Bronchoscopic Measurement of Collateral Ventilation: State of the Art.

Endoscopic lung volume reduction procedure with valves is a well-studied treatment option for advanced lung emphysema to target lung hyperinflation in carefully selected patients with COPD. Before valve implantation, collateral ventilation (CV) of the target lobe needs to be assessed to obtain an optimal treatment effect. The analysis of CV according to current standards occurs via an in vivo assessment with the Chartis®system (PulmonX Inc., Redwood City, CA, USA) and a computed tomography (CT) scan of the thorax with interlobar fissure analysis. The focus of this review is to provide detailed information about the Chartis®procedure and interpretation of Chartis® phenotypes. As a main tool in the assessment of CV and being a safe procedure, the Chartis® assessment should be performed by default to confirm interlobar fissure analysis in most emphysema patients. Based on the obtained results, lung volume reduction therapy options should be discussed in an interdisciplinary emphysema conference.

Survival-Adjusted FEV1 and BMI Percentiles for Patients with Cystic Fibrosis before the Era of Triple CFTR Modulator Therapy in Germany.

BACKGROUND: Pulmonary disease is the major cause for morbidity and mortality in cystic fibrosis (CF). In CF, forced expiratory volume in 1 s (FEV1) referenced against a healthy population (FEV1%predicted) and body mass index (BMI) do not allow for the comparison of disease severity across age and gender. OBJECTIVES: We aimed to determine updated FEV1 and BMI percentiles for patients with CF and to study their dependence on mortality attrition. METHODS: Age- and height-adjusted FEV1 and BMI percentiles for CF patients aged 6-50 years were calculated from 4,947 patients of the German CF Registry for the period 2016-2019 utilizing quantile regression and a Generalized Additive Model for Location, Scale and Shape (GAMLSS). Further, survival-adjusted percentiles were estimated. RESULTS: In patients with CF, FEV1 increased throughout childhood until maximal median values at 16 years in females (2.46 L) and 18 years in males (3.27 L). During adulthood, FEV1 decreased substantially. At 17 years of age, the 25th BMI percentile of patients with CF (females 18.50 and males 18.15 kg/m2) was below the 10th BMI percentile of the German reference cohort. From the age of 20 years, survival (96.3%) decreased tremendously. At 50 years of age (survival 15.0%), the 50th CF-specific FEV1 or BMI percentile among the survivors corresponded to the 92.5th percentile among the total CF birth cohort. CONCLUSIONS: Continuously updated disease-specific FEV1 and BMI percentiles with correction for survival may serve as age-independent measure of disease severity in CF (accessible via https://cfpercentiles.statup.solutions).

Cytokine levels in children and adults with wheezing and asthma show specific patterns of variability over time.

Levels of cytokines are used for in-depth characterization of patients with asthma; however, the variability over time might be a critical confounder. To analyze the course of serum cytokines in children, adolescents and adults with asthma and in healthy controls and to propose statistical methods to control for seasonal effects. Of 532 screened subjects, 514 (91·5%) were included in the All Age Asthma Cohort (ALLIANCE). The cohort included 279 children with either recurrent wheezing bronchitis (more than two episodes) or doctor-diagnosed asthma, 75 healthy controls, 150 adult asthmatics and 31 adult healthy controls. Blood samples were collected and 25 µl serum was used for analysis with the Bio-Plex Pr human cytokine 27-Plex assay. Mean age, body mass index and gender in the three groups of wheezers, asthmatic children and adult asthmatics were comparable to healthy controls. Wheezers (34·5%), asthmatic children (78·7%) and adult asthmatics (62·8%) were significantly more often sensitized compared to controls (4·5, 22 and 22·6%, respectively). Considering the entire cohort, interleukin (IL)-1ra, IL-4, IL-9, IL-17, macrophage inflammatory protein (MIP)-1- α and tumor necrosis factor (TNF)- α showed seasonal variability, whereas IL-1ß, IL-7, IL-8, IL-13, eotaxin, granulocyte colony-stimulating factor (G-CSF), interferon gamma-induced protein (IP)-10, MIP-1 ß and platelet-derived growth factor (PDGF)-BB did not. Significant differences between wheezers/asthmatics and healthy controls were observed for IL-17 and PDGF-BB, which remained stable after adjustment for the seasonality of IL-17. Seasonality has a significant impact on serum cytokine levels in patients with asthma. Because endotyping has achieved clinical importance to guide individualized patient-tailored therapy, it is important to account for seasonal effects.

