The nasal basal cell population shifts toward a diseased phenotype with impaired barrier formation capacity in allergic rhinitis.

BACKGROUND: The integrity of the airway epithelium is guarded by the airway basal cells that serve as progenitor cells and restore wounds in case of injury. Basal cells are a heterogenous population, and specific changes in their behavior are associated with chronic barrier disruption-mechanisms that have not been studied in detail in allergic rhinitis (AR). OBJECTIVE: We aimed to study basal cell subtypes in AR and healthy controls. METHODS: Single-cell RNA sequencing (scRNA-Seq) of the nasal epithelium was performed on nonallergic and house dust mite-allergic AR patients to reveal basal cell diversity and to identify allergy-related alterations. Flow cytometry, immunofluorescence staining, and in vitro experiments using primary basal cells were performed to confirm phenotypic findings at the protein level and functionally. RESULTS: The scRNA-Seq, flow cytometry, and immunofluorescence staining revealed that basal cells are abundantly and heterogeneously present in the nasal epithelium, suggesting specialized subtypes. The total basal cell fraction within the epithelium in AR is increased compared to controls. scRNA-Seq demonstrated that potentially beneficial basal cells are missing in AR epithelium, while an activated population of allergy-associated basal cells is more dominantly present. Furthermore, our in vitro proliferation, wound healing assay and air-liquid interface cultures show that AR-associated basal cells have altered progenitor capacity compared to nonallergic basal cells. CONCLUSIONS: The nasal basal cell population is abundant and diverse, and it shifts toward a diseased state in AR. The absence of potentially protective subtypes and the rise of a proinflammatory population suggest that basal cells are important players in maintaining epithelial barrier defects in AR.

Peribronchial Inflammation Resulting from Regulatory T Cell Deficiency Damages the Respiratory Epithelium and Disturbs Barrier Function.

Regulatory T cells (Tregs) that express the transcription factor Foxp3 have a critical role in limiting inflammatory processes and tissue damage. Whether Tregs are functional in maintaining epithelial barriers and in control of tight junction expression has not yet been explored. In this study, we investigated the effect of Treg deficiency on the airway epithelial barrier in an experimental murine model in which diphtheria toxin was repeatedly injected in Foxp3-diphtheria toxin receptor (DTR) mice to deplete Tregs. This resulted in spontaneous peribronchial inflammation and led to a systemic and local increase of IL-4, IL-5, CCL3, IFN-γ, and IL-10 and a local (lung) increase of IL-6 and IL-33 and decreased amphiregulin levels. Moreover, Treg depletion increased airway permeability and decreased epithelial tight junction (protein and mRNA) expression. CTLA4-Ig treatment of Treg-depleted mice almost completely prevented barrier dysfunction together with suppression of lung inflammation and cytokine secretion. Treatment with anti-IL-4 partly reversed the effects of Treg depletion on tight junction expression, whereas neutralization of IL-6 of IFN-γ had either no effect or only a limited effect. We conclude that Tregs are essential to protect the epithelial barrier at the level of tight junctions by restricting spontaneous T cell activation and uncontrolled secretion of cytokines, in particular IL-4, in the bronchi.

Development and validation of a human bronchial epithelial spheroid model to study respiratory toxicity in vitro.

The use of laboratory animals in research has been extensively criticized. While most of the critique has been centered around the ethical aspect, also the economic and scientific aspects have been frequently mentioned as points of concern. As a result, the use of alternative methods has gradually become more enticing. The most used alternatives to laboratory animals are the 2D monolayer cell cultures. However, the limited translatability of these monolayer cell cultures to in vivo has led to the development of 3D cell cultures that are believed to better capture the in vivo physiology and pathology. Here we report on the development of a physiologically more relevant 3D cell model (spheroids) comprised of human bronchial epithelial (16HBE14o-) cells, for use in respiratory toxicity research. Culturing 16HBE14o-cells as hanging-drops led to the formation of stable spheroids which showed an increased expression of CLDN1 when compared to 2D monolayer cultured cells. In addition, cell-cycle analysis revealed an increased sub-G0 population and signs of G0/G1 arrest in spheroids. Afterwards, standard operating procedures (SOPs) were established, and existing protocols optimized, for compatibility with spheroids. Spheroids were successfully used to assess cytotoxicity, genotoxicity, apoptosis/necrosis, and oxidative stress after exposure to known cytotoxic or genotoxic compounds. The development of the bronchial epithelial spheroids and the establishment of SOPs can contribute to a more reliable toxicity assessment of chemicals and may aid in bridging the gap between in vivo and in vitro experiments.

