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The receptor for advanced glycation endproducts (RAGE) is highly expressed in the lung but its physiological functions in this organ is still not completely understood. To determine the contribution of RAGE to physiological functions of the lung, we analyzed pulmonary mechanics and structure of wildtype and RAGE deficient (RAGE-/-) mice. RAGE deficiency spontaneously resulted in a loss of lung structure shown by an increased mean chord length, increased respiratory system compliance, decreased respiratory system elastance and increased concentrations of serum protein albumin in bronchoalveolar lavage fluids. Pulmonary expression of RAGE was mainly localized on alveolar epithelial cells and alveolar macrophages. Primary murine alveolar epithelial cells isolated from RAGE-/- mice revealed an altered differentiation and defective barrier formation under in vitro conditions. Stimulation of interferone-y (IFNy)-activated alveolar macrophages deficient for RAGE with Toll-like receptor (TLR) ligands resulted in significantly decreased release of proinflammatory cytokines and chemokines. Exposure to chronic cigarette smoke did not affect emphysema-like changes in lung parenchyma in RAGE-/- mice. Acute cigarette smoke exposure revealed a modified inflammatory response in RAGE-/- mice that was characterized by an influx of macrophages and a decreased keratinocyte-derived chemokine (KC) release. Our data suggest that RAGE regulates the differentiation of alveolar epithelial cells and impacts on the development and maintenance of pulmonary structure. In cigarette smoke-induced lung pathology, RAGE mediates inflammation that contributes to lung damage.

More than 150 municipal utilities (so-called Stadtwerke) were established in Germany from the beginning of the millennium, bringing the total number of Stadtwerke currently established within the country to approximately 900. With responsibility for more than half of the supply of electricity, gas and heat in Germany, these Stadtwerke play a central role in the transformation of the energy sector, or Energiewende. In addition, due to their local and regional ties, Stadtwerke have a particular role to play in energy politics, the economy and across society. This article focuses on the motives behind, and grounds for, the current wave of newly established Stadtwerke. Further, it discusses the factors that were critical to the successful formation of new Stadtwerke in recent years. The results of our survey indicate that the establishment of municipal Stadtwerke is a suitable measure to implement the energy transition at the local level, whereby the concept of public value has a high level of importance for the local decision-makers. Collaboration and cooperation, as well as a resilience-oriented strategy, are important success factors for new Stadtwerke.

The role of vitamin D (VitD) in calcium and bone homeostasis is well described. In the last years, it has been recognized that in addition to this classical function, VitD modulates a variety of processes and regulatory systems including host defense, inflammation, immunity, and repair. VitD deficiency appears to be frequent in industrialized countries. Especially patients with lung diseases have often low VitD serum levels. Epidemiological data indicate that low levels of serum VitD is associated with impaired pulmonary function, increased incidence of inflammatory, infectious or neoplastic diseases. Several lung diseases, all inflammatory in nature, may be related to activities of VitD including asthma, COPD and cancer. The exact mechanisms underlying these data are unknown, however, VitD appears to impact on the function of inflammatory and structural cells, including dendritic cells, lymphocytes, monocytes, and epithelial cells. This review summarizes the knowledge on the classical and newly discovered functions of VitD, the molecular and cellular mechanism of action and the available data on the relationship between lung disease and VitD status.

Constant exposure of the airways to inhaled pathogens requires efficient early immune responses protecting against infections. How bacteria on the epithelial surface are detected and first-line protective mechanisms are initiated are not well understood. We have recently shown that tracheal brush cells (BC) express functional taste receptors. Here we report that bitter taste signaling in murine BC induces neurogenic inflammation. We demonstrate that BC signaling stimulates adjacent sensory nerve endings in the trachea to release the neuropeptides CGRP and Substance P that mediate plasma extravasation, neutrophil recruitment and diapedesis. Moreover, we show that bitter tasting quorum-sensing molecules from Pseudomonas aeruginosa activate tracheal BC. BC signaling depends on the key taste transduction gene Trpm5, triggers secretion of immune mediators, among the most abundant members of the complement system, and is needed to combat Pseudomonas aeruginosa infections. Our data provide functional insight into first-line defense mechanisms against bacterial infections of the lung.