Elastase Exocytosis by Airway Neutrophils Is Associated with Early Lung Damage in Children with Cystic Fibrosis.

RATIONALE: Neutrophils are recruited to the airways of individuals with cystic fibrosis (CF). In adolescents and adults with CF, airway neutrophils actively exocytose the primary granule protease elastase (NE), whose extracellular activity correlates with lung damage. During childhood, free extracellular NE activity is measurable only in a subset of patients, and the exocytic function of airway neutrophils is unknown. OBJECTIVES: To measure NE exocytosis by airway neutrophils in relation to free extracellular NE activity and lung damage in children with CF. METHODS: We measured lung damage using chest computed tomography coupled with the Perth-Rotterdam Annotated Grid Morphometric Analysis for Cystic Fibrosis scoring system. Concomitantly, we phenotyped blood and BAL fluid leukocytes by flow and image cytometry, and measured free extracellular NE activity using spectrophotometric and Förster resonance energy transfer assays. Children with airway inflammation linked to aerodigestive disorder were enrolled as control subjects. MEASUREMENTS AND MAIN RESULTS: Children with CF but not disease control children harbored BAL fluid neutrophils with high exocytosis of primary granules, before the detection of bronchiectasis. This measure of NE exocytosis correlated with lung damage (R = 0.55; P = 0.0008), whereas the molecular measure of free extracellular NE activity did not. This discrepancy may be caused by the inhibition of extracellular NE by BAL fluid antiproteases and its binding to leukocytes. CONCLUSIONS: NE exocytosis by airway neutrophils occurs in all children with CF, and its cellular measure correlates with early lung damage. These findings implicate live airway neutrophils in early CF pathogenesis, which should instruct biomarker development and antiinflammatory therapy in children with CF.

[Evidence-based treatment of cystic fibrosis]. / Was ist gesichert in der Therapie der Mukoviszidose?

Mucoviscidosis (cystic fibrosis [CF]) is the most common autosomal recessive inherited multisystem disease with fatal outcome. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which lead to a dysfunctional chloride channel and a defective CFTR protein. As a consequence, retention of insufficiently hydrated mucus affects multiple essential organs, mainly the lungs and airways, pancreas, liver, biliary tract and intestines. This leads to inflammation and infection, fibrosis and progressive tissue destruction. Respiratory failure is the major cause of mortality; however, in the no more than 30 years since the molecular characterization of the basic CFTR defect causing CF, tremendous success has been made with respect to the long-term prognosis of people with CF. This improvement in the prognosis was achieved by the cooperative spirit and networking of the very active and international CF research community and by establishing a multidisciplinary clinical CF team that implements the existing evidence in various aspects of standardized care together with the CF patient. This narrative review article presents the evidence in selected aspects of CF treatment, with special consideration of the most recent development of highly effective CFTR modulator treatment. This treatment will soon become available for more than 90% of the global CF patients and transform the pathophysiology as well as the course of disease towards a treatable chronic condition in internal medicine.

Elastase activity on sputum neutrophils correlates with severity of lung disease in cystic fibrosis.

Neutrophil elastase (NE) is a key risk factor for severity of cystic fibrosis (CF) lung disease. Recent studies identified increased NE activity on the surface of airway neutrophils from CF-like mice and patients with CF. However, the role of surface-bound NE in CF lung disease remains unknown. We determined the relationship between surface-bound NE activity and severity of lung disease in CF.Surface-bound NE activity was measured on sputum neutrophils from 35 CF patients and eight healthy controls using novel lipidated Förster resonance energy transfer reporters and correlated with free NE activity, neutrophil counts, interleukin-8, myeloperoxidase and antiproteases in sputum supernatant, and with lung function parameters.Surface-bound NE activity was increased in CF compared to healthy controls (p<0.01) and correlated with free NE activity (p<0.05) and other inflammation markers (p<0.001). Surface-bound and free NE activity correlated with forced expiratory volume in 1 s % predicted (p<0.01 and p<0.05), but only surface-bound NE activity correlated with plethysmographic functional residual capacity % pred (p<0.01) in patients with CF.We demonstrate that surface-bound NE activity on airway neutrophils correlates with severity of lung disease in patients with CF. Our results suggest that surface-bound NE activity may play an important role in the pathogenesis and serve as novel biomarker in CF lung disease.