How to detect young athletes at risk of exercise-induced bronchoconstriction?

Exercise-induced bronchoconstriction (EIB) is a prevalent condition in elite athletes caused by transient airway narrowing during or after exercise. Young athletes nowadays start early to perform high level exercise, highlighting the need to screen for EIB in a younger population. The purpose of this review is to evaluate current evidence of pre-tests with high probability to predict a positive provocation test in young and adolescent athletes, aged 12-24 years and thus indicate whether a young athlete is at risk of having EIB. Up to now, there is no validated screening test available to increase the pre-test probability of a provocation test of EIB in young and adolescent athletes. We would recommend that a clinical guideline committee might consider the development of a flow chart to screen for EIB in adolescent athletes. It could be composed of a symptom-based questionnaire focusing on wheezing during exercise, atopic state, reversibility test (to exclude EIB with asthma) and completed with markers in blood/serum. However, more research is necessary.

Reported Cases and Diagnostics of Occupational Insect Allergy: A Systematic Review.

A significant part of adult-onset asthma is caused by occupational exposure to both high- and low-molecular-mass agents. Insects are occasionally described to cause occupational allergy in professions including anglers and fishers, laboratory workers, employees of aquaculture companies, farmers, bakers, sericulture workers and pet shop workers. Occupational insect allergies are often respiratory, causing asthma or rhinoconjunctivitis, but can be cutaneous as well. The European Union recently approved three insect species for human consumption, enabling an industry to develop where more employees could be exposed to insect products. This review overviews knowledge on occupational insect allergy risks and the tools used to diagnose employees. Despite the limited availability of commercial occupational insect allergy diagnostics, 60.9% of 164 included reports used skin prick tests and 63.4% of reports used specific IgE tests. In 21.9% of reports, a more elaborate diagnosis of occupational asthma was made by specific inhalation challenges or peak expiratory flow measurements at the workplace. In some work environments, 57% of employees were sensitized, and no less than 60% of employees reported work-related symptoms. Further development and optimization of specific diagnostics, together with strong primary prevention, may be vital to the health conditions of workers in the developing insect industry.

Staphylococcus aureus enterotoxin B disrupts nasal epithelial barrier integrity.

BACKGROUND: Staphylococcus aureus colonization and release of enterotoxin B (SEB) has been associated with severe chronic rhinosinusitis with nasal polyps (CRSwNP). The pathogenic mechanism of SEB on epithelial barriers, however, is largely unexplored. OBJECTIVE: We investigated the effect of SEB on nasal epithelial barrier function. METHODS: SEB was apically administered to air-liquid interface (ALI) cultures of primary polyp and nasal epithelial cells of CRSwNP patients and healthy controls, respectively. Epithelial cell integrity and tight junction expression were evaluated. The involvement of Toll-like receptor 2 (TLR2) activation was studied in vitro with TLR2 monoclonal antibodies and in vivo in tlr2-/- knockout mice. RESULTS: SEB applied to ALI cultures of polyp epithelial cells decreased epithelial cell integrity by diminishing occludin and zonula occludens (ZO)-1 protein expression. Antagonizing TLR2 prevented SEB-induced barrier disruption. SEB applied in the nose of control mice increased mucosal permeability and decreased mRNA expression of occludin and ZO-1, whereas mucosal integrity and tight junction expression remained unaltered in tlr2-/- mice. Furthermore, in vitro SEB stimulation resulted in epithelial production of IL-6 and IL-8, which was prevented by TLR2 antagonization. CONCLUSION & CLINICAL RELEVANCE: SEB damages nasal polyp epithelial cell integrity by triggering TLR2 in CRSwNP. Our results suggest that SEB might represent a driving factor of disease exacerbation, rather than a causal factor for epithelial defects in CRSwNP. Interfering with TLR2 triggering might provide a way to avoid the pathophysiological consequences of S. aureus on inflammation in CRSwNP.

