Irene H Heijink

• University of Groningen

Idiopathic pulmonary fibrosis (IPF) is one of the most aggressive forms of idiopathic interstitial pneumonias, characterized by chronic and progressive fibrosis subverting the lung’s architecture, pulmonary functional decline, progressive respiratory failure, and high mortality (median survival 3 years after diagnosis). Among the mechanisms associa...

Hyperinflation contributes to dyspnea intensity in COPD. Little is known about the molecular mechanisms underlying hyperinflation and how inhaled corticosteroids (ICS) affect this important aspect of COPD pathophysiology. To investigate the effect of ICS/long-acting β2-agonist (LABA) treatment on both lung function measures of hyperinflation, and t...

Background and objective: Cigarette smoking is one of the most prevalent causes of preventable deaths worldwide, leading to chronic diseases, including chronic obstructive pulmonary disease (COPD). Cigarette smoke is known to induce significant transcriptional modifications throughout the respiratory tract. However, it is largely unknown how genet...

Periostin may serve as a biomarker for type-2-mediated eosinophilic airway inflammation in asthma. We hypothesised that type-2 cytokine IL-13 induces airway epithelial expression of periostin, which in turn contributes to epithelial changes observed in asthma. We studied the effect of IL-13 on periostin expression in BEAS-2B and air-liquid interfac...

Exposure to respiratory pathogens is a leading cause of exacerbations of airway diseases such as asthma and chronic obstructive pulmonary disease (COPD). Pellino-1 is an E3 ubiquitin ligase known to regulate virally-induced inflammation. We wished to determine the role of Pellino-1 in the host response to respiratory viruses in health and disease....

Airway epithelial barrier dysfunction is frequently observed in asthma and may have important implications. The physical barrier function of the airway epithelium is tightly interwoven with its immunomodulatory actions, while abnormal epithelial repair responses may contribute to remodelling of the airway wall. We propose that abnormalities in the...

COPD is associated with features of accelerated aging, including cellular senescence, DNA damage, oxidative stress, and extracellular matrix (ECM) changes. We propose that these features are particularly apparent in patients with severe, early-onset (SEO-)COPD. Whether fibroblasts from COPD patients display features of accelerated aging and whether...

In asthma, the airway epithelium has an impaired capacity to differentiate and plays a key role in the development of airway inflammation and remodeling through mediator release. The study objective was to investigate the release of (IL)-1 family members from primary airway epithelial-cells during differentiation, and how they affect primary airway...

Asthma and Chronic Obstructive Pulmonary Disease (COPD) are chronic obstructive respiratory diseases characterized by airway obstruction, inflammation, and remodeling. Recent findings indicate the importance of microRNAs (miRNAs) in the regulation of pathological processes involved in both diseases. MiRNAs have been implicated in a wide array of bi...

In this review, the Basic and Translational Sciences Assembly of the European Respiratory Society (ERS) provides an overview of the 2019 ERS International Congress highlights. In particular, we discuss how the novel and very promising technology of single cell sequencing has led to the development of a comprehensive map of the human lung, the lung...

Epithelial-to-mesenchymal transition (EMT) plays a role in chronic obstructive pulmonary diseases (COPD). Cyclic adenosine monophosphate (cAMP) can inhibit transforming growth factor-β1 (TGF-β1) mediated EMT. Although compartmentalization via A-kinase anchoring proteins (AKAPs) is central to cAMP signaling, functional studies regarding their therap...

In this era of striving for personalized medicine approaches for complex diseases, preclinical studies have excited the field through their demonstration of the promise of stem cell therapy for the treatment of various lung diseases; with the most beneficial effects of stem cell-based strategies in preclinical settings originating from their antimi...

Asthma and chronic obstructive pulmonary disease (COPD) cause significant morbidity and mortality worldwide. In the context of disease pathogenesis, both asthma and COPD involve chronic inflammation of the lung and are characterised by the abnormal release of inflammatory cytokines, dysregulated immune cell activity and remodeling of the airways. T...

About 40% of asthmatics experience remission of asthma symptoms. A better understanding of biological pathways leading to asthma remission may provide insight into new therapeutic targets for asthma. As an important mechanism of gene regulation, investigation of DNA methylation provides a promising approach. Our objective was to identify difference...

