Highlights Lung and Allergy

Pollen oft he Common Ragweed
Pollen oft he Common Ragweed (Image: Andreas Holzinger, Universität Innsbruck)

Pulmonary Emphysema: Novel Elastase Isoform Discovered

Elastases are enzymes that break down tissue and can cause disease. Now a novel isoform has been discovered which could be involved in the development of emphysema. In the body, a delicate balance of elastase and elastase inhibitors provides for regular formation and destruction of elastic fibers in the lung tissue. A perturbation of this balance can lead to excess elastase activity and thus increased tissue degradation. This is also the case in pulmonary emphysema: here the elastases are not sufficiently inactivated, leading to a destruction of lung tissue in the course of decades. The newly discovered elastase isoform is present in a two-chain state and likewise leads to tissue damage, at the same time it appears to react less to inhibitors. It probably contributes to the development of emphysema.

Therese Dau et al.: Auto-processing of Neutrophil Elastase Near its Active Site Reduces the Efficiency of Natural and Synthetic Elastase Inhibitors. Nature Communications 6 (2015) | doi: 10.1038/ncomms7722

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Allergies Influence the Surface of Airways

In allergies, secreted allergy messenger molecules not only modify cells of the immune system, but also cells lining the surface of the airways. The authors treated airway epithelial cells with the allergy messenger molecules interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) and observed how genetic activity changed. A regulation pattern emerged which has long been known to exist in T cells as theTh1/Th2-paradigm: IL-4 is able to trigger the activation of genes of the so-called Th-2 immune response, which contributes to the development of asthma. IFN-gamma counteracts this process by facilitating the transcription of Th-1 genes. This mechanism, which has been described for the first time in epithelial cells, offers new insights into the complexity of the immune response and potential new approaches in allergy treatment.

Ulrich Zissler et al. : Interleukin-4 and IFN-gamma Orchestrate an Epithelial Polarization in the Airways. Mucosal Immunology (2015) | doi: 10.1038/mi.2015.110

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Surface Marker Facilitates Improved Diagnosis of Sarcoidosis

The analysis of an additional marker molecule called slan allows a more precise determination of monocyte subgroups and to analyze their involvement in disease. The findings shall facilitate the diagnosis of sarcoidosis, a disease which often leads to lung damage, and shall thus improve patients’ management of the disease. The study showed that in sarcoidosis, there is a selective increase of the slan-negative intermediary monocytes.

Thomas Hofer et al.: Slan-defined Subsets of CD16-positive Monocytes: Impact of Granulomatous Inflammation and M-CSF-Receptor Mutation. Blood 126 (2015) | doi: 10.1182/blood-2015-06-651331

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Cost of Lung Cancer

Based on the data from more than 17,000 lung cancer patients, statistics on the care situation and the associated costs were determined. Accordingly, the average financial cost per case of lung cancer amounts to about 20,000 euros. Depending on the kind of treatment, however, this amount varies greatly. About one third of the patients receive surgical treatment. Compared to other types of treatment such as radiation or chemotherapy (together nearly 47 percent of those affected), the prognosis of this group was significantly better. The study data provide a reference for comparative studies of more recent drug therapies.

Larissa Schwarzkopf et al.: Cost-components of Lung Cancer Care within the First Three Years after Initial Diagnosis in Context of Different Treatment Regimens. Lung Cancer (2015) | doi: 10.1016/j.lungcan.2015.09.005

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Exhaust Fumes, Ambrosia and Allergies

Pollen of the common ragweed (Ambrosia artemisiifolia) has higher concentrations of allergen when the plant is exposed to NO2 exhaust gases. The exposure modulated the protein composition of the pollen; in particular, different isoforms of the allergen Amb a 1 were significantly elevated. In addition, the pollen had a significantly increased binding capacity to specific IgE antibodies of individuals allergic to Ambrosia.

Feng Zhao et al.: Common Ragweed (Ambrosia artemisiifolia L.): Allergenicity and Molecular Characterisation of Pollen after Plant Exposure to Elevated NO2. Plant, Cell & Environment (2015) doi: 10.1111/pce.12601

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Mechanism of Enhancement of Pollen Allergy

Using pollen extract from the highly allergenic common ragweed, a mechanism was discovered revealing how non-allergenic pollen mediators can enhance allergic reactions. The main role here is played by B cells, which produce the IgE molecule, the key trigger for allergic reactions. By excluding various substances, the scientists analyzed which components of the pollen extract trigger the enhanced IgE secretion and discovered that this reaction is independent of the main allergen, but is rather induced by microcompounds in the extract.