New insights in neutrophilic asthma.

PURPOSE OF REVIEW: Recent advances in both murine models and clinical research of neutrophilic asthma are improving our understanding on the etiology and pathophysiology of this enigmatic endotype of asthma. We here aim at providing an overview of our current and latest insights on the pathophysiology and treatment of neutrophilic asthma. RECENT FINDINGS: Activation of the NLRP3 inflammasome pathway with increased IL-1ß has been demonstrated in various studies involving patients with asthma. It has been suggested that type 3 innate lymphoid cells are implicated in the inflammatory cascade leading to neutrophilic inflammation. The role of neutrophil extracellular traps is only at the start of being understood and might be an attractive novel therapeutic target. A diverse panel of nonallergic stimuli, such as cigarette smoke, intensive exercise, cold air or saturated fatty acids, have been linked with neutrophilic airway inflammation. Azithromycin treatment could reduce asthma exacerbations and quality of life in patients with persistent asthma. SUMMARY: Research of the last few years has accelerated our insights in mechanisms underlying neutrophilic asthma. This is in stark contrast with the lack of efficacy of different therapies targeting neutrophil chemotaxis and/or signalling cascade, such as IL-17A or CXCR2. Macrolide therapy might be a useful add-on therapy for patients with persistent asthma.

Cluster analysis of sputum cytokine-high profiles reveals diversity in T(h)2-high asthma patients.

BACKGROUND: Asthma is characterized by a heterogeneous inflammatory profile and can be subdivided into T(h)2-high and T(h)2-low airway inflammation. Profiling of a broader panel of airway cytokines in large unselected patient cohorts is lacking. METHODS: Patients (n = 205) were defined as being "cytokine-low/high" if sputum mRNA expression of a particular cytokine was outside the respective 10th/90th percentile range of the control group (n = 80). Unsupervised hierarchical clustering was used to determine clusters based on sputum cytokine profiles. RESULTS: Half of patients (n = 108; 52.6%) had a classical T(h)2-high ("IL-4-, IL-5- and/or IL-13-high") sputum cytokine profile. Unsupervised cluster analysis revealed 5 clusters. Patients with an "IL-4- and/or IL-13-high" pattern surprisingly did not cluster but were equally distributed among the 5 clusters. Patients with an "IL-5-, IL-17A-/F- and IL-25- high" profile were restricted to cluster 1 (n = 24) with increased sputum eosinophil as well as neutrophil counts and poor lung function parameters at baseline and 2 years later. Four other clusters were identified: "IL-5-high or IL-10-high" (n = 16), "IL-6-high" (n = 8), "IL-22-high" (n = 25). Cluster 5 (n = 132) consists of patients without "cytokine-high" pattern or patients with only high IL-4 and/or IL-13. CONCLUSION: We identified 5 unique asthma molecular phenotypes by biological clustering. Type 2 cytokines cluster with non-type 2 cytokines in 4 out of 5 clusters. Unsupervised analysis thus not supports a priori type 2 versus non-type 2 molecular phenotypes. www.clinicaltrials.gov NCT01224938. Registered 18 October 2010.

Impaired barrier function in patients with house dust mite-induced allergic rhinitis is accompanied by decreased occludin and zonula occludens-1 expression.