Background Both allergen-specific IgE and total IgE in serum play a major role in asthma. However, the role of IgE in chronic obstructive pulmonary disease (COPD) is poorly understood. It was the aim of this study to systematically analyze the relationship between serum IgE levels and disease characteristics in large COPD cohorts. Methods COSYCONET is a comprehensively characterized cohort of patients with COPD: total IgE and IgE specific to common aeroallergens were measured in serum of 2280 patients, and related to clinical characteristics of the patients. WISDOM is another large COPD population (2477 patients): this database contains the information whether total IgE in serum was elevated (≥ 100 IU/l) or normal in patients with COPD. Results Both in COSYCONET and WISDOM, total IgE was elevated (≥ 100 IU/l) in > 30% of the patients, higher in men than in women, and higher in currently than in not currently smoking men. In COSYCONET, total IgE was elevated in patients with a history of asthma and/or allergies. Men with at least one exacerbation in the last 12 months (50.6% of all men in COSYCONET) had higher median total IgE (71.3 IU/l) than men without exacerbations (48.3 IU/l): this difference was also observed in the subgroups of not currently smoking men and of men without a history of asthma. Surprisingly, a history of exacerbations did not impact on total IgE in women with COPD. Patients in the highest tertiles of total IgE (> 91.5 IU/ml, adjusted OR: 1.62, 95% CI 1.12–2.34) or allergen-specific IgE (> 0.19 IU/ml, adjusted OR: 2.15, 95% CI 1.32–3.51) were at risk of lung function decline (adjusted by: age, gender, body mass index, initial lung function, smoking status, history of asthma, history of allergy). Conclusion These data suggest that IgE may play a role in specific COPD subgroups. Clinical trials using antibodies targeting the IgE pathway (such as omalizumab), especially in men with recurrent exacerbations and elevated serum IgE, could elucidate potential therapeutic implications of our observations.

Respiratory infections, including pneumonia and COVID-19, are major causes of global mortality and morbidity. Recent advancements in organ-on-a-chip (OOC) technologies have paved the way for human-based disease models, offering new tools for studying disease mechanisms and accelerating drug development. The aim of this study was to establish a lung-liver fluidic system to study the interaction of both organ modules during infection. A two organ (lung-liver) fluidic system was established using primary human bronchial (HBECs) or alveolar type epithelial cells (AT) for the lung module and Huh-7 cells for the liver module. Inactivated non-typeable Haemophilus influenzae (NTHi) and Pseudomonas aeruginosa PAO1 (PAO1) were applied to the lung module . Secreted mediators were screened by dot-blot analysis and quantified. The impact of bacteria-exposed epithelial cells on the liver cell transcriptome was analyzed via mRNA sequencing. Lung and liver cells established stable cultures in a circulatory fluidic system. Activation of HBECs or ATCs with NTHi or PAO1 resulted in the secretion of multiple inflammatory mediators into the microfluidic medium including tumor necrosis factor-alpha (TNF-α), monocyte chemotactic protein-1 (MCP-1) and macrophage inflammatory protein-1-α (MIP-1α). Addition of lung cells and application of bacterial onto the HBEC module led to significant transcriptomic alterations in the liver cell module. Gene ontology enrichment analysis showed the induction of various pathways involved in host defense, metabolism, repair, and acute phase response. In conclusion, a two-organ lung-liver fluidic system was established to study the interaction of the organ modules during infection. Mediators like cytokines are released from epithelial culture modules into the fluidic circulation after exposure to bacterial pathogens that significantly modify the gene expression patterns of liver cells.

Neutrophilic inflammation results in loss of lung function in chronic obstructive pulmonary disease (COPD). Gram-negative bacteria, such as nontypeable Haemophilus influenzae (NTHi), trigger acute exacerbations of COPD (AECOPD) and contribute to chronic lung inflammation. The pro-inflammatory cytokine interleukin-17C (IL-17C) is expressed by airway epithelial cells and regulates neutrophilic chemotaxis. Here, we explored the function of IL-17C in NTHi- and cigarette smoke (CS)-induced models of COPD. Neutrophilic inflammation and tissue destruction were decreased in lungs of IL-17C-deficient mice ( Il-17c -/- ) chronically exposed to NTHi. Numbers of pulmonary neutrophils were decreased in Il-17c -/- mice after acute exposure to the combination of NTHi and CS. However, Il-17c -/- mice were not protected from CS-induced lung inflammation. In a preliminary patient study, we show that IL-17C is present in sputum samples obtained during AECOPD and associates with disease severity. Concentrations of IL-17C were significantly increased during advanced COPD (GOLD III/IV) compared to moderate COPD (GOLD I/II). Concentrations of IL-17A and IL-17E did not associate with disease severity. Our data suggest that IL-17C promotes harmful pulmonary inflammation triggered by bacteria in COPD.