Sebastian Oeder et al.: Pollen Derived Non-allergenic Substances Enhance Th2-Induced IgE Production in B-cells. Allergy 70 (2015) | doi: 10.1111/all.12707

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Increased Protein Turnover Contributes to Development of Pulmonary Fibrosis

The pathological changes of lung tissue in idiopathic pulmonary fibrosis is accompanied by increased activity of the central protein degradation machinery of the cell. The study showed for the first time that the conversion of normal fibroblasts into myofibroblasts depends on effective protein degradation by the 26S proteasome. Targeted inhibition of the 26S proteasome prevented the differentiation of primary human lung fibroblasts into profibrotic myofibroblasts.

Nora Semren et al.: Regulation of 26S Proteasome Activity in Pulmonary Fibrosis. American Journal of Respiratory and Critical Care Medicine 192 (2015) | doi: 10.1164/rccm.201412-2270OC

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How the Lung Repairs Its Wounds

In order to regenerate after injury, the lung replaces the damaged cells with stem cells. Messenger substances and proteins of the extracellular matrix (ECM) activate the stem cells needed for the repair. For the first time, the more than 8,000 proteins of the lung proteome have been quantified and profiled throughout the different phases of the repair process and have been analyzed using novel mass spectrometry techniques.

Herbert B. Schiller et al.: Time- and Compartment-Resolved Proteome Profiling of the Extracellular Niche in Lung Injury and Repair. EMBO Molecular Systems Biology 11 (2015) | doi: 10.15252/msb.20156123

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How the Intestinal Microbiota Prevents Allergies

The human body is inhabited by billions of symbiotic bacteria, carrying a diversity that is unique to each individual. This microbiota is involved in many physiological processes such as digestion and the defense against pathogens. A loss of bacterial symbionts promotes the development of allergies. This phenomenon has now been elucidated, revealing how the microbiota acts on the balance of the immune system: the presence of microbes specifically induces specific regulatory cells in the intestine which in turn can block immune cells responsible for triggering allergies.

Caspar Ohnmacht et al.: The Microbiota Regulates Type 2 Immunity Through RORγt+ T Cells. Science 28 (2015) | doi: 10.1126/science.aac4263

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Lung Aging Favors Development of COPD

The causes of chronic obstructive pulmonary disease (COPD) are not known, therefore there is a lack of causal treatments. Inflammatory processes in lung tissue play a crucial role in the development of COPD. The main cause is assumed to be a reaction of lung tissue to chronic exposure to toxic gases or particles such as from cigarette smoke. This results in excessive mucus production, cough and remodeling processes in the airways as well as the loss of alveoli. Increased activation of the immune system appears to be involved in these processes because the immune cell count in the lungs of COPD patients is significantly elevated. Furthermore, premature aging of the lung cells is considered a factor favoring the development of COPD.

Gerrit John-Schuster et al.: Inflammaging Increases Susceptibility to Cigarette Sme-induced COPD. Oncotarget (2015) | doi: 10.18632/oncotarget.4027

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Surfaces of Immune Cells Mapped

The immune system must constantly adapt to its environment in order to protect the organism effectively against pathogens. T cells are an example for this because one of their functions is to form the immune system’s memory. Using mass spectrometry and bioinformatics analysis, researchers have examined the protein composition on the surface of precursors of T cells– so-called naive CD4+ T cells, which form the basis for immunological memory. In doing so, they have mapped a multitude of surface proteins and have identified additional, previously unknown proteins.

Anke Graessel et al.: A Combined Omics Approach to Generate the Surface Atlas of Human Naive CD4+ T Cells During Early TCR Activation. Molecular & Cellular Proteomics 14 (2015) | doi: 10.1074/mcp.M114.045690

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New Approach for Treating Pulmonary Fibrosis

A new approach for treating idiopathic pulmonary fibrosis (IPF) has been identified. No causal therapy exists as yet for this chronic disease, and the patients have a poor prognosis. Collagen accumulates between the air sacs, reducing lung elasticity. The main focus of this study was to identify the causes of IPF. In the lungs of people with the disease, the researchers found elevated levels of the FKBP10 protein. If the researchers could succeed in inhibiting the production or activity of this protein, this could result in a new therapy approach.

Claudia A. Staab-Weijnitz et al.: FK506-Binding Protein 10 is a Potential Novel Drug Target for Idiopathic Pulmonary Fibrosis. American Journal of Respiratory and Critical Care Medicine 192 (2015) | DOI 10.1164/rccm.201412-2233OC

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3D Imaging for Study of Lung Tissue

For the first time researchers have studied living lung tissue using 3D imaging. Previously, cell cultures in the petri dish were limited to two dimensions and individual time points. The new method makes it possible to observe diseased lung tissue of patients and possible repair mechanisms in 3D with high temporal resolution. With this new method the scientists have opened up new possibilities for the evaluation of pathological changes, for functional studies and for testing pharmaceutical methods.