Heritable plant phenotypes track light and herbivory levels at fine spatial scales.

Organismal phenotypes often co-vary with environmental variables across broad geographic ranges. Less is known about the extent to which phenotypes match local conditions when multiple biotic and abiotic stressors vary at fine spatial scales. Bittercress (Brassicaceae: Cardamine cordifolia), a perennial forb, grows across a microgeographic mosaic of two contrasting herbivory regimes: high herbivory in meadows (sun habitats) and low herbivory in deeply shaded forest understories (shade habitats). We tested for local phenotypic differentiation in plant size, leaf morphology, and anti-herbivore defense (realized resistance and defensive chemicals, i.e., glucosinolates) across this habitat mosaic through reciprocal transplant-common garden experiments with clonally propagated rhizomes. We found habitat-specific divergence in morphological and defensive phenotypes that manifested as contrasting responses to growth in shade common gardens: weak petiole elongation and attenuated defenses in populations from shade habitats, and strong petiole elongation and elevated defenses in populations from sun habitats. These divergent phenotypes are generally consistent with reciprocal local adaptation: plants from shade habitats that naturally experience low herbivory show reduced investment in defense and an attenuated shade avoidance response, owing to its ineffectiveness within forest understories. By contrast, plants from sun habitats with high herbivory show shade-induced elongation, but no evidence of attenuated defenses canonically associated with elongation in shade-intolerant plant species. Finally, we observed differences in flowering phenology between habitat types that could potentially contribute to inter-habitat divergence by reducing gene flow. This study illuminates how clonally heritable plant phenotypes track a fine-grained mosaic of herbivore pressure and light availability in a native plant.

Inactivation of Vibrio sp. in pure cultures and mussel homogenates using high hydrostatic pressure.

The objective of this study was to determine the effect of high hydrostatic pressure (HHP) on the inactivation of Vibrio sp. in pure cultures and mussel homogenates. Four Vibrio strains including V. alginolyticus, V. cholerae, V. parahaemolyticus and V. vulnificus were used. HHP treatments were performed with both pure Vibrio sp. cultures in alkaline peptone water (2% NaCl) and artificially inoculated mussel homogenates at pressure levels of 250, 350 and 450 MPa for 1 and 3 min at 25°C. Counts of Vibrio were determined before and after treatment using drop plating method. The effect of high pressure on the reduction level significantly differed among the respective Vibrio species. Vibrio vulnificus was the most susceptible species to HHP. To achieve a >5 log reduction in mussel homogenates, pressure treatment needs to be (i) 350-450 MPa for ≥1 min at 25°C for both V. alginolyticus and V. cholerae, (ii) 250 MPa for ≥3 min or 350-450 MPa for ≥1 min for V. vulnificus and (iii) 350 MPa for ≥3 min or 450 MPa for ≥1 min for V. parahaemolyticus. SIGNIFICANCE AND IMPACT OF THE STUDY: High hydrostatic pressure (HHP) has been applied to inactivate spoilage and pathogenic micro-organisms in a variety of food products, including seafood. Vibrio sp. are frequently reported as the main cause of foodborne illness associated with consumption of raw or undercooked seafood particularly shellfish worldwide. To date, data on the inactivation of Vibrio sp. via HHP are still limited and most of the trials only investigated HHP application in oysters and clams. This study demonstrates the efficacy of HHP inactivating Vibrio sp. in both pure culture and mussel homogenates.

[Chronic Pseudomonas aeruginosa airway colonization in cystic fibrosis patients : Prevention concepts]. / Chronische Atemwegskolonisierung mit Pseudomonas aeruginosa bei Mukoviszidose : Ansätze zur Prävention.

Pseudomonas aeruginosa (PsA) is a hallmark pathogen of the lung disease in cystic fibrosis (CF) patients. Chronic PsA colonization is a central factor in the course of CF lung disease. PsA contributes considerably to morbidity and mortality, and also has a significant impact on quality of life and the costs of CF treatment. Prevention of chronic colonization has therefore been a major goal in the treatment of CF patients for many years now. In the present article, studies are presented which suggest that prevention of chronic colonization can be achieved. Approaches to prevent chronic PsA colonization are critically evaluated and recommendations for preventative approaches are generated from this discussion.

The HER2 Signaling Network in Breast Cancer--Like a Spider in its Web.

