Netherlands

BACKGROUND
Allergic bronchopulmonary aspergillosis (ABPA) is caused by allergic inflammation triggered by inhaled fungal spores. ABPA is characterized by high IgE levels and high eosinophil counts and is usually treated with systemic steroids and azoles. Dupilumab is an agent with IL-4 and IL-13 antagonistic properties, counteracting IgE production and eosinophils. Dupilumab efficacy in asthmatic ABPA has been suggested in small case series and retrospective analysis of the LIBERTY trial, showing improved FEV1, reduced exacerbation frequency and decreases in IgE and FeNO. 

METHODS
Retrospective case series. Patients provided written consent to collect data. Comparisons were made between 6 months prior and 6 months after first dupilumab dose. 

RESULTS
Baseline: Six patients were included. Median age 76 years (61-83 years), five were male. All patients had allergic asthma on ICS and bronchodilators. ABPA diagnosis (ISHAM 2013 criteria) was at least one year old, in two patients &gt;10 years. Five patients were on maintenance prednisone (7.5-10mg/day). Five patients were previously treated with azoles, three patients with omalizumab. Median FEV1 before dupilumab was 76.5% (27-96.3%) and median total IgE was 1921 kU/L (66-4147 kU/L). Treatment: Dupilumab dose was 300mg/14 days. Efficacy: After start of dupilumab, five patients reported a subjective improvement. Four patients had a documented increase in FEV1. Exacerbations for which additional steroids were prescribed decreased with median 2.5 (1-4) exacerbations in six months before vs. median 0 exacerbations (range 0-1) in six months after dupilumab. Three patients had a documented fall in total IgE below 1000 kU/L. After six months, oral prednisone was discontinued in two out of five patients. Prednisone was continued in reduced dose in three out of five patients, of which one had steroid withdrawal syndrome and one had discontinued dupilumab. Safety: One patient discontinued dupilumab due to arthralgia.

CONCLUSIONS
In six patients with ABPA and asthma treated with dupilumab, improvements were observed in symptoms, exacerbations, FEV1, prednisone dose and total IgE. Retrospective data suggest dupilumab is an effective alternative to treat ABPA in selected asthmatic patients.

Dutch Lung Congress

Case series: asthmatic patients with allergic bronchopulmonary aspergillosis (ABPA) treated with dupilumab

dupilumab

allergic bronchopulmonary aspergillosis

abpa

asthma

Welcome to the largest national, multi-specialty research event **featuring research from 750 medical students, residents and fellows, and international medical graduates.**


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Ricardo Correa, MD, EdD
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Stephanie Strohbeen, MD
 
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Jessica Li, MD/PhD Candidate
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Charles Lopresto, DO

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AMA Research Challenge 2022

Welcome to the largest national, multi-specialty research event featuring research from 750 medical students, residents and fellows, and international medical graduates.


BACKGROUND
Allergic bronchopulmonary aspergillosis (ABPA) is caused by allergic inflammation triggered by inhaled fungal spores. ABPA is characterized by high IgE levels and high eosinophil counts and is usually treated with systemic steroids and azoles. Dupilumab is an agent with IL-4 and IL-13 antagonistic properties, counteracting IgE production and eosinophils. Dupilumab efficacy in asthmatic ABPA has been suggested in small case series and retrospective analysis of the LIBERTY trial, showing improved FEV1, reduced exacerbation frequency and decreases in IgE and FeNO. 

METHODS
Retrospective case series. Patients provided written consent to collect data. Comparisons were made between 6 months prior and 6 months after first dupilumab dose. 

RESULTS
Baseline: Six patients were included. Median age 76 years (61-83 years), five were male. All patients had allergic asthma on ICS and bronchodilators. ABPA diagnosis (ISHAM 2013 criteria) was at least one year old, in two patients >10 years. Five patients were on maintenance prednisone (7.5-10mg/day). Five patients were previously treated with azoles, three patients with omalizumab. Median FEV1 before dupilumab was 76.5% (27-96.3%) and median total IgE was 1921 kU/L (66-4147 kU/L). Treatment: Dupilumab dose was 300mg/14 days. Efficacy: After start of dupilumab, five patients reported a subjective improvement. Four patients had a documented increase in FEV1. Exacerbations for which additional steroids were prescribed decreased with median 2.5 (1-4) exacerbations in six months before vs. median 0 exacerbations (range 0-1) in six months after dupilumab. Three patients had a documented fall in total IgE below 1000 kU/L. After six months, oral prednisone was discontinued in two out of five patients. Prednisone was continued in reduced dose in three out of five patients, of which one had steroid withdrawal syndrome and one had discontinued dupilumab. Safety: One patient discontinued dupilumab due to arthralgia.