BACKGROUND: Tight junction (TJ) defects have recently been associated with asthma and chronic rhinosinusitis. The expression, function, and regulation of nasal epithelial TJs remain unknown in patients with allergic rhinitis (AR). OBJECTIVE: We investigated the expression, function, and regulation of TJs in the nasal epithelium of patients with house dust mite (HDM)-induced AR and in an HDM-induced murine model of allergic airway disease. METHODS: Air-liquid interface cultures of primary nasal epithelial cells of control subjects and patients with HDM-induced AR were used for measuring transepithelial resistance and passage to fluorescein isothiocyanate-dextran 4 kDa (FD4). Ex vivo transtissue resistance and FD4 permeability of nasal mucosal explants were measured. TJ expression was evaluated by using real-time quantitative PCR and immunofluorescence. In addition, the effects of IL-4, IFN-γ, and fluticasone propionate (FP) on nasal epithelial cells were investigated in vitro. An HDM murine model was used to study the effects of allergic inflammation and FP treatment on transmucosal passage of FD4 in vivo. RESULTS: A decreased resistance in vitro and ex vivo was found in patients with HDM-induced AR, with increased FD4 permeability and reduced occludin and zonula occludens-1 expression. AR symptoms correlated inversely with resistance in patients with HDM-induced AR. In vitro IL-4 decreased transepithelial resistance and increased FD4 permeability, whereas IFN-γ had no effect. FP prevented IL-4-induced barrier dysfunction in vitro. In an HDM murine model FP prevented the allergen-induced increased mucosal permeability. CONCLUSION: We found impaired nasal epithelial barrier function in patients with HDM-induced AR, with lower occludin and zonula occludens-1 expression. IL-4 disrupted epithelial integrity in vitro, and FP restored barrier function. Better understanding of nasal barrier regulation might lead to a better understanding and treatment of AR.

Crucial role of transient receptor potential ankyrin 1 and mast cells in induction of nonallergic airway hyperreactivity in mice.

RATIONALE: Airway hyperreactivity (AHR) is a key feature of bronchial asthma, and inhalation of irritants may facilitate development of nonallergic AHR. Swimmers exposed to hypochlorite (ClO(-))-containing water show a higher risk of developing AHR. We developed a mouse model in which instillation of ClO(-) before ovalbumin (OVA) induces AHR without bronchial inflammatory cells. OBJECTIVES: To investigate the mechanisms of ClO(-)-OVA-induced nonallergic AHR. METHODS: The involvement of the transient receptor potential ankyrin (TRPA)1 channel was checked in vivo by the use of TRPA1(-/-) mice and in vitro by Ca(2+) imaging experiments. The role of substance P (SP) was investigated by pretreating animals with the receptor antagonist RP67580, by replacing ClO(-) with SP in vivo, and by immunofluorescent staining of large airways of exposed mice. The role of mast cells was evaluated by exposing mast cell-deficient Kit(Wh)/Kit(Wsh) mice to ClO(-)-OVA with or without mast cell reconstitution. MEASUREMENTS AND MAIN RESULTS: ClO(-)-OVA did not induce AHR in TRPA1(-/-) mice, and ClO(-) generates a Ca(2+) influx in TRPA1-transfected cells. Pretreatment with RP67580 reduces ClO(-)-OVA-induced AHR, although no increased SP expression was shown in the airways. SP-OVA exposure resulted in the same AHR as induced by ClO(-)-OVA. Kit(Wsh)/Kit(Wsh) mice did not develop AHR in response to ClO(-)-OVA unless they were reconstituted with bone marrow-derived mast cells. CONCLUSIONS: Induction of AHR by exposure to ClO(-)-OVA depends on a neuroimmune interaction that involves TRPA1-dependent stimulation of sensory neurons and mast cell activation.

Diagnosing serious infections in acutely ill children in ambulatory care (ERNIE 2 study protocol, part A): diagnostic accuracy of a clinical decision tree and added value of a point-of-care C-reactive protein test and oxygen saturation.