The human epidermal growth factor receptor 2 (HER2) is a major player in the survival and proliferation of tumour cells and is overexpressed in up to 30 % of breast cancer cases. A considerable amount of work has been undertaken to unravel the activity and function of HER2 to try and develop effective therapies that impede its action in HER2 positive breast tumours. Research has focused on exploring the HER2 activated phosphoinositide-3-kinase (PI3K)/AKT and rat sarcoma/mitogen-activated protein kinase (RAS/MAPK) pathways for therapies. Despite the advances, cases of drug resistance and recurrence of disease still remain a challenge to overcome. An important aspect for drug resistance is the complexity of the HER2 signaling network. This includes the crosstalk between HER2 and hormone receptors; its function as a transcription factor; the regulation of HER2 by protein-tyrosine phosphatases and a complex network of positive and negative feedback-loops. This review summarises the current knowledge of many different HER2 interactions to illustrate the complexity of the HER2 network from the transcription of HER2 to the effect of its downstream targets. Exploring the novel avenues of the HER2 signaling could yield a better understanding of treatment resistance and give rise to developing new and more effective therapies.

The role of lipocalins in airway disease.

The pathogenesis of allergic airway inflammation and disease is complex and still not fully understood. Many cells, factors and mediators are involved in the different aspects of induction, maintenance and persistence of airway inflammation. The heterogeneity and redundancy of this system is one of the main reasons why novel therapeutic targets focusing on the pathogenesis of asthma only hesitantly reach the market and clinical application. Thus, it seems mandatory that we proceed in our efforts to better understand this micro cosmos to succeed in the development of safe and effective drugs for the treatment of more severe and refractory forms of asthma and chronic obstructive pulmonary disease. One of the more recently discovered mediators in the context of airway inflammation are the lipocalins (Lcns). They are a family of proteins that share functional and structural similarities and are involved in the transport of small hydrophobic molecules such as steroids and lipids into the cell. Lcns are found in many different cell types from plants and bacteria through invertebrate cells to cells of vertebrate origin. The purpose of this review is to summarize the role of Lcns in airway diseases, focusing on allergic and infectious inflammation. In particular, we will summarize the present knowledge about Lipocalin 1 and Lipocalin 2, where exciting new discoveries in the recent years have highlighted their role in pulmonary disease and infection. This new class of proteins is another putative candidate for the development of novel drugs against airway inflammation.

Increased breath naphthalene in children with asthma and wheeze of the All Age Asthma Cohort (ALLIANCE).

Exhaled breath contains numerous volatile organic compounds (VOCs) known to be related to lung disease like asthma. Its collection is non-invasive, simple to perform and therefore an attractive method for the use even in young children. We analysed breath in children of the multicenter All Age Asthma Cohort (ALLIANCE) to evaluate if 'breathomics' have the potential to phenotype patients with asthma and wheeze, and to identify extrinsic risk factors for underlying disease mechanisms. A breath sample was collected from 142 children (asthma: 51, pre-school wheezers: 55, healthy controls: 36) and analysed using gas chromatography-mass spectrometry (GC/MS). Children were diagnosed according to Global Initiative for Asthma guidelines and comprehensively examined each year over up to seven years. Forty children repeated the breath collection after 24 or 48 months. Most breath VOCs differing between groups reflect the exposome of the children. We observed lower levels of lifestyle-related VOCs and higher levels of the environmental pollutants, especially naphthalene, in children with asthma or wheeze. Naphthalene was also higher in symptomatic patients and in wheezers with recent inhaled corticosteroid use. No relationships with lung function or TH2 inflammation were detected. Increased levels of naphthalene in asthmatics and wheezers and the relationship to disease severity could indicate a role of environmental or indoor air pollution for the development or progress of asthma. Breath VOCs might help to elucidate the role of the exposome for the development of asthma. The study was registered at ClinicalTrials.gov (NCT02496468).

Macrophage PD-1 associates with neutrophilia and reduced bacterial killing in early cystic fibrosis airway disease.