CONCLUSIONS
In six patients with ABPA and asthma treated with dupilumab, improvements were observed in symptoms, exacerbations, FEV1, prednisone dose and total IgE. Retrospective data suggest dupilumab is an effective alternative to treat ABPA in selected asthmatic patients.

poster

[![](https://assets.underline.io/uploads/markdown_image/1/image/261902fdf187a88bfa74da226ff77186.png)](https://drive.google.com/file/d/1gUViQJJHCSgM38OhwpDoTdN89evCsZ-7/view?usp=sharing)
[![](https://assets.underline.io/uploads/markdown_image/1/image/1605292c232e6f185c7f87ee38e8502a.png)](https://drive.google.com/file/d/1kPkznVX_6cx-n846z_pUtyVDZql9KImc/view?usp=sharing)


### **Welcome Message**

Welcome to the inaugural **Dutch Lung Congress.** We have all missed our opportunities to network and interact with our colleagues in the last twelve months or more. While our desire was to meet face to face once again, when it became evident that this would not be possible until much later in 2021 (or even into 2022) the hard working committee organizing the Dutch Lung Congress found, what we hope will be, an excellent alternative to facilitate our annual meeting.

The Dutch Lung Congress aims to bring together everyone interested in research related to pulmonary diseases in the Netherlands. We hope this event will provide opportunities for multidisciplinary interactions to enhance our approaches for addressing these challenging diseases. Each session will include input from patients, clinical and basic and/or translational scientists discussing the latest information around the central themes chosen by the organizing committee. One advantage of holding our congress as a virtual event this year is that we will have the opportunity to hear from world leading experts from all over the globe. We hope you enjoy the programme the organizing committee have put together and will engage in dynamic discussions with all the speakers.

One highlight of our congress will be the Young Investigator Session. Remember to join us for this exciting session when we will hear from the presenters who submitted the top scoring abstracts. This promises to be a session full of exciting science that will display the strengths that constitute the future talent in our field.

When we are not listening to these great presentations we can all meet in Gathertown. Within this interactive platform you will be able to meet colleagues and friends for networking. Enjoy a private chat over a virtual coffee, visit the booths of our sponsors and other parties, chat with the Young Investigator Board members or take some timeout in the relaxation spaces. While in Gathertown take the opportunity to visit all the diverse posters on display. Chat live with the presenters or leave them a question on the discussion board for them to engage with you. Make sure you check for any messages each time you enter Gathertown to make the most of your networking opportunities.

We look forward to seeing you during the DLC and the great scientific (and other) discussions we are anticipating during our 2021 meeting.

On behalf of the DLC organizing Committee
 **Janette Burgess
 Chair, DLC Organizing Committee**
![](https://assets.underline.io/uploads/markdown_image/1/image/f461fb275d9667fb2a76a30813388e90.png)



### Special Session: Publieksmiddag
![](https://assets.underline.io/uploads/markdown_image/1/image/77e768dd500e6205175e5cafba59abdc.png)






![](https://assets.underline.io/uploads/markdown_image/1/image/f461fb275d9667fb2a76a30813388e90.png)
**More about the committee team:**:
[Barbro N. Melgert, PhD] (https://drive.google.com/file/d/1q_IIH3JvTivumCUzzsZGX7BgD41HxQmk/view?usp=sharing)
// [Bas Holverda, PhD] (https://drive.google.com/file/d/1QKXHmTTQjgs4OZVuM8doXU055S-fu_uU/view?usp=sharing)
// [Frits Franssen, PhD] (https://drive.google.com/file/d/1d7HRUJaqGuRFzkPN3SVgkbBfqFkDkWq2/view?usp=sharing)
// [Janette Burgess, PhD] (https://drive.google.com/file/d/1VHFlrEN6uCQGeeW3Lj4I8aTw7HsB0GFr/view?usp=sharing)
// [Michel van den Heuvel, PhD] (https://drive.google.com/file/d/1JeOEP8MHxiK_4lONr8UM2HaxdxpkAmA2/view?usp=sharing)
// [Patrick Bhairosing] (https://drive.google.com/file/d/1xI8ORq-g1bbVcrlRDviZ9NhAwanc4dFl/view?usp=sharing)
// [Gimano Amatngalim, PhD] (https://drive.google.com/file/d/1fyVDDKARLNjRk_JZk8_GyhGMjmp6DWHp/view?usp=sharing)
// [Peter Kunst, PhD] (https://drive.google.com/file/d/1QhtB4nQezpAjbfUAcBnINc-Bm3Shy2Lf/view?usp=sharing)
// [Dr. Michel van den Heuvel, Prof., MD, PhD] (https://drive.google.com/file/d/1JBdNEBXZCEikEZhJ6MoD5DhQfXMz3bP6/view?usp=sharing)
![](https://assets.underline.io/uploads/markdown_image/1/image/f461fb275d9667fb2a76a30813388e90.png)