BACKGROUND: Acute illness is the most common presentation of children to ambulatory care. In contrast, serious infections are rare and often present at an early stage. To avoid complications or death, early recognition and adequate referral are essential. In a recent large study children were included prospectively to construct a symptom-based decision tree with a sensitivity and negative predictive value of nearly 100%. To reduce the number of false positives, point-of-care tests might be useful, providing an immediate result at bedside. The most probable candidate is C-reactive protein, as well as a pulse oximetry. METHODS: This is a diagnostic accuracy study of signs, symptoms and point-of-care tests for serious infections. Acutely ill children presenting to a family physician or paediatrician will be included consecutively in Flanders, Belgium. Children testing positive on the decision tree will get a point-of-care C-reactive protein test. Children testing negative will randomly either receive a point-of-care C-reactive protein test or usual care. The outcome of interest is hospital admission more than 24 hours with a serious infection within 10 days. Aiming to include over 6500 children, we will report the diagnostic accuracy of the decision tree (+/- the point-of-care C-reactive protein test or pulse oximetry) in sensitivity, specificity, positive and negative likelihood ratios, and positive and negative predictive values. New diagnostic algorithms will be constructed through classification and regression tree and multiple logistic regression analysis. DISCUSSION: We aim to improve detection of serious infections, and present a practical tool for diagnostic triage of acutely ill children in primary care. We also aim to reduce the number of investigations and admissions in children with non-serious infections. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02024282.

Airway inflammation in patients with chronic non-asthmatic cough.

INTRODUCTION: Chronic non-asthmatic cough (CC) is a clinical challenge and underlying pathophysiological mechanisms remain still not completely understood. One of the most common comorbidities in CC is gastro-oesophageal reflux disease (GORD). Airway epithelium damage can contribute to airway inflammation in CC. AIMS: We studied airway inflammation in patients with CC compared to healthy controls. Patients with GORD were treated with proton pump inhibitors (PPI) and cough response to PPI was evaluated. PATIENTS AND METHODS: Sputum was induced in 41 adults with CC and 20 healthy non-smokers who were age and sex matched. We compared sputum differential cell count by cytospin and cytokine and chemokine production at the mRNA and/or protein levels by real-time (RT)-PCR and cytokine bead array (CBA), between patients with CC and healthy subjects. Furthermore we studied airway inflammation in patients with different comorbidities. RESULTS: No differences in sputum differential cell counts were observed between patients with CC and healthy subjects. Sputum monocyte chemoattractant protein-1 (MCP-1) protein levels were significantly higher in patients when compared to controls. Thymic stromal lymphopoietin (TSLP) mRNA was significantly more often expressed in sputum of patients with CC than from healthy controls. Sputum transforming growth factor (TGF)-ß levels did not differ between patients and controls, but were significantly lower in the PPI responders compared to the non-responders; p=0.047. There is no evidence for impaired T helper cell (Th)1/Th2/Th17 balance in CC. Patients with reflux oesophagitis (RO) have significantly more sputum eosinophils than patients without RO. CONCLUSIONS: CC is a condition presenting with different disease phenotypes. High sputum MCP-1 levels are present in a large group of patients with CC and a majority of these patients with CC have increased sputum TSLP levels, most likely produced by damaged airway epithelial cells.

Effects of high altitude and cold air exposure on airway inflammation in patients with asthma.

AIMS: Eighteen patients with asthma were evaluated during preparation to climb to extreme altitude in order to study the effects of low fractional inspired oxygen (FiO(2)), prolonged exposure to cold air and high altitude on lung function, asthma control and airway inflammation. METHODS: Spirometry and airway inflammation (fractional exhaled nitric oxide (FeNO) and induced sputum) were studied under different test conditions: hypoxic (FiO(2)=11%) exercise test, 24-hour cold exposure (-5°C) and before, during and after an expedition that involved climbing the Aconcagua mountain (6965 m). RESULTS: Forced expiratory volume in 1 s (FEV(1)) and FeNO values were slightly lower (p<0.04) after 1 h of normobaric hypoxia. FEV(1) decreased (p=0.009) after 24-hour cold exposure, accompanied by increased sputum neutrophilia (p<0.01). During the expedition FEV(1) and forced vital capacity decreased (maximum FEV(1) decrease of 12.3% at 4300 m) and asthma symptoms slightly increased. After the expedition the Asthma Control Test score and prebronchodilator FEV(1) were reduced (p<0.02), sputum neutrophil count was increased (p=0.04) and sputum myeloperoxidase levels, sputum interleukin 17 mRNA, serum and sputum vascular endothelial growth factor A levels were significantly higher compared with baseline. Patients with asthma with the lowest oxygen saturation during the hypoxic exercise test were more prone to develop acute mountain sickness. CONCLUSIONS: Exposure to environmental conditions at high altitude (hypoxia, exercise, cold) was associated with a moderate loss of asthma control, increased airway obstruction and neutrophilic airway inflammation. The cold temperature is probably the most important contributing factor as 24-hour cold exposure by itself induced similar effects.