Franziska E. Uhl et al.: Preclinical Validation and Imaging of Wnt-induced Repair in Human 3D Lung Tissue Cultures. European Respiratory Journal 46 (2015) | doi: 10.1183/09031936.00183214

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Nanoparticles for Lung Cancer Therapy

Nanoparticles – extremely tiny particles that penetrate into remote parts of the body - can act as site-specific transport vehicles for drugs in lung cancer. A team of scientists has developed special nanocarriers which release active ingredients targeted at their site of action in the human lung. In human lung tumor tissue, this approach resulted in a significantly higher effectiveness of chemotherapeutic agents.

Sabine van Rijt et al.: Protease Mediated Release of Chemotherapeutics from Mesoporous Silica Nanoparticles to Ex Vivo Human and Mouse Lung Tumors. ACS Nano 9 (2015) | doi: 10.1021/nn5070343

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Insights into the Pathogenesis of Psoriasis and Eczema

Psoriasis and eczema are at first sight completely different diseases. In a subgroup of patients, however, a clear distinction is not possible using the diagnostic gold standard. In an investigation of skin samples from patients suffering simultaneously from eczema and psoriasis, in their clinically normal skin highly specific genes and signaling pathways could be identified for both diseases. Bioinformatic analyses showed that the analysis of the gene expression of only two genes was sufficient for a classification. The newly developed diagnostic method is of therapeutic benefit due to its reliable differentiation of the two diseases and represents a first step toward personalized medicine in the field of chronic inflammatory skin diseases.

Maria Quaranta et al.: Intra-individual Genome Expression Analysis Reveals a Specific Molecular Signature of Psoriasis and Eczema. Science Translational Medicine 6 (2014) |doi: 10.1126/scitranslmed.3008946

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Protective Surfaces

Unmodified silica nanoparticles contained in many industrial and pharmaceutical products can promote a proallergic immune response. In a first study of the significance of the surface structures of nanoparticles with regard to allergic sensitization and inflammation, an increased accumulation of inflammatory cells, in particular Th2 cells and type 2 macrophages were observed in the lung tissue. Subsequently, structural changes were also found in the lung. Chemical modification of the surface of the nanoparticles was able to reduce these effects. Modifications with amino and phosphate groups, but not those with polyethylene glycol, led to a reduction of the inflammatory response.

Viviana Marzaioli:  Surface Modifications of Silica Nanoparticles are Crucial for their Inert Versus Proinflammatory and Immunomodulatory Properties. International Journal of Nanomedicine (2014) | doi: 10.2147/IJN.S57396

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Early Detection of Changes in the Lung Improves Diagnosis

For the first time, a phase-contrast microCT was tested on living organisms for the diagnosis of lung diseases. Using this technique, detailed images of the lung can be rendered and different diseases can be differentiated. Conventional x-ray techniques produce images dependent on the radiation absorption of the tissue, but phase-contrast imaging registers the smallest changes of the phase, which occur through interactions with the tissue. The new method will facilitate the early detection of lung diseases.

Felix Meinel et al.: Improved Diagnosis of Pulmonary Emphysema Using In vivo Dark-Field Radiography. Investigative Radiology 49 (2014) | doi: 10.1097/RLI.0000000000000067

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Improved Test System for Inhalation Therapies

An improved drug screening for aerosolized pulmonary drugs promises to ensure higher success rates and lower costs. Lung tissue is surrounded on the one side by air and on the other by tissue fluid. Thus, the cells are accessible for inhalation therapy in which the drugs are administered in the form of aerosols. With the new cell-based system ALICE-CLOUD, the effectiveness of aerosol drugs on lung cells exposed to air can be tested under physiological conditions – it mimics the air-liquid conditions in vitro in lung tissue.

Anke-Gabriele Lenz et al.: Efficient Bioactive Delivery of Aerosolized Drugs to Human Pulmonary Epithelial Cells Cultured at Air-liquid Interface Conditions. American Journal of Respiratory Cell and Molecular Biology 51 (2014) | doi: 10.1165/rcmb.2013-0479OC

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Growth Hormone TGF-β1 Protects Bronchial Barrier

Air pollutants such as tobacco smoke damage the epithelial cells of the lungs, which are a natural barrier against pollutants. Hence, disease-causing agents have access to the body and elicit inflammation and chronic diseases such as the chronic-obstructive pulmonary disease COPD. Now it has been shown that the growth factor TGF-β1 in the early phase following cell damage due to tobacco smoke has a positive effect on the maintenance of the lung epithelial barrier. Previously, TGF-β1 had been attributed to have a disease-promoting effect.

Andrea C. Schamberger et al.: Cigarette Smoke-Induced Disruption of Bronchial Epithelial Tight Junctions is Prevented by Transforming Growth Factor-Beta. American Journal of Respiratory Cell and Molecular Biology 50 (2014) | doi:10.1165/rcmb.20

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