Disturbances in mitochondrial structure and function in lung epithelial cells have been implicated in the pathogenesis of various lung diseases, including chronic obstructive pulmonary disease (COPD). Such disturbances not only affect cellular energy metabolism, but also alter a range of indispensable cellular homeostatic functions in which mitocho...

Nasal gene expression profiling is a new approach to investigate the airway epithelium as a biomarker to study the activity and treatment responses of obstructive pulmonary diseases. We investigated to what extent gene expression profiling of nasal brushings is similar to that of bronchial brushings. We performed genome wide gene expression profili...

Lungs are vital organs for respiration, being enabled by their complex three-dimensional organization [1]. Airway tubes bifurcate into millions of highly vascularized alveolar sacs, the alveoli, which are responsible for gas exchange. The gas exchange surface of the lungs makes up one of the largest surface areas of the human body. The alveoli rece...

Epithelial-to-mesenchymal transition (EMT) plays a role in chronic obstructive pulmonary diseases (COPD). Cyclic adenosine monophosphate (cAMP) can inhibit transforming growth factor-β1 (TGF-β1) mediated EMT. Although compartmentalization via A-kinase anchoring proteins (AKAPs) is central to cAMP signaling, functional studies on their therapeutic v...

Exacerbations of COPD can be triggered by viral infections. Macrophages are involved in airway inflammation in COPD and in limiting inflammatory events in the lung. These opposing tasks are handled by differentially polarized macrophages. MHCII-high expressing macrophages are pro-inflammatory and critical in efficient immune responses against intra...

RATIONALE: Histological stains have been used as the gold standard to visualize extracellular matrix (ECM) changes associated with airway remodeling in asthma, yet they provide no information on the biochemical and structural characteristics of the ECM, which are vital to understanding alterations in tissue function. OBJECTIVE: Demonstrate the use...

The European Respiratory Society (ERS) International Congress is the largest respiratory congress and brings together leading experts in all fields of respiratory medicine and research. ERS Assembly 3 shapes the basic and translational science aspects of this congress, aiming to combine cutting-edge novel developments in basic research with novel c...

The aim was to investigate whether microRNA (miRNA) expression is modulated by inhaled corticosteroid (ICS) treatment We performed genome-wide miRNA analysis on bronchial biopsies of 69 moderate/severe chronic obstructive pulmonary disease (COPD) patients at baseline and after 6- and 30-month treatment with the ICS fluticasone propionate or placebo...

When taken together fibrotic lung diseases are the leading cause of mortality worldwide, but our understanding of the underlying mechanisms driving these processes is limited. The lung consists of defined parts including the airways and parenchyma. The principal building blocks of these parts are the extracellular matrix (ECM). The ECM supports cel...

This book presents state-of-the-art pre-clinical models and clinical applications of stem-cell-based therapies applied to different lung diseases, with a special focus on the translation of bench data into clinical studies. Starting with the assumption that abnormal lung tissue repair and regeneration has emerged as the driving force underlying pat...

The airway epithelium regulates responses to aeroallergens, acting as a physical and immunological barrier. In asthma, epithelial barrier function and the expression of adherens junction protein E-cadherin is compromised, but it is unknown whether this is cause or consequence of the disease. We hypothesized that airway epithelial loss of E-cadherin...

Background: Despite compelling data describing pro-regenerative effects of all-trans retinoic acid (ATRA) in pre-clinical models of chronic obstructive pulmonary disease (COPD), clinical trials using retinoids for emphysema patients have failed. Crucial information about the specific role of RA signaling in adult rodent and human lung epithelial p...

Extracellular Hsp70 (eHsp70) can activate immune cells via Toll-like receptors (TLR) 2 and 4, and induce cytokine synthesis. The aim of this study was to explore inflammation-associated effects of eHsp70 alone and in combination with cigarette smoke extract (CSE) in primary bronchial epithelial cells. We assessed IL-6 and IL-8 concentrations, TLR2,...