IL-17A in human respiratory diseases: innate or adaptive immunity? Clinical implications.

Since the discovery of IL-17 in 1995 as a T-cell cytokine, inducing IL-6 and IL-8 production by fibroblasts, and the report of a separate T-cell lineage producing IL-17(A), called Th17 cells, in 2005, the role of IL-17 has been studied in several inflammatory diseases. By inducing IL-8 production and subsequent neutrophil attraction towards the site of inflammation, IL-17A can link adaptive and innate immune responses. More specifically, its role in respiratory diseases has intensively been investigated. We here review its role in human respiratory diseases and try to unravel the question whether IL-17A only provides a link between the adaptive and innate respiratory immunity or whether this cytokine might also be locally produced by innate immune cells. We furthermore briefly discuss the possibility to reduce local IL-17A production as a treatment option for respiratory diseases.

Frequent Allergic Sensitization to Farmed Edible Insects in Exposed Employees.

BACKGROUND: Exposure to insects used in pet food, scientific research, or live fish bait can cause an occupational allergy. The recent shift toward enhanced insect production for human consumption and animal feed will likely expose more employees. OBJECTIVE: To investigate sensitization and symptoms in employees exposed to edible insects in Flanders. METHODS: Fifteen insect-exposed employees were recruited and sensitization was explored by skin prick test, basophil activation test, and immunoblotting. Lung function, FeNO, histamine provocation, and sputum induction were studied. Airborne dust sampling was performed and proteins were studied by silver stain and immunoblotting. RESULTS: Sixty percent of employees self-reported upper respiratory tract symptoms related to insect exposure. Ten employees (71.4%) had a positive histamine provocation test concentration causing a 20% drop in FEV1 less than 8 mg/mL and four (26.7%) had FeNO levels above 25 ppb. Four employees (30.7%) had a positive skin prick test for at least one insect, and seven (58.3%) had a positive basophil activation test. In eight participants with insect sensitization, four (50%) had co-occurring house dust mite sensitization. Two participants had strong IgE binding to a 50-kDa migratory locust allergen, one to a 25-kDa mealworm allergen, and one to mealworm α-amylase. In one center, facility adjustment resulted in a substantial decrease in the inhalable dust fraction. CONCLUSIONS: Insect exposure leads to high levels of sensitization among employees. Most employees reported symptoms of the upper respiratory system, and two-thirds of employees had bronchial hyperreactivity. Prevention and health surveillance will be important in the developing insect-rearing industry.

Endotyping of IgE-Mediated Polyethylene Glycol and/or Polysorbate 80 Allergy.

BACKGROUND: Polyethylene glycol (PEG) and polysorbate 80 (PS80) allergy preclude from SARS-CoV-2 vaccination. The mechanism(s) governing cross-reactivity and PEG molecular weight dependence remain unclear. OBJECTIVES: To evaluate PEGylated lipid nanoparticle (LNP) vaccine (BNT162b2) tolerance and explore the mechanism of reactivity in PEG and/or PS80 allergic patients. METHODS: PEG/PS80 dual- (n = 3), PEG mono- (n = 7), and PS80 mono-allergic patients (n = 2) were included. Tolerability of graded vaccine challenges was assessed. Basophil activation testing on whole blood (wb-BAT) or passively sensitized donor basophils (allo-BAT) was performed using PEG, PS80, BNT162b2, and PEGylated lipids (ALC-0159). Serum PEG-specific IgE was measured in patients (n = 10) and controls (n = 15). RESULTS: Graded BNT162b2 challenge in dual- and PEG mono-allergic patients (n = 3/group) was well tolerated and induced anti-spike IgG seroconversion. PS80 mono-allergic patients (n = 2/2) tolerated single-dose BNT162b2 vaccination. Wb-BAT reactivity to PEG-containing antigens was observed in dual- (n = 3/3) and PEG mono- (n = 2/3), but absent in PS80 mono-allergic patients (n = 0/2). BNT162b2 elicited the highest in vitro reactivity. BNT162b2 reactivity was IgE mediated, complement independent, and inhibited in allo-BAT by preincubation with short PEG motifs, or detergent-induced LNP degradation. PEG-specific IgE was only detectable in dual-allergic (n = 3/3) and PEG mono-allergic (n = 1/6) serum. CONCLUSION: PEG and PS80 cross-reactivity is determined by IgE recognizing short PEG motifs, whereas PS80 mono-allergy is PEG-independent. PS80 skin test positivity in PEG allergics was associated with a severe and persistent phenotype, higher serum PEG-specific IgE levels, and enhanced BAT reactivity. Spherical PEG exposure via LNP enhances BAT sensitivity through increased avidity. All PEG and/or PS80 excipient allergic patients can safely receive SARS-CoV-2 vaccines.

