dependent functional fluid secretion assay was developed which can be used to identify TMEM16A potentiating compounds in future. These compounds may act as lead for novel therapies that promote epithelial fluid secretion in individuals with CF, independent of their mutation type.

A personalized nasal organoid fluid-secretion assay to identify TMEM16A potentiators as treatment for cystic fibrosis

Rationale: COPD is characterized by a progressive and irreversible loss of lung function, to which emphysema is a contributor. Emphysema is characterized by destruction of alveolar walls, that are composed of the alveolar epithelium, the endothelium and mesenchymal cells. It is increasingly realized that microvascular endothelial cell (dys)function contributes toemphysema development. Therefore, the aim is to study the role of that pulmonary microvascular endothelial cells in alveolar repair and regeneration. 
Methods: EpCAM+ (i.e. epithelial) cells isolated from mouse lungs (BALB/c) were seeded in matrigel and deposited on a monolayer of the pulmonary microvascular endothelial cell line (HPMEC.ST1.R), resulting in both airway and alveolar epithelial organoids. Human resected lung tissue was used to isolate HTII-280+ alveolar cells and CD31+ endothelial cells. Endothelial cells (P2) were allowed to form a monolayer in the bottom of a culture plate and freshly isolated HTII-280+ alveolar cells were seeded in basement membrane matrix (BME2) inside the insert. 
Results and Conclusion: The presence of HPMEC.ST1.R cells increased alveolar organoid number but not airway organoids isolated from murine lungs. Similarly, human primary lung endothelial cells cultured and expanded in vitro (P2), induced an increase (1.7X) in human alveolar organoid number, at day 10 after isolation from human lung tissue. Collectively these results show that pulmonary endothelial cells support alveolar progenitor cell function as shown by an increased number of alveolar organoids. We hypothesize that this function is disturbed in emphysema, and therefore we are currently analyzing the impact of COPD-relevant triggers such as cigarette smoke and inflammatory mediators on endothelial cell-driven alveolar repair using this co-culture model. Furthermore, we are expanding our model to include human induced pluripotent stem cell (hiPSC)-derived lung cells.


The role of pulmonary endothelial cells in alveolar repair and regeneration

Rationale: Chronic obstructive pulmonary disease (COPD) is characterized by several phenotypes, including emphysema resulting from the destruction of alveolar tissue in the lung parenchyma. Emphysema is likely partly due to a reduced repair capacity of the alveolar epithelial type II cell (AECII). Previously we showed in mouse lung organoids that amphiregulin (AREG), which is ligands of the epidermal growth factor receptor (EGFR) that is present on AECII, regulates epithelial cell differentiation and proliferation(1). In this study, we evaluated the hypothesis that impaired alveolar regeneration in patients with COPD could be explained by aberrant AREG-EGFR signaling in COPD-derived AECIIs in an organoid model.

Method: We examined lung tissue from Stage IV COPD patients (n=12) and non-COPD subjects (n=9) for expression of AREG, EGF, EGFR and SPC by immunohistochemical staining. Next, we investigated whether the function of COPD AECII was impaired using a human organoid model. AECII isolated from lungs with COPD (n=2) and non-COPD subjects (n=2) were cultured as organoids and cultured with or without AREG.

Result: COPD patients had a lower number of SPC positive cells per surface of lung parenchyma and EGFR-expressing AECII per total cell number of lung parenchyma when compared to non COPD controls. No differences were found in the number of AREG-expressing cells per lung parenchyma. AECII-derived organoids from COPD patients were significantly smaller in size than organoids from controls. In non COPD controls, AREG treatment appeared to result in smaller organoids compared to untreated organoids. SPC immunofluorescent staining revealed that the AECII proportion within the total cell number was not different between COPD or AREG-treated groups. 

Conclusions: The lower number of EGFR-expressing AECII in COPD could explain a possible impaired ability to form organoids, which might imply an impaired repair capacity. More insight regarding the growth and formation of AECII-derived organoids in COPD is necessary to establish the link between EGFR signaling and AECII proliferation.


Alveolar epithelial type II cell behavior in COPD.

Introduction Pharmacological treatment is the cornerstone of asthma management. Asthma patients may also exhibit treatable traits (TTs) like persistent smoking, hyperventilation (PaCO2<4.7 kPa), frequent exacerbations, overweight (BMI ≥25 kg/m2), exercise intolerance (6MWD ≤70%pred), physical inactivity (≤7000 steps/day), fatigue (CIS ≥36 points), depressive symptoms (measured using the Beck Depression Inventory (BDI ≥4 points), dyspnea (Modified Medical Research Council ≥2), qualifying for non-pharmacological interventions. The aim of this study was to investigate the prevalence of these nine non-pharmacological TTs in asthma patients at the time of first referral to a pulmonologist for an outpatient consultation.

Methods Data from asthma patients were collected in two Dutch hospitals (Amphia Breda, RadboudUMC Nijmegen). Data from a third hospital (Franciscus & Vlietland Rotterdam) were used for validation. All adult asthma patients who were referred for an integral diagnostic pathway without exacerbation <6 weeks were deemed eligible. 

Results 346 adults were studied (59% women, age 48 ±16 yrs, FEV1: 88 ±17%pred). Most patients (n=190, 58%) displayed uncontrolled asthma (ACQ >1.5 points). Median number of TTs was 2 (range 0-8). A majority of 174 (53%) patients had ≥3 TTs. Patients with uncontrolled asthma had significantly more TTs compared to patients with controlled and partially controlled asthma (3.4±1.8 vs 1.7±1.3 and respectively 2.2±1.4; P<0.001). 

Conclusion Treatable traits for non-pharmacological interventions frequently occur in asthma patients referred for the first time to a pulmonologist. Asthma control is associated with the number of non-pharmacological treatable traits.

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Two novel allosteric ligands of FZD4 regulate the WNT/β-catenin pathway in COPD

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