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Background: COPD involves emphysema and small airway wall thickening. Chronic inflammation and aberrant repair processes play a role in both, but the exact mechanisms are unknown. Pulmonary fibroblasts are key regulators of repair and are affected by chronic inflammation. So far, a comprehensive analysis comparing COPD and control fibroblasts on protein level is lacking.
Aim: To identify COPD-related protein changes in lung fibroblasts using a shotgun proteomics approach.
Methods: Lung fibroblasts were isolated from 13 stage IV COPD patients and 10 matched controls. Isolated proteins were subjected to shotgun proteomic analysis using LC-MS/MS. Differential protein expression comparing COPD patients and controls was assessed using linear regression modeling correcting for age and sex. Differentially expressed proteins were cross-referenced with literature via high-throughput text-mining with TenWise KMAP-API to determine associations with COPD.
Results: After removal of lowly expressed proteins, we detected the expression of 774 proteins in primary lung fibroblasts of which 40 proteins were significantly differentially expressed between COPD and control fibroblasts, with the most significant being HNRNPA2B1 and FHL1 . 20 of the 40 proteins had significantly higher expression while the other 20 had lower expression in COPD fibroblasts compared to controls. The proteins were enriched for pathways relating to the immune system and protein folding, among others. Of the 40 proteins 13 were previously associated with COPD in literature cross-referencing, including FHL1 and GSTP1.
Conclusions: We identified 40 differentially expressed proteins in COPD stage IV compared to control fibroblasts, who are enriched for immune system pathways that suggest a role in chronic inflammation in COPD. These proteins include previously described COPD related proteins (e.g. FHL1 and GSTP1), validating their altered expression in COPD lung fibroblasts. But they also include new COPD research targets like HNRNPA2B1 ad CAPN2. Thus this study demonstrates the robustness of the proteomic approach and provides several intriguing new research foci for further functional studies in COPD.

Proteomics approach to identify COPD-related changes in pulmonary fibroblasts

Background Pharmacotherapy is key in asthma control, including preventing lung function decline, in primary care. However, patients’ physical functioning (e.g., physical capacity, PC (=can do) and physical activity, PA (=do do)) correlates poorly with lung function. Therefore, a better insight in the physical function of patients with asthma is needed, using the “can do, do do” concept. 
Objective To explore the “can do, do do” concept in adult asthma patients at referral for the first time to an outpatient consultation of a pulmonologist. 
Methods PC was measured using the six-minute walk test (6MWT). PA by using an accelerometer. Patients were classified into quadrants: low PC (6MWD <70% predicted), low PA (<7000 steps/day, "can't do, don't do"); preserved PC, low PA ("can do, don't do”); low PC, preserved PA ("can't do, do do"); or preserved PC, preserved PA ("can do, do do").
Results 479 asthma patients had a median (IQR) 6MWD of 74 (66–82) % predicted, and walked 6829 (4593–9075) steps/day. Only 29% was classified as "can do, do do", while 30% was classified as “can’t do, don’t do”. The Asthma Control Questionnaire and the Asthma Quality of Life Questionnaire were worst in the “can’t do” groups. 
Conclusion Low PC and/or PA was found in a majority of asthma patients at the index referral to a pulmonologist. An impaired PC is accompanied by a significantly reduced asthma control and disease-specific quality of life. This justifies further studies on safety and efficacy of non-pharmacological interventions, such as physiotherapy.