Placental growth factor contributes to bronchial neutrophilic inflammation and edema in allergic asthma.

Placental growth factor (PlGF) and its receptor vascular endothelial growth factor receptor 1 (VEGFR1) play an important role in pathological conditions related to angiogenesis, vascular leakage, and inflammation. This study investigated their contributions to inflammation and the formation of edema in allergic asthma. The expression of PlGF and VEGFR1 was measured in induced sputum of patients with asthma (n = 11) and healthy subjects (n = 11), and in bronchial biopsies of house dust mite (HDM)-allergic patients stimulated with HDM allergens. The effects of the endonasal administration of human PlGF-2 and PlGF deficiency on inflammation and edema were evaluated in a murine model of allergic asthma. The migration of human neutrophils in response to hPlGF-2 was tested in vitro. The expression of PlGF and VEGFR1 was significantly higher in the sputum of patients with asthma, and in Der p 1-induced PlGF in biopsies from HDM-allergic patients. PlGF was increased in the bronchi of ovalbumin (OVA)-challenged mice compared with control mice (65 ± 17 pg/mg versus 18 ± 1 pg/mg, respectively; P < 0.01), and VEGFR1 was expressed in bronchial epithelium, endothelium (control mice), and inflammatory cells (OVA-challenged mice). The endonasal instillation of hPlGF-2 in wild-type, OVA-challenged mice led to an increase in bronchial neutrophils, lung tissue wet/dry ratio, and IL-17. PlGF-deficient mice showed lower numbers of BAL-infiltrating neutrophils, a reduced lung wet/dry ratio, and lower production of IL-17, macrophage inflammatory protein-2, and granulocyte chemotactic protein-2/LPS-induced chemokine compared with wild-type, OVA-challenged mice. hPlGF-2 induced the migration of human neutrophils in vitro in a VEGFR1-dependent way. PlGF and its receptor VEGFR1 are up-regulated in allergic asthma and play a proinflammatory role by inducing tissue edema, and increasing tissue neutrophilia and the production of IL-17.

Exposome mapping in chronic respiratory diseases: the added value of digital technology.

PURPOSE OF REVIEW: The development and progression of chronic respiratory diseases are impacted by a complex interplay between genetic, microbial, and environmental factors. Here we specifically summarize the effects of environmental exposure on asthma, allergic rhinitis, and chronic rhinosinusitis. We furthermore discuss how digital health technology may aid in the assessment of the environmental exposure of patients and how it may be of added value for them. RECENT FINDINGS: It is well established that one gets allergic symptoms if sensitized and exposed to the same allergen. Viruses, bacteria, pollutants, irritants, and lifestyle-related factors modify the risk of getting sensitized and develop symptoms or may induce symptoms themselves. Understanding these processes and how the various factors interact with each other and the human body require big data and advanced statistics. Mobile health technology enables integration of multiple sources of data of the patients' exposome and link these to patient outcomes. Such technologies may contribute to the increased understanding of the development of chronic respiratory disease. SUMMARY: Implementation of digital technologies in clinical practice may in future guide the development of preventive strategies to tackle chronic respiratory diseases and eventually improve outcomes of the patient.