BACKGROUND: Macrophages are the major resident immune cells in human airways coordinating responses to infection and injury. In cystic fibrosis (CF), neutrophils are recruited to the airways shortly after birth, and actively exocytose damaging enzymes prior to chronic infection, suggesting a potential defect in macrophage immunomodulatory function. Signaling through the exhaustion marker programmed death protein 1 (PD-1) controls macrophage function in cancer, sepsis, and airway infection. Therefore, we sought to identify potential associations between macrophage PD-1 and markers of airway disease in children with CF. METHODS: Blood and bronchoalveolar lavage fluid (BALF) were collected from 45 children with CF aged 3 to 62 months and structural lung damage was quantified by computed tomography. The phenotype of airway leukocytes was assessed by flow cytometry, while the release of enzymes and immunomodulatory mediators by molecular assays. RESULTS: Airway macrophage PD-1 expression correlated positively with structural lung damage, neutrophilic inflammation, and infection. Interestingly, even in the absence of detectable infection, macrophage PD-1 expression was elevated and correlated with neutrophilic inflammation. In an in vitro model mimicking leukocyte recruitment into CF airways, soluble mediators derived from recruited neutrophils directly induced PD-1 expression on recruited monocytes/macrophages, suggesting a causal link between neutrophilic inflammation and macrophage PD-1 expression in CF. Finally, blockade of PD-1 in a short-term culture of CF BALF leukocytes resulted in improved pathogen clearance. CONCLUSION: Taken together, these findings suggest that in early CF lung disease, PD-1 upregulation associates with airway macrophage exhaustion, neutrophil takeover, infection, and structural damage.

Risk factors for cystic fibrosis arthropathy: Data from the German cystic fibrosis registry.

BACKGROUND: Epidemiology and potential risk factors for cystic fibrosis arthropathy (CFA) were studied in a relevant cystic fibrosis (CF) patient cohort. METHODS: Cohort study of patients included in the German CF registry in 2016-2017. Descriptive analysis, exploratory tests and multivariable logistic regression were used to assess prevalence of CFA and associated potential risk factors for adult patients with/without chronic Pseudomonas aeruginosa infection. RESULTS: 6069 CF patients aged from 0 to 78 years were analysed. CFA was observed in 4.9% of the patients. Prevalence was significantly higher in adult patients (8.4%) compared to patients <18 years (0.7%; p<0.0001). Logistic regression analyses in adult patients (n=3319) showed that CFA was significantly associated with increasing age (OR=1.04; 95% CI: 1.02-1.05; p<0.0001), female gender (OR=2.10; 95%CI:1.52-2.90; p<0.0001), number of hospitalizations (OR=1.24; 95%CI:1.12-1.36; p<0.0001), chronic P. aeruginosa infection (OR=1.83; 95%CI:1.28-2.61; p=0.0009), CF-related diabetes (OR=1.69; 95%CI:1.23-2.33; p=0.0013), pancreatic insufficiency (OR=2.39; 95%CI:1.28-4.46; p=0.0060) and sinusitis/polyps (OR=1.91; 95%CI:1.39-2.62; p<0.0001). In a subgroup analysis of adults without chronic P. aeruginosa infection (n=1550) CFA was also significantly associated with increasing age, female gender, increasing number of hospitalizations, pancreatic insufficiency as well as sinusitis/polyps; antimycotic treatment associated only in this subgroup while association with CF-related diabetes was not significant. CONCLUSION: CFA is a frequent and clinically relevant co-morbidity particularly in adult CF patients. CFA is significantly more common in patients with chronic P. aeruginosa colonization but associations with other indicators for a more severe disease course were identified regardless of P. aeruginosa colonization status.

Glutathione peroxidase-2 protects from allergen-induced airway inflammation in mice.

The aim of the present study was to identify and validate the biological significance of new genes/proteins involved in the development of allergic airway disease in a murine asthma model. Gene microarrays were used to identify genes with at least a two-fold increase in gene expression in lungs of two separate mouse strains with high and low allergic susceptibility. Validation of mRNA data was obtained by western blotting and immunohistochemistry, followed by functional analysis of one of the identified genes in mice with targeted disruption of specific gene expression. Expression of two antioxidant enzymes, glutathione peroxidase-2 (GPX2) and glutathione S-transferase omega (GSTO) 1-1 was increased in both mouse strains after induction of allergic airway disease and localised in lung epithelial cells. Mice with targeted disruption of the Gpx-2 gene showed significantly enhanced airway inflammation compared to sensitised and challenged wild-type mice. Our data indicate that genes encoding the antioxidants GPX2 and GSTO 1-1 are common inflammatory genes expressed upon induction of allergic airway inflammation, and independently of allergic susceptibility. Furthermore, we provide evidence to illustrate the importance of a single antioxidant enzyme, GPX2, in protection from allergen-induced disease.