"Can do" versus "do do" in patients with asthma at first referral to a pulmonologist

Introduction: Sarcoidosis is a granulomatous disease that can affect any organ. Diagnosis can be challenging and often requires tissue sampling; a non-invasive diagnostic method is lacking. Electronic nose (eNose) analysis is an emerging method for profiling exhaled volatile organic compounds. We aimed to evaluate whether eNose data could distinguish between sarcoidosis, other interstitial lung diseases (ILDs) and healthy controls, and between different phenotypes or clinical characteristics of sarcoidosis patients.
Methods: In this cross-sectional single centre study, exhaled breath of outpatients with sarcoidosis was analysed using an eNose (SpiroNose). Clinical characteristics were collected from medical files. eNose sensor data were analysed with partial least square discriminant and ROC analysis. Regression analysis was conducted to correlate sIL-2R values with the main principal component.
Results: 569 patients were included (252 with sarcoidosis, 317 with ILD) and 48 healthy controls. The mean age of sarcoidosis patients was 53.1±11.4 years, 53.2% was male, 61% never smoked, and 88.9% had pulmonary involvement. eNose data could distinguish sarcoidosis patients from healthy controls (AUC 1.00; Figure 1) and ILD patients (AUC 0.89). There were no differences in eNose data between sarcoidosis patients with or without fibrosis (AUC 0.60), immunosuppressive treatment (AUC 0.59), or pulmonary involvement (AUC 0.64). eNose data did differentiate the 1st and 4th sIL-2R quartiles (AUC 0.83; Figure 2). A moderate correlation of eNose data with individual sIL-2R values (r=0.32, p<0.05) was found.
Conclusion: Exhaled breath analysis using eNose technology may be a novel diagnostic tool for sarcoidosis. No differences were found between different phenotypes of sarcoidosis.

Use of electronic nose technology in sarcoidosis

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.

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

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

"Objectives: The COVID-19 pandemic has spread across the world, leading to government measures such as national lockdowns and social distancing which are associated with a negative impact on mental health. This study evaluated the impact of COVID-19 on anxiety, depression and resilience in Dutch individuals with CF or PCD and their caregivers during the second wave of the pandemic.
Methods: Adolescents (12-18 years), adults and caregivers of children (0-18 years) with CF or PCD completed questionnaires on anxiety (GAD-7), depression (PHQ-9), and resilience (BRS) from Sept 2020-Febr 2021. The psychosocial impact of COVID-19 was measured by the Exposure and Family Impact Survey (CEFIS) Part 2, which was translated into Dutch using EMA guidelines. Results from the GAD-7 and PHQ-9 were compared to participants’ pre-pandemic scores.
Results: 110 participants (CF: 62, PCD: 48. Patients: 41, caregivers: 69) showed a high prevalence of anxiety and depression (scores ≥ 5 on the GAD-7 and/or PHQ-9) during the pandemic: 31% & 36% respectively for CF, 44% & 33% PCD, 53% & 35% patients, 30% & 35% caregivers, but did not differ from pre-pandemic scores (all p-values > 0.05). Resilience was within the normal range (mean for CF: 3.3; PCD: 3.3; patients: 3.5; caregivers: 3.3). Mean CEFIS scores corresponded to a normal impact (patients: 24.7; caregivers: 21.6), 0 patients and 3 caregivers tested positive for COVID-19. 
Conclusion: The prevalence of elevated symptoms of anxiety and depression during the pandemic was high and there was no detected change in these symptoms compared to pre-pandemic. These results do still emphasize the need for psychological care in individuals with CF or PCD and their caregivers."
![](https://assets.underline.io/uploads/markdown_image/1/image/5e9b7384c43c56bb73e0c9d117000979.png)

Anxiety, depression and resilience during COVID-19 in Dutch individuals with cystic fibrosis (CF) or primary ciliary dyskinesia (PCD) and their caregivers

"Introduction: The covid-19 pandemic has boosted the use of in FEV1 telemonitoring in pediatric asthma, while a consensus on its most efficient and effective implementation is still lacking. To find answers, it is important to study how such an intervention is perceived, experienced and used both by patients and healthcare professionals (HCP).

Objective: To provide perspectives on how FEV1 home monitoring should be used in pediatric asthma.

Methods: This is a qualitative multicenter prospective observational study which included asthma patients aged 6-16 years old and HCP. Primary outcomes were survey results of two surveys which were sent to all participants, one at study start and one after 3 to 4 months. Secondary outcomes consisted of FEV1 usage during four months after receiving the FEV1 device.

Results: 39 participants (26 patients and 13 HCP) were included in this study. Survey response rates were 97% at start and 87% at study end. Both patients and HCP were receptive to online FEV1 home monitoring and found it contributive to asthma control, self-management and disease perception. The main concerns were about reliability of the FEV1 device and validity of home-performed FEV1 maneuvers. 69% of included patients used their device regularly during the study period with a large inter-individual variation.