Impaired interaction of fibroblasts with pneumocytes contributes to the progression of chronic lung disease such as idiopathic pulmonary fibrosis (IPF). Mucin 5B (MUC5B) is associated with IPF. Here we analyzed the interaction of primary fibroblasts and alveolar type 2 (AT2) pneumocytes in the organoid model. Single-cell analysis, histology, and qRT-PCR revealed that fibroblasts expressing high levels of fibrosis markers regulate STAT3 signaling in AT2 cells, which is accompanied by cystic organoid growth and MUC5B expression. Cystic growth and MUC5B expression were also caused by the cytokine IL-6. The PI3K-Akt signaling pathway was activated in fibroblasts. The drug dasatinib prevented the formation of MUC5B-expressing cystic organoids. MUC5B associated with AT2 cells in samples obtained from IPF patients. Our model shows that fibrotic primary fibroblasts induce impaired differentiation of AT2 cells via STAT3 signaling pathways, as observed in IPF patients. It can be used for mechanistic studies and drug development.

Glycyrrhizin, an active component of liquorice root extract, exhibits antiviral and immunomodulatory properties by direct inhibition of the pro-inflammatory alarmin HMGB1 (High-mobility group box 1). The aim of this study was to explore the role of liquorice intake on the viral entry receptor ACE2 (angiotensin-converting enzyme 2) and the immunoregulatory HMGB1 in healthy individuals and to explore HMGB1 expression in coronavirus disease 2019 (COVID-19) or non-COVID-19 in ARDS (acute respiratory distress syndrome patients). This study enrolled 43 individuals, including hospitalised patients with i) acute respiratory distress syndrome (ARDS) due to COVID-19 (n = 7) or other underlying causes (n = 12), ii) mild COVID-19 (n = 4) and iii) healthy volunteers (n = 20). Healthy individuals took 50 g of liquorice (containing 3% liquorice root extract) daily for 7 days, while blood samples were collected at baseline and on day 3 and 7. Changes in ACE2 and HMGB1 levels were determined by Western blot analysis and enzyme-linked immunosorbent assay, respectively. Additionally, HMGB1 levels were measured in hospitalised COVID-19 patients with mild disease or COVID-19 associated acute respiratory distress syndrome (ARDS) and compared with a non-COVID-19-ARDS group. Liquorice intake significantly reduced after 7 days both cellular membranous ACE2 expression (-51% compared to baseline levels, p = 0.008) and plasma HMGB1 levels (-17% compared to baseline levels, p<0.001) in healthy individuals. Half of the individuals had a reduction in ACE2 levels of at least 30%. HMGB1 levels in patients with mild COVID-19 and ARDS patients with and without COVID-19 were significantly higher compared with those of healthy individuals (+317%, p = 0.002), but they were not different between COVID-19 and non-COVID-19 ARDS. Liquorice intake modulates ACE2 and HMGB1 levels in healthy individuals. HMGB1 is enhanced in mild COVID-19 and in ARDS with and without COVID-19, warranting evaluation of HMGB1 as a potential treatment target and glycyrrhizin, which is an active component of liquorice root extract, as a potential treatment in COVID-19 and non-COVID-19 respiratory disease.

Background The use of electronic cigarettes (ECIGs) is increasing, but the impact of ECIG-vapor on cellular processes like inflammation or host defense are less understood. The aim of the present study was to compare the acute effects of traditional cigarettes (TCIGs) and ECIG-exposure on host defense, inflammation, and cellular activation of cell lines and primary differentiated human airway epithelial cells (pHBE). Methods We exposed pHBEs and several cell lines to TCIG-smoke or ECIG-vapor. Epithelial host defense and barrier integrity were determined. The transcriptome of airway epithelial cells was compared by gene expression array analysis. Gene interaction networks were constructed and differential gene expression over all groups analyzed. The expression of several candidate genes was validated by qRT-PCR. Results Bacterial killing, barrier integrity and the expression of antimicrobial peptides were not affected by ECIG-vapor compared to control samples. In contrast, TCIGs negatively affected host defense and reduced barrier integrity in a significant way. Furthermore ECIG-exposure significantly induced IL-8 secretion from Calu-3 cells but had no effect on NCI-H292 or primary cells. The gene expression based on array analysis distinguished TCIG-exposed cells from ECIG and room air-exposed samples. Conclusion The transcriptome patterns of host defense and inflammatory genes are significantly distinct between ECIG-exposed and TCIG-treated cells. The overall effects of ECIGs on epithelial cells are less in comparison to TCIG, and ECIG-vapor does not affect host defense. Nevertheless, although acute exposure to ECIG-vapor induces inflammation, and the expression of S100 proteins, long term in vivo data is needed to evaluate the chronic effects of ECIG use.