Cigarette smoking is a major risk factor for the inflammatory disease, chronic obstructive pulmonary disease (COPD). The mechanism by which cigarette smoke (CS) induces chronic lung inflammation is still largely unknown. We hypothesize that immunogenic airway epithelial cell death is involved in the initiation of the inflammatory response. We previ...

Chronic mucus hypersecretion (CMH) is a common feature in chronic obstructive pulmonary disease (COPD) and is associated with worse prognosis and quality of life. This study aimed to identify microRNA (miRNA)–mRNA regulatory networks underlying CMH. The expression profiles of miRNA and mRNA in bronchial biopsies from 63 COPD patients were associate...

Chronic mucus hypersecretion (CMH) contributes to the morbidity and mortality of asthma, and remains uncontrolled by current therapies in the subset of patients with severe, steroid-resistant disease. Altered cross-talk between airway epithelium and airway smooth muscle cells (ASMCs), driven by pro-inflammatory cytokines such as interleukin (IL)-1β...

Background: Understanding effects of Acute Smoke Exposure (ASE) on airway epithelial gene expression and their relationship with the effects of Chronic Smoke Exposure (CSE) may provide biological insights into the development of smoking-related respiratory diseases. Methods: Bronchial airway epithelial cell brushings were collected from 63 indiv...

Mesenchymal stem or stromal cells (MSCs) are multipotent cells that play a pivotal role in various phases of lung development and lung homeostasis, and potentially also lung regeneration. MSCs do not only self-renew and differentiate into renew tissues, but also have anti-inflammatory and paracrine properties to reduce damage and to support tissue...

Background: COPD patients have increased risk of pneumonia when treated with fluticasone propionate (FP), whereas this is generally not the case with budesonide (BUD) treatment. We hypothesized that BUD and FP differentially affect the expression of immune defense genes. Methods: Human bronchial epithelial 16HBE cells and air-liquid interface (A...

Inflammation and ageing are intertwined in chronic obstructive pulmonary disease (COPD). The histone deacetylase SIRT1 and the related activation of FoxO3 protect from ageing and regulate inflammation. The role of SIRT1/FoxO3 in COPD is largely unknown. This study evaluated whether cigarette smoke, by modulating the SIRT1/FoxO3 axis, affects airway...

The epithelial lining of the airway forms the first barrier against environmental insults such as inhaled cigarette smoke, which is the primary risk factor for the development of chronic obstructive pulmonary disease (COPD). The barrier is formed by airway epithelial junctions, which are interconnected structures that restrict permeability to inhal...

Background Nasal gene expression profiling is a promising method to characterize COPD non-invasively. We aimed to identify a nasal gene expression profile to distinguish COPD patients from healthy controls. We investigated whether this COPD-associated gene expression profile in nasal epithelium is comparable with the profile observed in bronchial e...

Several clinically used drugs are mitotoxic causing mitochondrial DNA (mtDNA) variations, and thereby influence cancer treatment response. We hypothesized that radiation responsiveness will be enhanced in cellular models with decreased mtDNA content, attributed to altered reactive oxygen species (ROS) production and antioxidant capacity. For this p...

Expression of antioxidant genes. Data represents the mean ± SEM from at least 2 independent biological repeats, normalized to each parental line at baseline **p<0.01. (TIF)

Representative images of the glycolysis stress test for BEAS-2B, A549 and 143B. Basal measurements are followed by subsequent injections of 10 mM glucose, 1.0 μM oligomycin and 0.1 M 2-deoxyglucose. (TIF)

Quantification of representative images for γH2AX foci. γH2AX foci amount (mean ± SEM) is shown at baseline and 24 hours after irradiation, relative to each cell line at baseline conditions. (TIF)

Quantitative PCR primer sequences. (TIF)

Chronic obstructive pulmonary disease (COPD) is characterized by unresolved neutrophilic airway inflammation, and is caused by chronic exposure to toxic gases, such as cigarette smoke (CS), in genetically susceptible individuals. Recent data indicate a role for Damage Associated Molecular Patterns (DAMPs) in COPD. Here, we investigated the genetics...