Conclusion: Patients and HCP are receptive towards online FEV1 home monitoring. Frequency of measurements varied largely among individuals, yet perceived benefits remained similar. This emphasizes that online FEV1 home monitoring strategies should be used as a means to reach individual goals, rather than being a goal on its own."
![](https://assets.underline.io/uploads/markdown_image/1/image/abdf8f2785aec73cb5ea6edda04edf5f.png)

It’s not just the FEV1 that matters, but the personal goals we reach along the way: Viewpoint article

Background: Dysfunctional of alveolar microvascular endothelial cells drives microangiopathies in chronic obstructive pulmonary disease (COPD). Tobacco smoking and air pollution are two major causes of COPD. We hypothesized that cigarette smoke (CS) and diesel exhaust particles (DEP) might impact on pulmonary microvascular endothelial repair in vitro.
Methods: Immortalized human pulmonary microvascular endothelial cells (HPMECs) were starved for 24 h followed by treatments with either vehicle control, CS extract (CSE) (1%, 2.5%, 5%), DEP (50, 100, 200 µg/ml), or IL-1ß (0.1, 1ng/ml) for 24h. Post-analyses comprised PCR analysis and scratch wound healing assays. 
Results: In the wound healing assay, 83% closure was observed within the vehicle group at 12h, which was reduced to 76%, 59% and 57% by 1%, 2.5%, and 5% CSE respectively; 87%, 89% and 82% by 50-, 100-, and 200 µg/ml DEP respectively; and increased to 93% and 97% by IL-1ß (0.1-, 1ng/ml). After 24h treatments, the wound closed 96-100% in vehicle, IL-1ß (0.1-, 1ng/ml) and DEP (50-, 100 µg/ml) groups; however, the wound closed 95%, 85%, 73% and 91% by 1%, 2.5%, 5%CSE and DEP (200 µg/ml) respectively. The wound closed slower when cells were first pretreated for 24 h with DEP. The gene expression levels of the pro-inflammatory IL-6 and CXCL8/IL-8 were increased in HPMECs treated with DEP (100 µg/ml) or IL-1ß (0.1-, 1ng/ml) but not by CSE; the gene expression of the aging associated marker P16 decreased by CSE (2.5%, 5%) or DEP (50-, 200 µg/ml) whereas the expression of P21 increased by IL-1ß (0.1-, 1ng/ml). The expression level of the oxidative stress responsive gene MGST1 increased by CSE, DEP or IL-1ß in a concentration-dependent manner.
Conclusions: Both CSE and DEP exposure impair the wound repair function of pulmonary microvascular endothelial cells and this dysfunction was associated with changes in markers of oxidative stress, and to a lesser extent senescence and inflammation. 


Cigarette smoke and air pollution induce dysfunctional pulmonary microvascular endothelial repair

Rationale: It is difficult to predict clinical outcome to long-acting bronchodilators (LABD) in chronic obstructive pulmonary disease (COPD). Therefore, the multidimensional response to LABD was profiled in COPD patients participating in the ACTIVATE study and randomized to LABD.
Methods: In the ACTIVATE study, patients were randomized to aclicinium bromide/formoterol fumarate (AB/FF) or placebo for four weeks. The primary outcomes included (1) lung function as measured by functional residual capacity (FRC), residual volume (RV), and spirometric outcomes; (2) exercise performance as measured by a constant work rate cycle ergometry test (CWRT); and (3) physical activity (PA) using an activity monitor. Self-organizing maps (SOMs) were used to create an ordered respresentation of the patients who were randomly assigned to four weeks of AB/FF and cluster them into different outcome groups.
Results: 250 patients were randomized to AB/FF (n=126) or placebo (n=124). Patients in the AB/FF group (39.6% women) had moderate-to-severe COPD, static hyperinflation (FRC: 151.4 (27.7)% predicted) and preserved exercise capacity. Six clusters with differential outcomes were identified. Patients in cluster 1 and 2 had significant improvements in lung function compared to the remaining AB/FF-treated patients. Patients in clusters 1 and 3 had significant improvements in CWRT time, and patients in clusters 2, 3 and 6 had significant improvements in PA compared to the remaining AB/FF-treated patients.
Conclusions: Individual responses to 4 weeks of AB/FF-treatment in COPD are differential and the degree of change differs across domains of lung function, exercise capacity and PA. These results indicate that clinical response to LABD therapy is difficult to predict and non-linear, and show doctors that it is important to look at multiple outcomes simultaneously when evaluating the clinical response to LABD therapy.
Clinical Trial Registration: The original ACTIVATE study was registered on ClinicalTrials.gov, registration number NCT02424344.

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