Lipocalin2 protects against airway inflammation and hyperresponsiveness in a murine model of allergic airway disease.

BACKGROUND: Allergen-induced bronchial asthma is a chronic airway disease that involves the interplay of various genes with environmental factors triggering different inflammatory pathways. OBJECTIVE: The aim of this study was to identify possible mediators of airway inflammation (AI) in a model of allergic AI via microarray comparisons and to analyse one of these mediators, Lipocalin2 (Lcn2), for its role in a murine model of allergic airway disease. METHODS: Gene microarrays were used to identify genes with at least a twofold increase in gene expression in the lungs of two separate mouse strains with high and low allergic susceptibility, respectively. Validation of mRNA data was obtained by Western blotting, followed by functional analysis of one of the identified genes, Lcn2, in mice with targeted disruption of specific gene expression. Epithelial cell cultures were undertaken to define induction requirements and possible mechanistic basis of the results observed in the Lcn2 knock-out mice. RESULTS: Lcn2 was up-regulated upon allergen sensitization and airway challenges in lung tissues of both mouse strains and retraced on the protein level in bronchoalveolar lavage fluids. Functional relevance was assessed in mice genetically deficient for Lcn2, which showed enhanced airway resistance and increased AI associated with decreased apoptosis of lung inflammatory cells, compared with wild-type controls. Similarly, application of Lcn2-blocking antibodies before airway challenges resulted in increased inflammation and reduced apoptosis. CONCLUSION: These data indicate a protective role for Lcn2 in allergic airway disease, suggesting a pro-apoptotic effect as the underlying mechanism.

BCG priming of dendritic cells enhances T regulatory and Th1 function and suppresses allergen-induced Th2 function in vitro and in vivo.

BACKGROUND: The inverse correlation of mycobacterial infection with asthma prevalence and the inhibitory effects of vaccination with Bacille Calmette-Guérin (BCG) on airway hyperreactivity in asthma models suggest modulation of dendritic cell (DC) and T cell functions by mycobacterial compounds. METHODS: To delineate these immunological effects, the immunogenicity of BCG Copenhagen, BCG Chicago and BCG Pasteur was compared in a mouse model. Bone marrow-derived dendritic cells (BMDCs) from BALB/c mice were stimulated with ovalbumin (OVA) with or without BCG. BMDCs were phenotypically characterized by flow cytometry, and we used ELISA to measure the cytokine production of BMDCs as well as of co-cultivated allergen-specific T cells in response to OVA-pulsed. Immunomodulatory effects of BCG were studied in a model of allergic airway inflammation by adoptive transfer of allergen-pulsed BMDCs. RESULTS: Immunomodulation with BCG induced production of IL-10 and IL-12 by BMDCs. Co-cultured allergen-specific T cells produced less IL-5, IL-13 and IFN-gamma but more IL-10. Also the number of FoxP3(+) regulatory T cells was enhanced. Strongest effects were seen with BCG Chicago and BCG Pasteur. In vivo, administration of BCG modulated OVA-pulsed BMDCs then reduced eosinophilic airway inflammation but enhanced infiltration with granulocytes. Airway hyperreactivity and mucus production were reduced and more FoxP3(+) T cells were observed. CONCLUSION: BCG-induced suppression of Th2-type allergic airway inflammation was associated with enhancement of regulatory T cell function but also of Th1-associated neutrophilic airway inflammation. These findings raise concerns regarding the safety profile of BCG as a potential tool for prevention and therapy of allergic airway disease.

Cytokines in sensitization to aeroallergens.

Knowledge about the immunological mechanisms underlying asthma bronchiale is a prerequisite for development of new (causal) interventions. A large number of studies has proven asthma to be a complex disease with subtypes with different immunological features. Cytokines and chemokines, which are secreted by immune cells as well as structural cells play an important role not only in maintenance and amplification but have significant impact in the initiation of pulmonary inflammations - the asymptomatic sensitization phase. This article describes important immunological mediators in the context of the pulmonary sensitization phase. Moreover chances and constraints of intervention strategies aiming at these mediators are discussed. Several new aspects like classification of immunological phenotypes in bronchial asthma for individualized strategies and taking the sensitization phase into account, reveal possible targets among both "old acquaintances" like IL-4 and newly identified mediators (e.g. IL-17, IL-33).