Corresponding author's email: c.j.vermeulen@umcg.nl RATIONALE Despite the beneficial effects of inhaled corticosteroids in the treatment of asthma symptoms, a cure for the disease has not been found yet. An interesting observation is that a subset of asthmatics goes into spontaneous remission. A better understanding of the biological mechanisms lea...

We previously reported that epithelial-derived interleukin (IL)-1α drives fibroblast-derived inflammation in the lung epithelial–mesenchymal trophic unit. Since miR-146a-5p has been shown to negatively regulate IL-1 signalling, we investigated the role of miR-146a-5p in the regulation of IL-1α-driven inflammation in chronic obstructive pulmonary di...

Background Goblet cell metaplasia, a common feature of chronic obstructive pulmonary disease (COPD), is associated with mucus hypersecretion which contributes to the morbidity and mortality among patients. Transcription factors SAM-pointed domain-containing Ets-like factor (SPDEF) and forkhead box protein A2 (FOXA2) regulate goblet cell differentia...

Airway mucus hypersecretion contributes to the morbidity and mortality in patients with chronic inflammatory lung diseases. Reducing mucus production is crucial for improving patients' quality of life. The transcription factor SAM-pointed domain-containing Ets-like factor (SPDEF) plays a critical role in the regulation of mucus production, and ther...

In allergen-sensitised asthmatic individuals, allergen-specific type-2 T-helper cells proliferate and secrete type-2 cytokines ( e.g. interleukin (IL)-4, -5 and -13), driving the airway inflammatory response that gives rise to the clinical symptoms of asthma. Both early-life sensitisation to aeroallergens and lower respiratory viral infections are...

Background The asthma gene PCDH1 encodes Protocadherin-1, a putative adhesion molecule of unknown function expressed in the airway epithelium. Here, we characterize the localization, differential expression, homotypic adhesion specificity and function of PCDH1 in airway epithelial cells in asthma. Methods We performed confocal fluorescence microsc...

PCDH1 localized within the lateral border and basal to Adherens and Tight Junctions in differentiated primary bronchial epithelial cells. E-cadherin, Occludin and β-Tubulin = yellow; PCDH1 = magenta and DAPI staining of the nucleus = light-blue. Scale bars, 5 μm. (TIF)

PCDH1 localization at cell-cell contacts with strongest signal towards the apicolateral borders of the pseudo-stratified epithelial ALI culture. Representative PBECs cultured at ALI culture until mucociliary differentiation were fixed at day 28, stained with monoclonal antibody PCDH1-EC1 and labeled with Alexa Fluor® 488 conjugated secondary antibo...

Cigarette smoke (CS) exposure is a major risk factor for COPD. We investigated whether CS-induced DAMP release or DAMP-mediated inflammation contributes to susceptibility for COPD. Samples, including bronchial brushings were collected from young and old individuals, susceptible and non-susceptible for the development of COPD, before and after smoki...

Previously, we observed increased serum levels of damage-associated molecular patterns (DAMPs) during COPD exacerbations. Here, gene expression of DAMP receptors was measured in peripheral blood neutrophils of COPD patients during stable disease and severe acute exacerbation. The expression of toll-like receptor (TLR)2, TLR4 and NLR family, pyrin d...

Introduction Epithelial-fibroblast communication is a key aspect of inflammation and remodelling in COPD. We previously showed that epithelial cells drive fibroblast-induced inflammation when co-cultured. The WNT signalling pathway ligands WNT-4 and -7B are predominantly expressed in epithelial cells, while WNT-5A and -5B are mostly expressed in fi...

Background: Hyperinflation contributes to dyspnea intensity in COPD. Little is known about the underlying molecular mechanisms of hyperinflation, an important aspect of COPD pathophysiology, and how inhaled corticosteroids (ICS) affect it. Objectives: To investigate the effects of extra-fine and standard sized ICS/long-acting β2-agonist (LABA) trea...

RATIONALE - The GLUCOLD study has identified a subset of COPD patients who respond favourably to inhaled corticosteroid (ICS) treatment and were distinguishable by their gene-expression profiles. The availability of longitudinal gene expression data and genetic information in GLUCOLD, pre- and post-treatment, allows our group to not only look at st...